1 s2.0 S0753332223015329 Main

Biomedicine & Pharmacotherapy 168 (2023) 115734
Contents lists available at ScienceDirect
Biomedicine & Pharmacotherapy

journal homepage: www.elsevier.com/locate/biopha
Review
Diabetes mellitus: Classification, mediators, and complications; A gate to

identify potential targets for the development of new effective treatments
Samar A. Antar a, b, 1, Nada A. Ashour c, 1, Marwa Sharaky d, Muhammad Khattab e,
Naira A. Ashour f, Roaa T. Zaid g, Eun Joo Roh h, i, Ahmed Elkamhawy j, k, *,
Ahmed A. Al-Karmalawy l, g
a
Center for Vascular and Heart Research, Fralin Biomedical Research Institute, Virginia Tech, Roanoke, VA 24016, USA
b
Department of Pharmacology and Biochemistry, Faculty of Pharmacy, Horus University, New Damietta 34518, Egypt
c
Department of Pharmacology and Toxicology, Faculty of Pharmacy, Tanta University, Tanta 31527, Egypt
d
Cancer Biology Department, Pharmacology Unit, National Cancer Institute (NCI), Cairo University, Cairo, Egypt
e
Department of Chemistry of Natural and Microbial Products, Division of Pharmaceutical and Drug Industries, National Research Centre, Cairo, Egypt
f
Department of Neurology, Faculty of Physical Therapy, Horus University, New Damietta 34518, Egypt
g
Pharmaceutical Chemistry Department, Faculty of Pharmacy, Ahram Canadian University, 6th of October City, Giza 12566, Egypt
h
Chemical and Biological Integrative Research Center, Korea Institute of Science and Technology (KIST), Seoul 02792, Republic of Korea
i
Division of Bio-Medical Science & Technology, University of Science and Technology, Daejeon 34113, Republic of Korea
j
BK21 FOUR Team and Integrated Research Institute for Drug Development, College of Pharmacy, Dongguk University-Seoul, Goyang 10326, Republic of Korea
k
Department of Pharmaceutical Organic Chemistry, Faculty of Pharmacy, Mansoura University, Mansoura 35516, Egypt
l
Department of Pharmaceutical Chemistry, Faculty of Pharmacy, Horus University-Egypt, New Damietta 34518, Egypt
A R T I C L E I N F O A B S T R A C T
Nowadays, diabetes mellitus has emerged as a significant global public health concern with a remarkable in
Keywords:
Diabetes
crease in its prevalence. This review article focuses on the definition of diabetes mellitus and its classification
Diagnosis into different types, including type 1 diabetes (idiopathic and fulminant), type 2 diabetes, gestational diabetes,
Abbreviations: DM, Diabetes Mellitus; T1D, Type 1 diabetes; T2D, Type 2 diabetes; LADA, Latent autoimmune diabetes in adults; LADY, Latent autoimmune
diabetes in youth; GAD, Glutamic Acid Decarboxylase; MODY, Maturity-onset diabetes of the young; HNF-1, Hepatic transcription factor-1; FPG, Fasting Plasma
Glucose; OGTT, Oral glucose tolerance test; HbA1c, Hemoglobin A1c; TNF-α, Tumor Necrosis Factor-alpha; NF-κB, Nuclear factor kappa B; JNKs, Janus kinase
pathways; IRS-1, Insulin receptor substrate 1; c-RP, C-reactive protein; MCP-1, Monocyte chemoattractant protein; IL-6, Interlukin-6; IFN-γ, Interferon-γ; PAI-1,
Plasminogen activator inhibitor 1; AGEs, Advanced Glycation End Products; ROS, Reactive Oxygen Species; RAGE, Receptor advanced glycation end product; NK,
Natural killer; iNOS, Inducible nitric oxide synthase; CVD, Cardiovascular diseases; AT, Adipose tissue; MCP-1, Monocyte chemoattractant protein-1; LDL, Low-
density lipoprotein; PPAR-ɣ, Peroxisome proliferator-activated receptor gamma; NSAIDs, Non-steroid anti-inflammatory drugs; BAT, Brown adipose tissue; WAT,
White adipose tissue; GSIS, Glucose-stimulated insulin secretion; FFAs, Free fatty acids; CAT, Catalase; GLT, Glutathione; SOD, Superoxide dismutase; ROOH,
Reactive hydroperoxides; MDA, Malondialdehyde; ETC, Electron transport chain; MAM, Mitochondria-associated ER membranes; TLRs, Toll-like receptors; CEB/Ps,
CCAAT enhancer-binding proteins; MEF2, Myocyte enhancer factor 2; HIF-1, Hypoxia-inducible factors alpha; IST, Insulin signal transduction; IRS-1, Insulin receptor
substrate-1; IKK-B, Inhibitor of nuclear factor kappa B; GSK-3, Glycogen synthase kinase 3; AMPK, AMP-activated protein kinase; mTOR, Mammalian target of
rapamycin; p38 MAPK, p38 mitogen-activated protein kinases; MRC, Mitochondrial Respiratory Chain; DAG, Diacylglycerol; IST., Insulin signal transduction.; LPS,
Lipopolysaccharides; SCFAs, Short-chain fatty acids; IP-10, IFN-inducible protein 10; ImP, Imidazole propionate; BCAA, Branched-chain amino acids; TMAO, Tri
methylamine-N-oxide; NAFLD, Non-alcoholic fatty liver disease; HCV, Hepatitis C virus; NASH, Nonalcoholic steatohepatitis; CIN, Contrast-induced nephropathy;
GFR, Glomerular filtration rate; TGF-β1, Transforming growth factor-beta 1; JAK-STAT, Janus kinase-signal transducer and activator of transcription; SMPDL3b,
Sphingomyelin phosphodiesterase acid-like 3b; JAML, Junctional adhesion molecule-like protein; CaMKII, Nitric oxide (NO) Ca2+/calmodulin-dependent protein
kinase II; SERCA2a, Sarcoplasmic/endoplasmic reticulum Ca2+ ATPase 2a; HDACs, Histone deacetylases; PBMCs, Peripheral blood mononuclear cells; TIRAP, Toll/
IL-1R domain-containing adaptor protein; HIF1α, Hypoxia-inducible factor 1 alpha; VEGF-1, Vascular endothelial growth factor-1; Sema4d, Semaphorin 4d; VE-
Cadherin, Vascular endothelial cadherin; Ang1, Angiopoietin 1; EPA, Eicosapentaenoic acid; DHA, Docosahexaenoic acid; 12-HETE, Hydroxyeicosatrienoic acids;
DPP4i, Dipeptidyl peptidase 4 inhibitors; HCN2, Hyperpolarization-activated cyclic nucleotide-gated 2; ApoE, Apolipoprotein E; NTR, p75 neurotrophin receptor;
NT-3, Neurotrophic factor-3; NGF, Nerve growth factor.
* Correspondence to: BK21 FOUR Team and Integrated Research Institute for Drug Development, College of Pharmacy, Dongguk University-Seoul, Goyang 10326,
Republic of Korea.
E-mail address: a_elkamhawy@mans.edu.eg (A. Elkamhawy).
1
Equally contributed.
https://doi.org/10.1016/j.biopha.2023.115734
Received 4 August 2023; Received in revised form 13 October 2023; Accepted 13 October 2023
Available online 17 October 2023
0753-3322/© 2023 The Authors. Published by Elsevier Masson SAS. This is an open access article under the CC BY license
(http://creativecommons.org/licenses/by/4.0/).
S.A. Antar et al. Biomedicine & Pharmacotherapy 168 (2023) 115734
Etiology hybrid forms, slowly evolving immune-mediated diabetes, ketosis-prone type 2 diabetes, and other special types.
Genetics Diagnostic criteria for diabetes mellitus are also discussed. The role of inflammation in both type 1 and type 2
Complications diabetes is explored, along with the mediators and potential anti-inflammatory treatments. Furthermore, the
Inflammation
involvement of various organs in diabetes mellitus is highlighted, such as the role of adipose tissue and obesity,
Treatment
gut microbiota, and pancreatic β-cells. The manifestation of pancreatic Langerhans β-cell islet inflammation,
oxidative stress, and impaired insulin production and secretion are addressed. Additionally, the impact of dia
betes mellitus on liver cirrhosis, acute kidney injury, immune system complications, and other diabetic com
plications like retinopathy and neuropathy is examined. Therefore, further research is required to enhance
diagnosis, prevent chronic complications, and identify potential therapeutic targets for the management of
diabetes mellitus and its associated dysfunctions.
1. Introduction dysglycemia. Alteration in glucose and C-peptide levels can be utilized

in risk ratings to further improve prediction [5].
1.1. Definition of diabetes mellitus (DM)
1.2.1.1. Idiopathic T1D. A rare variant of T1D has been reported and
Chronic hyperglycemia is a metabolic disorder caused by either a known as “idiopathic diabetes”, which is not caused by autoimmunity
lack of insulin secretion, impaired insulin action, or both. Notably, in having lesser severity than autoimmune T1D. People with idiopathic
sulin plays an important role as an anabolic hormone, affecting the diabetes may experience episodic ketoacidosis as well as insulin insuf
metabolism of carbohydrates, lipids, and proteins [1]. The metabolic ficiency. This variant is more common in individuals of Asian or African
abnormalities associated with diabetes mainly affect tissues such as heritage [6].
adipose tissue, skeletal muscles, and the liver due to insulin resistance.
The severity of symptoms can vary depending on the duration and type 1.2.1.2. Fulminant T1D. This is a unique kind of T1D that was originally
of diabetes. Individuals with high blood sugar levels, particularly those identified in 2000. It shares certain characteristics with idiopathic T1D,
with a complete lack of insulin, such as children, may experience including not being immune-mediated [7]. Keto-acidosis occurs shortly
symptoms such as increased appetite, polydipsia, dysuria, weight loss, after the initiation of hyperglycemia, and serum C-peptide levels, which
increased appetite, and vision problems. Some people with diabetes may is a marker of the endogenous release of insulin, are undetectable while
not experience any symptoms, especially type 2 diabetic patients in their blood glucose levels are high (288 mg/dL). About 20% of Japanese
early stages [2]. Without proper treatment, uncontrolled diabetes can people with acute-onset T1D (5000–7000 instances) have this condition,
lead to various complications such as coma, confusion, and in rare cases, which has been mostly characterized in East Asian nations. It causes an
death from ketoacidosis or nonketotic hyperosmolar syndrome not incredibly quick and practically complete β-cell death that leaves almost
treated [1]. no residual insulin output. This condition is mainly attributed to some
In 2014, the WHO announced that 8.5% of adults aged 18 and above environmental and hereditary causes. Through an increased immune
were affected by diabetes. In 2019, diabetes was responsible for 1.5 response without discernible formation of autoantibodies attacking
million deaths, with 48% of these occurring before the age of 70. pancreatic β-cells, an antiviral immune response may cause the loss of
Additionally, diabetes led to another 460,000 deaths due to kidney pancreatic β-cells. There have also been reports of this type of diabetes
disease, and roughly 20% of cardiovascular-related deaths were attrib and pregnancy [8].
uted to elevated blood glucose levels. From 2000–2019, there was a 3%
rise in standardized mortality rates related to diabetes. In lower-middle- 1.2.2. Type 2 diabetes
income countries, the mortality rate associated with diabetes increased A key component of type 2 diabetes (T2D) pathogenesis is defective
by 13%. In contrast, the likelihood of succumbing to any of the four insulin secretion [9]. Insulin secretion varies widely in response to in
primary non-communicable diseases (which include cardiovascular sulin sensitivity to maintain adequate glucose levels. The disposition
diseases, cancer, chronic respiratory diseases, or diabetes) between the index is a measure of the curvilinear relationship between the sensitivity
ages of 30 and 70 declined by 22% worldwide from 2000 to 2019 [3]. of insulin and the secretion of insulin. Besides, type 2 diabetic patients
Herein, the search criteria were based on the screening of all the have a low disposition index; therefore, they are unable to appropriately
respected and available research and review articles in the literature enhance their insulin production to combat insulin resistance. Even
about diabetes. The authors screened over 500 scientific articles from when the absolute insulin levels in insulin-resistant obese T2D patients
different databases like PubMed and Google Scholar. Fig. (1). are higher than in insulin-sensitive lean control subjects, the levels are
still too low given the severity of their insulin resistance. Insulin pro
1.2. Classification of DM duction (first phase) is significantly reduced or eliminated due to
glucose stimulation. T2D patients have a high ratio of proinsulin to in
1.2.1. Type 1 diabetes sulin (C-peptide). The maximal insulin production and
Type 1 diabetes (T1D) can be detected well before abnormal insulin hyperglycemia-induced potentiation of insulin responses to non-glucose
secretion starts, with a steady decline starting at least two years before stimuli are substantially diminished [10]. Hyperglycemia tends to
diagnosis [4]. Around the same time, there is a decline in β-cell sensi worsen and become more challenging to cure over time. The continuing
tivity to glucose. As the first insulin response decreases, the last insulin decline in β-cell function is another feature of T2D progression [11].
response rises, potentially indicating a compensation mechanism. Early
in the post-diagnosis phase, the decline in insulin responsiveness keeps 1.2.3. Gestational diabetes
speeding up. Within the first few years after diagnosis, a biphasic decline Pregnancy-related hyperglycemia increases the risk of bad outcomes
in insulin secretion has been seen, with the first year being steeper than for the mother, fetus, and newborn [12]. This risk is present whether the
the second. Once a diagnosis is made, the decrease in insulin secretion hyperglycemia adopts the T2D form diagnosed before or during preg
may continue for years, eventually leaving little to no insulin produc nancy. Newborns born to mothers with gestational diabetes are at an
tion. Higher glucose levels are a sign of T1D even when they are within elevated risk of developing diabetes in adulthood [13]. The increased
the normal range. When T1D develops, there are significant glucose incidence of pregnancy-related complications, such as premature birth,
variations. It may be possible to anticipate the development of diabetes large-for-gestational-age births, macrosomia (birth weight > 4.5 kg),
more accurately in at-risk persons by using metabolic markers, such as
2
cesarean delivery, and preeclampsia is primarily due to hyperglycemia acute and phasic β-cell failure in this condition. Interestingly, after in
during pregnancy, which leads to larger neonates. Gestational diabetes sulin therapy and restoration of normal blood glucose levels, there is a
can be influenced by several risk factors, such as having a family history significant and prolonged improvement in insulin secretory function in
of the condition, being obese, advanced maternal age, having polycystic β-cell [18].
ovarian syndrome, leading a sedentary lifestyle, and exposure to envi
ronmental pollutants. [14]. The identification of gestational diabetes 1.2.5. Other special types of DM
relies on specific criteria, which involve evaluating fasting blood sugar
levels, blood sugar levels after a 75 g oral glucose load, and other rele 1.2.5.1. Genetic defects of the beta-cell. Maturity-onset diabetes of the
vant parameters, as mentioned previously [15]. young (MODY): This type of diabetes is associated with abnormal
monogenetic in β-cell function. It typically appears at a young age,
1.2.4. Hybrid forms of diabetes usually before 25 years old, and is characterized by reduced insulin
secretion with little to no abnormalities in insulin action. The condition
1.2.4.1. Slowly evolving immune-mediated diabetes (LADA). Slowly is inherited in an autosomal dominant manner, meaning that only one
evolving immune-mediated diabetes, also known as latent autoimmune copy of the affected gene from either parent is sufficient to cause the
diabetes in adults (LADA resembles type 2 diabetes clinically but is condition. Mutations in several genes, including hepatic transcription
characterized by the presence of pancreatic autoantibodies associated factor (HNF)− 1, glucokinase, HNF-4, HNF-1α, IPF-1, and NeuroD1,
with autoimmune diabetes. Initially, individuals with LADA can be have been identified as causes of MODY [19].
managed with oral medications and lifestyle modifications like those
with type 2 diabetes [16]. However, they tend to progress to requiring 1.2.5.2. Genetic defects in insulin action. Genes mutations of insulin re
insulin therapy at a faster rate compared to typical type 2 diabetes pa ceptors: Certain gene mutations of insulin receptors can lead to abnor
tients. LADA is more prevalent in certain regions than rapid-onset type 1 malities in insulin action. these mutations associated with insulin can
diabetes. There is a comparable subtype known as latent autoimmune cause a variety of metabolic abnormalities, ranging from elevated in
diabetes in youth (LADY) observed in children and adolescents with sulin levels and mild high blood sugar to severe diabetes. In some cases,
clinical type 2 diabetes and pancreatic autoantibodies. The criteria used individuals with these mutations may display additional symptoms such
to diagnose LADA typically involve positive glutamic acid decarboxylase as acanthosis nigricans (skin darkening), virilization (development of
(GAD) autoantibodies, age older than 35 years at the time of diagnosis, male characteristics), and enlarged cystic ovaries in women. Despite the
and no immediate need for insulin therapy in the first 6–12 months after presence of mutant insulin, the impaired binding of these molecules to
diagnosis. The prevalence of GAD autoantibodies in clinically diagnosed the insulin receptor can lead to either mild or even normal glucose
type 2 diabetes individuals varies between ethnic and regional groups, metabolism [20].
ranging from 5% to 14% [17].
1.2.5.3. Diseases of the exocrine pancreas. Diabetes can arise from
1.2.4.2. Ketosis-prone type 2 diabetes. Ketosis-prone type 2 diabetes is a several conditions that lead to widespread damage to the pancreas. Such
unique clinical condition primarily seen in young African Americans and conditions include infection, pancreatitis, pancreatic carcinoma,
populations in sub-Saharan Africa. It is characterized by episodes of trauma, and pancreatectomy (surgical removal of the pancreas). Typi
ketosis and severe insulin deficiency at the initial presentation, resem cally, significant damage to the pancreas is necessary for diabetes to
bling type 1 diabetes or diabetic ketoacidosis. However, individuals with develop, but even small, affected portions of the pancreas due to ade
this condition eventually enter remission and do not require insulin nocarcinomas can be linked to diabetes. Additionally, certain diseases
treatment. Nonetheless, around 90% of these individuals experience like cystic fibrosis, hemochromatosis, and fibrocalculous pancreatop
further episodes of ketosis within 10 years. Ketosis-prone type 2 diabetes athy can also disrupt insulin secretion and harm β-cells [21].
is less common in populations of European descent but can be observed
in various ethnic groups. The exact underlying cause is not fully un 1.2.5.4. Endocrinopathies. Excess amounts of certain hormones can
derstood, and no genetic evidence or markers of autoimmunity have antagonize insulin action and lead to diabetes. Conditions such as
been identified. It is believed that glucose toxicity may play a role in acromegaly that is (excess growth hormone), glucagonoma that is
Fig. (1). The newest classification of DM represents the different types and subtypes of diabetes, including Type 1 Diabetes, Type 2 Diabetes, Gestational Diabetes,
Hybrid Forms of Diabetes (LADA and Ketosis-prone Type 2 Diabetes), and Other Special Types of Diabetes.
3
(excess glucagon) pheochromocytoma that is (excess epinephrine), and independent samples or cross-validation within the dataset helps
Cushing’s syndrome that is (excess cortisol) can cause diabetes, indeed, ensure the quality of the clustering analysis.
diabetes can be exacerbated, especially in individuals who have preex e) Standardization:
isting defects in secretion of insulin. Conditions like somatostatinomas Standardizing data is necessary to enable the comparison of vari
and aldosteronomas can induce hypokalemia, which further contributes ables with different scales. Standardization ensures that variables
to the development and progression of diabetes in affected individuals contribute equally to the clustering results.
[20]. f) Limitations:
1.2.5.5. Drug- or chemical-induced diabetes. Certain drugs and toxins Common limitations include small sample sizes, issues affecting
have the potential to interfere with insulin secretion or action, either on generalizability, and short follow-up periods. Additionally, some studies
their own or by triggering diabetes in individuals who already have may group medications, potentially affecting the results.
insulin resistance. For instance, drugs like nicotinic acid and glucocor In a rational classification of diabetic subtypes, one could consider
ticoids can impact insulin action. Additionally, specific toxins like Vacor these factors and conduct a comprehensive analysis of a large and
and intravenous pentamidine could permanently damage β-cells. How diverse diabetic population. This analysis would involve selecting rele
ever, it’s important to note that drug-induced reactions leading to dia vant variables, applying appropriate clustering methods, validating re
betes are relatively rare occurrences [19]. sults, standardizing data, and addressing common limitations. The goal
would be to identify clinically meaningful subgroups that may guide
1.2.5.6. Infections. Some viruses have been linked to the destruction of personalized treatment and prevention strategies for diabetic patients,
beta-cells and the emergence of diabetes. These viruses include cox taking into account their unique characteristics, risk factors, and
sackievirus B, congenital rubella, mumps, adenovirus, and cytomega comorbidities.
lovirus. Their role in inducing diabetes is especially notable in There are several subtypes of DM, each with its characteristics and
individuals who have genetic predispositions or markers associated with severity. We will summarize the subtypes and their relative seriousness:
type 1 diabetes. In susceptible individuals, these viruses can trigger an
autoimmune response, leading to the destruction of beta-cells and the a) Severe Autoimmune Diabetes (SAID) - Cluster 1:
development of diabetes [21].
• Type 1 diabetes.
1.2.5.7. Uncommon forms of immune-mediated diabetes. In this category, • Typically affects younger individuals.
two known conditions are mentioned: • An autoimmune condition where the immune system attacks beta
1.2.5.7.1. Stiff-man syndrome. This is an autoimmune condition cells.
affecting the central nervous system, which is characterized by painful • Low BMI, insulin deficiency, and poor blood sugar control.
spasms and stiffness in the axial muscles. Individuals with this syndrome • Requires insulin treatment.
typically show elevated levels of glutamic acid decarboxylase (GAD) • Seriousness: This type can be serious, especially if not managed
autoantibodies and are at an elevated risk of developing diabetes [20]. properly, as it involves an autoimmune response that can lead to
1.2.5.7.2. Anti-insulin receptor antibody-related diabetes. Antibodies insulin dependence and complications.
against the insulin receptor can interfere with insulin binding, leading to
diabetes. In certain instances, these antibodies can function as insulin b) Severe Insulin-Deficient Diabetes (SIDD) - Cluster 2:
agonists, leading to hypoglycemia instead of hyperglycemia. Individuals
diagnosed with systemic lupus erythematosus and other autoimmune • Similar to Cluster 1 but lacks GADA antibodies.
disorders may show the presence of antibodies that target the insulin • Younger individuals with low BMI.
receptor. Acanthosis nigricans are often present in individuals with this • Defective beta cell function.
condition [22]. • Seriousness: Like Cluster 1, it can be serious due to insulin deficiency,
but the absence of GADA antibodies distinguishes it.
1.2.5.8. Other classifications. To classify diabetic subtypes rationally
c) Severe Insulin-Resistant Diabetes (SIRD) - Cluster 3:
based on the information provided by the given articles, we can sum
marize the following key points [23–25]:
• Overweight individuals with high insulin resistance.
a) Comorbidities and risk factors: • Cells produce insulin, but they do not respond to it.
• Higher risk of non-alcoholic fatty liver disease.
Diabetic patients may have a range of associated comorbidities
and risk factors that should be considered when classifying subtypes. • Seriousness: This type is serious because it can lead to complications,
especially related to insulin resistance and obesity.
These comorbidities can include cardiovascular diseases (CVDs),
genetic factors, GI symptoms, fasting incretin tone, and trajectories
d) Mild Obesity-Related Diabetes (MOD) - Cluster 4:
of HbA1c levels.
b) Variable selection:
• Occurs in obese or overweight individuals.
The optimal number of variables for classification is essential.
Some studies have used a limited set of variables (e.g., age, BMI, • Not associated with significant insulin resistance.
• Milder form of diabetes.
HbA1c), while others employed more extensive datasets. The choice
of variables should balance validity and economic efficiency. • Seriousness: Generally, less serious than the severe subtypes, but
obesity-related health risks may still apply.
c) Clustering methods:
Various clustering methods were employed, including k-means
e) Mild Age-Related Diabetes (MARD) - Cluster 5:
clustering, hierarchical clustering, PCA (Principal Component
Analysis), and TBA (Tree-based algorithm). The choice of method
can impact the results, and it’s essential to consider outliers and • Typically affects older individuals.
missing data when using these methods. • Mild difficulty with blood sugar control.
d) Validation: • The most common type accounts for about 40% of cases.
Validating clustering results is critical. External validation on • Seriousness: While it may be less severe in terms of immediate
symptoms, long-term management is important, especially in older
4
individuals. Table (1)

Prediabetes: Other special types of DM.
• This is not a subtype but a condition where blood glucose levels are Other specific types Brief description Examples Reference
higher than normal but not in the diabetic range. of DM
• Individuals with prediabetes have an increased risk of developing The genetic defect This condition • Chromosome 20, [20]
DM but can reverse it with lifestyle changes. of β-cell function arises due to HNF-4 α(MODY1)
specific genetic • Chromosome 7,
In terms of seriousness, the severity of each subtype depends on mutations and glucokinase
presents with (MODY2)
various factors, including how well it is managed and the individual’s multiple clinical • Chromosome 12,
overall health. However, Cluster 3 (SIRD) is highlighted as being at the manifestations that HNF-1 α(MODY3)
highest risk of developing kidney disease, which is a severe complication necessitate diverse • Chromosome 13,
of diabetes. Cluster 2 has the greatest risk of diabetic retinopathy, which treatment insulin promoter
approaches. Some factor-1 (IPF-1;
can lead to vision problems [26].
of these MODY4)
It’s important to note that early detection and appropriate treatment manifestations • Chromosome 17,
are crucial for managing the seriousness of diabetes, regardless of the manifest during HNF-1β (MODY5)
subtype. Proper management can help prevent or delay complications the neonatal • Chromosome 2,
and improve the prognosis [27]. period, while NeuroD1 (MODY6)
others become • Mitochondrial DNA
apparent during • Others
1.2.5.9. Other genetic syndromes are sometimes associated with diabetes. early adulthood.
Certain genetic syndromes are accompanied by an increased incidence Genetic defects in This condition is • Type A insulin [20,21]
of diabetes. Examples like Wolfram’s syndrome, Klinefelter syndrome, insulin action caused by specific resistance
genetic mutations • Leprechaunism
Turner syndrome, and Down syndrome. Wolfram’s syndrome is a ge and is • Rabson-Mendenhall
netic disorder inherited in an autosomal recessive manner. It is char characterized by syndrome
acterized by insulin-deficient diabetes, with a complete absence of profound insulin • Lipoatrophic diabetes
β-cells observed during autopsy. In addition to diabetes, affected in resistance, even in • Others
the absence of
dividuals may exhibit other manifestations as part of the syndrome [19,
obesity. Diabetes
20] as shown in Table (1). develops when β
cells are unable to
1.3. Diagnostic criteria for DM effectively
compensate for the
resistance of
The diagnosis of DM is commonly made through the measurement of
insulin present in
hemoglobin (HbA1c) plasma glucose levels or oral glucose tolerance test the body.
(OGTT) or fasting plasma glucose (FPG). These values are used to esti Diseases of the Hyperglycemia can • Cystic fibrosis [19,21]
mate the correlation between HbA1c or FPG and retinopathy, which exocrine be caused by • Trauma &
pancreas various conditions pancreatectomy
helps in setting cut-off values for glucose and HbA1c to diagnose dia
that impact the • Fibrocalculous
betes [28]. DM is diagnosed when the level of fasting plasma glucose is pancreas, such as pancreatopathy
less than 126 mg/dL (7.0 mmol/L), the 2 h OGTT plasma glucose level is trauma, tumors, • Neoplasia
more than 200 mg/dL (11.1 mmol/L), or the HbA1c level is less than inflammation, and • Pancreatitis
6.5% (48 mmol/mol), or random plasma glucose level is higher than other related • Hemochromatosis
factors. • Others
200 mg/dL (11.1 mmol/L) [29]. The International Expert Committee in
Endocrinopathies It is observed in • Glucagonoma [20,21]
2009 proposed the adoption of HbA1c as a diagnostic and treatment diseases • Hyperthyroidism
monitoring tool in cases of diabetes, a recommendation that has gained characterized by • Cushing’s syndrome
widespread support from numerous organizations and experts globally. the excessive • Acromegaly
secretion of • Pheochromocytoma
HbA1c has advantages over FPG for diagnosing diabetes, including
hormones that • Aldosteronoma
better correlation with microvascular complications, higher pre antagonize the • Somatostatinoma
analytical stability, and a lower coefficient of variation (3.6%) action of insulin. • Others
compared to FPG (5.7%) and after 2 h of OGTT (16.6%). HbA1c has Drug- or chemical- Certain • Vacor [21]
been found to have a stronger association with microvascular compli induced diabetes medications and • Glucocorticoids
chemicals can • Pentamidine
cations, especially retinopathy, and serves as a marker for protein gly
interfere with the • Thyroid hormone
cation and glycemic control, which are related directly to the diagnosis secretion or • Thiazides
and development of diabetes-related complications [30]. If HbA1c is function of insulin, • Alpha-adrenergic
used as the sole diagnostic test, the test must be repeated within two while others have agonists
the potential to • Beta-adrenergic
weeks with asymptomatic patients [31]. However, ethnicity can influ
cause damage to β agonists
ence the cutoff values for diagnosing diabetes, with different cutoff cells. • Dilantin
values adopted by various nations and ethnic groups [32]. For example, • Nicotinic acid
a Japanese study measured the cutoff values at 5.5% (37 mmol/mol) • Pyrinuron
and 6.5% (48 mmol/mol), while an Egyptian study reported a cutoff • Interferon-alpha
• Others
value of 6.3% (45 mmol/mol). Australian researchers suggested using
Infections Certain viruses • Congenital rubella [20,21]
two cutoff values, 5.5% to "rule out" diabetes and 7.0% to "rule in". have been linked to • Cytomegalovirus
Ethnicity can also affect the prevalence of diabetes and prediabetes [33]. the direct • Others
HbA1c was used in most trials to identify diabetes in fewer patients than destruction of β
FPG or OGTT. However, other research found that using HbA1c, more cells.
Uncommon forms Rare immune- • Anti-insulin receptor [19,21]
people were diagnosed with diabetes [34]. of immune- mediated diseases antibodies
have been • “Stiff man” syndrome
(continued on next page)
5
Table (1) (continued ) interplay of mechanisms involving oxidative stress, beta-cell dysfunc
Other specific types Brief description Examples Reference tion, insulin resistance, inflammation, and mitochondrial dysfunction.
of DM These factors collectively disrupt glucose homeostasis and contribute to
mediated associated with • Others
the development and worsening of diabetes. It’s essential to understand
diabetes this condition. and mitigate the impact of environmental toxins on metabolic health to
Other genetic The risk of diabetes • Down syndrome [19–21] reduce the risk of diabetes-related complications.
syndromes are is elevated in • Turner syndrome
sometimes individuals with Klinefelter syndrome
•
3. The role of inflammation in diabetes
associated with various genetic • Wolfram syndrome
diabetes disorders and • Huntington chorea
chromosomal • Friedreich ataxia The resistance of Insulin and its related complications are partly
abnormalities. • Laurence-Moon-Biedl driven by the inflammatory response, which is a primary molecular
syndrome mechanism underlying their pathophysiology [36]. Insulin resistance
Porphyria
and the onset of DM are connected to the presence of chronic low-grade
•
• Myotonic dystrophy
• Prader-Willi inflammation. That can trigger other pathophysiologic mechanisms,
syndrome such as β-cell dysfunction and impairment of insulin signaling. The
• Others relationship between DM and inflammation is not understood, but cy
tokines such as tumor necrosis factor-alpha (TNF-α) and nuclear factor
kappa B (NF-κB) can induce Janus kinase pathways (JNKs) that lead to
2. The effect of chemicals and toxins in DM
an impairment in insulin signaling by stimulating insulin receptor sub
strate 1 (IRS-1) serine phosphorylation. Patients with diabetes have been
There are several mechanisms through which long-term exposure to
found to have elevated levels of various circulatory mediators such as
environmental toxins, such as arsenic (As) and other heavy metals, can
TNF-α, c-reactive protein (c-RP), monocyte chemoattractant protein (
contribute to the progression of diabetes mellitus (DM). Here’s an
MCP-1), Interlukin-6 (IL-6), IL-1β, IL-18, E-selectin, Interferon-γ (IFN-γ),
explanation of how these toxins may lead to the development and pro
and plasminogen activator inhibitor 1(PAI-1) [37–39]. Therefore,
gression of DM [35]:
managing these inflammatory processes could be beneficial for treating
diabetes. Studies have approved the significance of anti-inflammatory
a) Increased oxidative stress: Environmental toxins like arsenic can
agents in maintaining the homeostasis of glucose. Oxidative stress can
induce oxidative stress in the body. Oxidative stress refers to an
be associated with insulin resistance as it triggers monocytes and
imbalance between the production of harmful reactive oxygen spe
macrophage activation, leading to inflammatory responses responsible
cies (ROS) and the body’s ability to detoxify them. Prolonged
for insulin resistance and DM.
exposure to these toxins can overwhelm the body’s antioxidant de
fense systems, leading to oxidative damage to various cells and
tissues. 3.1. Inflammation in T1D
b) Beta-cell dysfunction: The pancreas contains beta cells responsible
for producing insulin, which regulates blood glucose levels. Oxida Type 1 diabetes (T1D) is an autoimmune disorder characterized by
tive stress and the disruption of mitochondrial function caused by the targeted destruction of insulin-producing pancreatic β cells, while
toxins like arsenic can impair the function of these beta cells. This other cells in the pancreas remain unaffected [40]. However, T1D dis
dysfunction can result in decreased insulin production or secretion. plays significant variation in terms of severity of the autoimmune
c) Insulin resistance: Toxins can also contribute to insulin resistance, a response, age of onset, and response to treatment [41]. It has been
condition where the body’s cells become less responsive to insulin. established that both humoral (related to antibodies) and cellular
This often occurs in the context of obesity and metabolic dysfunction, (involving immune cells) immunity contribute to the development of
which are associated with chronic exposure to environmental toxins. T1D [42]. Early theories regarding predisposition suggest that envi
d) Inflammation: Oxidative stress and mitochondrial dysfunction trig ronmental factors, such as infections, nutrition, and certain chemicals,
gered by toxins can lead to chronic inflammation. Inflammation can may trigger the activation of self-directed immune reactions. These
further exacerbate insulin resistance, disrupt insulin signaling path theories remain relevant, although the exact initial trigger for T1D is still
ways, and impair the overall ability of cells to respond to insulin. not fully understood [43,44].
e) Mitochondrial dysfunction: Toxins like arsenic can disrupt mito
chondrial function, which plays a critical role in energy metabolism. 3.1.1. Inflammatory infiltrates in T1D
Impaired mitochondrial function can lead to decreased ATP pro Patients with T1D experience insulitis, an inflammation produced by
duction, causing a shift from oxidative phosphorylation to glycolysis the condition that affects the β-cell pancreatic islets [45]. Mechanisms of
for energy generation. This metabolic shift can affect the ability of peripheral and central immunological tolerance that result in the pro
beta cells to couple insulin secretion with glucose levels. duction of reactive T cells in the peripheral blood [46]. Furthermore,
f) Selenium deficiency: Selenium is an essential nutrient for the body findings from animal models reveal that both CD4 + and CD8 + T cells
and is involved in antioxidant defense mechanisms. Some toxins, like (also known as Effector T-cells/Teff) play a role in the initiation of type 1
arsenic, can deplete selenium levels in the body, potentially reducing diabetes (T1D) by targeting various β-cell autoantigens and related
the activity of selenoproteins like glutathione peroxidase 1 (GPx-1). peptide epitopes. Moreover, research has shown that regulatory T cells
Lower GPx-1 activity can lead to an increased burden of hydrogen (Tregs) become dysfunctional in the context of this autoimmune disease.
peroxide (H2O2) and oxidative stress. Adoptive T-cell transfer models of T1D have demonstrated that different
g) Combined effects of multiple toxins: Humans are often exposed to T-cell subtypes can lead to an unfavorable peri-islet inflammatory
various toxins simultaneously, and these toxins may have additive or infiltrate, ultimately resulting in overt diabetes. [47]. Notably, the
synergistic effects on diabetes risk. This means that the combined immunological profile of B cells (CD20 +) changes as the disease pro
impact of exposure to multiple environmental contaminants can be gresses, and early research indicates a close correlation with the
more detrimental than exposure to each toxin individually. migration patterns of CD8 + T cells, which may exhibit high or low islet
infiltration. Macrophages also play a crucial role in islet inflammation as
In summary, long-term exposure to environmental toxins can they release cytokines like TNF-α and IL-1 and produce reactive oxygen
contribute to the progression of diabetes mellitus through a complex species (ROS).[48,49] as shown in Fig. (2). Additional research has
revealed that the pancreatic exocrine tissue of patients with T1D
6
in determining how the autoimmune process proceeds. The harmful

effects of the attack on pancreatic islets through inflammation and
autoimmune response can result in a cycle where initial stress caused by
cytokines can worsen β-cell function, leading to further metabolic stress
[56].
3.1.3. Anti-inflammatory trials on T1D

Since T1D has a strong genetic component, the immune cell pattern,
and type present in each patient are important factors to consider when
designing clinical studies aimed at delaying or stopping the progression
of the disease (Table 2).
3.2. Inflammation in T2D
Various pathophysiological studies have provided significant in

Fig. (2). Mechanism of hyperglycemia in promoting vascular complications sights into the development and progression of diabetes concerning in
through enhancing the production of the advanced glycation end products sulin secretion and resistance. In individuals at risk of developing T2D,
(AGEs), NO, ROS, NF-κB, and Receptor advanced glycation end prod insulin resistance is initially observed, but it is compensated for by an
uct (RAGE). increase in insulin secretion from the β cells. However, as the disease
advances, the pancreatic functional reserve becomes inadequate to meet
contains a significant presence of neutrophils and lymphocytes. This the rising demand for insulin secretion, leading to a point where, at the
finding further supports the hypothesis that these cells could play a role time of diabetes diagnosis, the beta cells are no longer capable of pro
in the development of the disease. [50]. While the intricate interplay of ducing sufficient insulin. While the extent of insulin resistance and beta
various cell types appears to contribute to the progression of diabetes, cell dysfunction may vary among individuals with T2D, it is widely
some studies have also identified the presence of natural killer (NK) recognized that abnormal insulin sensitivity can occur up to 15 years
cells, dendritic cells, and natural killer T (NKT) cells in the islet infil before the clinical diagnosis of diabetes. Therefore, apart from investi
tration. However, it is suggested that these cells might only play a minor gating the mechanisms behind insulin resistance, recent research has
role in the overall process of diabetes development [51,52]. also focused on understanding the pathways that contribute to β cell
failure. This research aims to develop a better understanding of the
3.1.2. Mediators of inflammation in T1D disease progression and identify potential targets for intervention to
Inflammation of pancreatic β-cells is caused by IFN-γ interaction reduce the risk of developing diabetes [74].
with some inflammatory cytokines, like IL-1 and TNF-α in T1D patients In recent times, mounting evidence has highlighted the significance
[53,54]. The combined effects of these inflammatory substances of low-grade inflammation in the pathogenesis of T2D. Individuals who
culminate in an increase in inducible nitric oxide synthase (iNOS), eventually develop T2D often show indications of inflammation even
which produces NO [55] as shown in Fig. (3). Additionally, studies have before the disease’s onset. Research studies have established a robust
demonstrated that the biology of the β-cell can directly affect how the link between inflammatory markers and abnormalities in lipid and
body reacts to an inflammatory environment by influencing the β-cell carbohydrate metabolism, as well as associations with atherosclerosis
death that is induced by IFN-γ and PTPN2. The methods described above and obesity. A sedentary lifestyle and obesity are recognized as major
strongly suggest that there may be a variety of ways in which pancreatic factors contributing to insulin resistance and the development of T2D.
β-cells can die. The regulation and management of local inflammatory Chronic low-grade inflammation has been observed in obesity, insulin
cytokine production during this phase will likely play a significant role resistance, early stages of atherosclerosis, and T2D. Adipose tissue (AT),
previously thought to be passive, has been found to have an active
endocrine function, expressing pro-inflammatory mediators that are
increased in obesity and linked to insulin resistance. Macrophages play a
role in the inflammatory pathways within AT and are associated with
adipocyte dysfunction. Macrophages in AT secrete pro-inflammatory
factors and can modulate adipocyte activity [58,75].
Moreover, in obese individuals, peripheral blood mononuclear cells
demonstrate an inflammatory state, showing elevated levels of pro-
inflammatory cytokines. The dysregulation of AT in insulin resistance
conditions results in chronic low-grade systemic inflammation, as AT
serves as a significant source of inflammatory factors. These research
findings underscore the role of AT dysfunction and inflammation in the
development of insulin resistance and T2D. The interaction between
inflammation and insulin signaling pathways further contributes to in
sulin resistance and endothelial dysfunction, thereby increasing the
susceptibility to cardiovascular disorders [75].
3.2.1. Mediators of inflammation T2D

In T2D, chronic low-grade inflammation is one of the diabetic
pathogeneses. Various mediators of inflammation contribute to β-cell
dysfunction, insulin resistance, and the improvement of T2D. The key
mediators of inflammation in T2D include cytokines, adipokines, che
mokines, and inflammatory signaling molecules [75].
Fig. (3). Schematic mechanisms of NF-κB activation induced by TNF-α
signaling pathways.
7
Table (2)
Reported anti-inflammatory mediators in T1D.
Drug Mechanism of Action Main Findings Side Effects References
Rituximab Monoclonal anti-CD20 Moderate effectiveness in the initial two clinical trials Common side effects may include [57–59]
antibody Rate of C peptide ↓, insulin requirements↓, HbA1c ↓ infusion reactions, infections, and
infusion-related symptoms.
Teplizumab Two humanized anti- The decreased loss rate of β-cell functions in individuals Common side effects may include [60]
Otelixizumab CD3 monoclonal recently diagnosed with T1D infections, gastrointestinal symptoms,
antibodies (mAbs) and rash.
Etanercept TNF antagonism Improved metabolic control and increased endogenous Common side effects may include [61,62]
insulin production in young T1D patients. injection site reactions, infections, and
HbA1c ↓, endogenous insulin production ↑ headaches.
Alpha-1 antitrypsin (AAT) Anti-inflammatory Improved β-cell function and decreased IL-1β response in Side effects are generally rare but may [63,64]
serum protein monocytes and dendritic cells in T1D patients include fever, rash, and injection site
IL-1β response to monocytes and dendritic monocytes ↓, reactions.
β-cell function ↑
Vitamin D analogue Alfacalcidol β-cell preservation especially in male subjects Common side effects may include [65–67]
Potential therapeutic target with anti-inflammatory gastrointestinal symptoms, headache,
properties, but limited β-cell protection demonstrated in and fatigue.
recent T1D cases
Vitamin D analogue Calcitriol In the treatment group, there was an ↑ in fasting C peptide [68]
levels from the time of diagnosis to one year, while the
daily insulin dosage showed a significant ↓.
Proinsulin peptide Human leukocyte ↑ C-peptide, ↑ Proinsulin induces the production of IL-10, Side effects are generally rare but may [69]
antigen-DR4 which is a favorable outcome for β-cell health, as indicated include injection site reactions and
(DRB1 *0401) by the proinsulin/C-peptide ratio, a marker of β-cell stress. hypersensitivity reactions.
Engineered DNA plasmid BHT-3021 ↓ CD8 + T cells reactivity to proinsulin, C peptide level [70]
encoding proinsulin maintained, no change can be observed to Interferon-ɣ, IL-
10, IL-4
IL-1beta antagonism Canakinumab No C peptide response Common side effects may include [71]
infections, upper respiratory tract
infections, and gastrointestinal
symptoms.
IL-1 receptor blockade Anakinra ↓ insulin requirements compared with controls, ↓ insulin Common side effects may include [72]
dose adjusted. injection site reactions, infections, and
No C peptide response. gastrointestinal symptoms.
IL-1 receptor blockade IL-1β Anakinra/canakinumab The relationship between C peptide ↑ & inflammation is [73]
antagonism (plasma-↑ immunomodulation or reverse.
transcriptional meta-
analysis)
3.2.1.1. Cytokines. The primary cytokines implicated in T2D are IL-1β, 3.2.1.3. Chemokines. Chemokines are chemotactic cytokines that
IL-6, TNF-α, and leptin. IL-1β is a crucial inflammatory cytokine that attract immune cells to sites of inflammation. In T2D, chemokines such
may contribute to the dysfunction and apoptosis of beta cells. IL-6 and as interleukin-8 (IL-8) and monocyte chemoattractant protein-1 (MCP-
TNF-α are significant cytokines produced by adipocytes that can impair 1) are involved in the recruitment of immune cells, particularly mac
insulin action and promote insulin resistance. TNF-α is particularly rophages, to adipose tissue. The infiltration of macrophages into adipose
abundant in adipose tissue and is associated with obesity, insulin tissue further promotes inflammation and contributes to insulin resis
resistance, and beta-cell dysfunction. IL-6 exerts multiple effects on tance [79–81].
glucose metabolism and insulin sensitivity, and elevated levels are
observed in obese individuals, predicting future T2D risk. Leptin, pro 3.2.1.4. Inflammatory signaling molecules. Inflammatory signaling mol
duced by adipocytes, plays a role in regulating energy homeostasis and ecules, such as c-Jun N-terminal kinase (JNK) and nuclear factor-kappa
has various actions. It is involved in insulin resistance, appetite regu B (NF-κB), are activated in the presence of obesity and metabolic
lation, and modulation of the immune system. Leptin levels are posi dysfunction. These signaling pathways are involved in the production of
tively correlated with obesity and insulin levels [76]. pro-inflammatory cytokines and the activation of inflammatory re
These cytokines have been associated with several aspects of T2D sponses, leading to impaired glucose metabolism and insulin resistance
development, including inflammation, insulin resistance, dysfunction of [75].
beta cells, and metabolic abnormalities. They play roles in promoting
adipose tissue dysfunction, impairing insulin signaling, inducing 3.2.1.5. Adiponectin. Adiponectin is a protein produced by fat cells that
oxidative stress, and contributing to chronic low-grade inflammation. has anti-inflammatory and potentially antiatherogenic properties. Its
Understanding the roles and interactions of these cytokines is crucial for levels are reduced in individuals with insulin resistance, heart disease,
unraveling the mechanisms underlying T2D and developing potential and T2D. Adiponectin improves insulin sensitivity, inhibits liver glucose
therapeutic strategies for its prevention and treatment [77]. production, promotes fatty acid oxidation in muscles, and has positive
effects on blood vessel function. It also reduces inflammation by inhib
3.2.1.2. Adipokines. Adipokines are cytokines that are released by adi iting certain signaling pathways and the production of inflammatory
pose tissue, and they play a role in the development of insulin resistance molecules. Additionally, adiponectin protects against atherosclerosis by
and T2D. One such adipokine is adiponectin, which possesses anti- preventing the accumulation of cholesterol in immune cells besides
inflammatory properties. However, its levels are reduced in in reducing the adhesion of these cells to blood vessel walls. On the other
dividuals with insulin resistance and obesity. This deficiency is linked to hand, IL-6, another molecule, decreases the expression and release of
insulin resistance and an increase in the production of pro-inflammatory adiponectin [82,83].
cytokines. Conversely, leptin, another adipokine, is elevated in obesity
and has been associated with inflammation and insulin resistance [78]. 3.2.1.6. Resistin. Resistin is a hormone generated by fat cells, mainly in
8
white adipose tissue, and is involved in insulin resistance. Interestingly, 4. Role of some organs in T2D related to inflammation
resistin administration has been shown to significantly increase the
expression of a specific protein called SOCS-3 in fat cells [84,85]. 4.1. Role of adipose tissue and obesity in T2D
3.2.1.7. CD40 ligand (CD40L). CD40 ligand (CD40L) is a mediator of The liver and muscles contribute significantly to systemic insulin
inflammation that is present in certain immune cells and activated resistance [105]. Steatosis is expected to have a main role in impaired
platelets. It plays a role in promoting blood clotting processes and hepatic insulin sensitivity that results in fasting hyperglycemia. Steatosis
inflammation that contribute to the improvement of atherosclerosis is the accumulation of fats in the liver that happens before T2D and is
[86]. frequently associated with obesity [106]. Furthermore, excessive calorie
In T2D, inflammation plays a crucial role in both its development intake leads to the buildup of fat in subcutaneous tissue, followed by the
and progression. Multiple mediators of inflammation, including cyto deposition of fat in other tissues like the liver, pancreas, muscles, and
kines, adipokines, chemokines, and inflammatory signaling molecules, perivascular tissue [107]. While pancreatic fat buildup increases tissue
contribute to beta cell dysfunction, insulin resistance, and the exacer insulin resistance, it also serves to further define β-cell failure. The
bation of T2D. Adiponectin, resistin, and CD40L are particularly presence of inflammatory biomarkers is inversely correlated with insulin
involved in the inflammatory processes linked to insulin resistance, resistance, the prevalence of T2D and CVD, and obesity-related illnesses
obesity, and T2D. Gaining a comprehensive understanding of these in such as metabolic syndrome, hypertension, and dyslipidemia. Particu
flammatory pathways and their interactions can offer valuable insights larly, eating too much and not moving enough can lead to diseases like
into the underlying mechanisms of T2D, potentially leading to knowl obesity and metabolic syndrome. Activation of at least two key inflam
edge of therapeutic targets for the prevention and management of the matory pathways, such as the transcription factor NF-κB, and the
disease [75] as shown in Fig. (4). stress-activated JNK as well as subacute chronic inflammation serve as
common and potentially unifying mechanisms for these diseases.
3.2.2. Current knowledge of T2D treatments Numerous studies have demonstrated that adipokines enhance
In addition to their primary modes of action, the current treatment obesity-induced metabolic and cardiovascular diseases and stimulate
methods for T2D also contain anti-inflammatory qualities [87]. As additional inflammatory responses; however, they have also demon
measured by circulating c-reactive protein (c-RP) and IL-6 concentra strated that adipokines amplify this inflammatory state by stimulating
tions, non-pharmacological therapy for weight loss, such as lifestyle the production of pro-inflammatory cytokines [108]. Studies have
changes, as well as pharmacological and bariatric surgery procedures, indicated that brown adipose tissue (BAT) plays a crucial role in regu
appear to lower inflammation and improve cardiovascular and all-cause lating energy and glucose homeostasis, as evidenced by its association
mortality, Table 3. with peripheral insulin resistance and blood sugar levels in animal
models. In contrast, white adipose tissue (WAT), particularly visceral
3.2.3. Anti-inflammatory drugs in T2D WAT located in the trunk, upper body, or abdomen, is the primary origin
Over the past few years, numerous medicinal strategies targeting of inflammatory markers in T2D. [107]. However, white adipose tissue
specific inflammatory pathways have been developed to support the (WAT) is also a target of the inflammatory response in diabetic patients.
idea of anti-inflammatory therapy for cardiometabolic disorders such as WAT generates numerous bioactive substances associated with inflam
atherosclerotic, CVD, and diabetes Table 4 [74]. matory pathways, including TNF-α, IL-6, IL-1, IL-10, adiponectin, leptin,
chemokines, monocyte chemoattractant protein, resistin, angiotensi
nogen, and serum amyloid protein. The infiltration of macrophages and
immune cells (B & T cells) into adipose tissue leads to chronic low-grade
Fig. (4). The key Mediators of inflammation in type 2 diabetes.
9
Table (3)
Current treatments of T2D.
Drugs Mechanism of action and main funding Receptors Side effects References
targeted
Rosuvastatin Lowered high-sensitivity of c-RP along with low-density HMG-CoA Common side effects may include muscle pain, [61]
lipoprotein (LDL) and cholesterol; however, effects of statins on Reductase liver enzyme abnormalities, and gastrointestinal
glycaemic control are inconsistent, indicating that they do not symptoms.
improve glycemic control and do not, therefore, offer an
integrated anti-inflammatory therapy for diabetes and
cardiovascular diseases (CVD).
Insulin Can cause ↓ levels of inflammatory markers. Reduced Insulin Common side effects may include hypoglycemia, [88]
inflammation by insulin is achieved through lowering NF-κB Receptor injection site reactions, and weight gain.
activity in mononuclear cells of the blood.
Thiazolidinediones Have anti-inflammatory properties through ↑ the peroxisome PPAR-ɣ Common side effects may include weight gain, [89]
proliferator-activated receptor gamma (PPAR-ɣ), associated with edema, and an increased risk of fractures.
decreased expression of NF-κB targets and trans-repression of NF-
κB.
Metformin Has metabolic and anti-inflammatory effects on the immune cells AMPK Common side effects may include gastrointestinal [90]
and vascular tissues that could be independent of glycemia. symptoms (diarrhea, nausea), vitamin B12
deficiency, and lactic acidosis (rare).
Sodium-glucose A novel family of anti-diabetic medications works by enhancing SGLT2 Common side effects may include urinary tract [91]
cotransporter-2 the renal excretion of glucose. The circulating indicators of infections, genital yeast infections, and increased
inhibitors inflammation may be improved by SGLT2 inhibitors in people, urination.
(SGLT2 inhibitors) according to preliminary evidence; nevertheless, more research is
required.
Table (4)
Anti-inflammatory drugs in T2D.
Drugs Mechanism of action Main findings Side Effects References
Anakinra IL-1 receptor blockade studies on their use in the prevention of Common side effects may include injection [92,93]
atherosclerosis and CVD have HbA1c, leukocyte site reactions, infections, and headaches.
↓, CR↓ insulin secretion↑, insulin requirement ↓,
and Insulin sensitivity ↑.
Gevokizumab IL-1beta antagonism studies on their use in the prevention of Common side effects may include upper [94]
atherosclerosis and CVD have HbA1c ↓, CRP > ↓, respiratory tract infections, injection site
and insulin secretion ↑. reactions, and gastrointestinal disturbances.
Canakinumab IL-1beta antagonism T2D patients with high CVD risk have CRP ↓, Common side effects may include infections, [95,96]
HbA1c ↓, insulin secretion ↑, fibrinogen ↓, IL-6 ↓. injection site reactions, and gastrointestinal
symptoms.
Salsalate IKKbeta–NF-kappaB FBG ↓, CRP ↓, insulin sensitivity ↑, adiponectin ↑, Common side effects may include [97,98]
inhibition HbA1c ↓, insulin secretion ↑, triglyceride ↓, gastrointestinal symptoms, headache, and
leukocyte ↓, and uric acid ↓. dizziness.
Soluble TNF receptor–Fc fusion TNF antagonism insulin secretion ↑, FBG ↓, CRP ↓, LDL ↓, Common side effects may include injection [99]
protein (etanercept) adiponectin ↑, no effect on sensitivity of insulin site reactions, infections, and headaches.
Infliximab TNF antagonism Fasting glucose ↑, ratio of high molecular weight Common side effects may include infections, [100]
to total adiponectin ↑, no effect on CRP. gastrointestinal symptoms, and infusion
reactions.
Diacerein Decrease in TNF and IL-1β HbA1c ↓, FBG ↓, insulin secretion ↑ Common side effects may include [101]
levels by an unknown gastrointestinal symptoms, skin reactions,
mechanism of action and liver enzyme abnormalities.
Methotrexate DHFR inhibitor – No effects on CRP, IL-1beta or IL-6 Common side effects may include nausea, [102]
antimetabolite fatigue, and liver function abnormalities.
Methotrexate + Sulphasalazine DHFR inhibitor & HbA1c ↓ Side effects may vary depending on the [103]
glycocorticosteroids/ (DMARD) combination specific drugs used in the combination.
hydroxychloroquine Common side effects of methotrexate include
nausea and fatigue.
Salicylates; aspirin Non-steroid anti- Treat thrombosis in rheumatoid disorders and Common side effects may include [104]
inflammatory drugs primary and secondary CVD prevention. gastrointestinal irritation, bleeding risk, and
(NSAIDs) tinnitus (with high-dose aspirin).
inflammation due to an elevation in the production of chemokines and Inceptor, an inhibitory receptor for insulin, aids in the internaliza
cytokines, establishing a pathological link between diabetes, obesity, tion of the insulin receptor (IR) through a process called clathrin-
and insulin resistance [107] as shown in Fig. (5). mediated endocytosis. In T2D, β-cells undergo exhaustion as they pro
liferate in number and enlarge to enhance insulin secretion into the
bloodstream. However, challenged beta-cells can undergo dedifferenti
4.2. Role of pancreatic β-cell in T2D
ation or apoptosis, leading to dysfunction. These dysfunctional beta-
cells have cytotoxic effects that worsen the symptoms of T2D [109].
T2D is significantly influenced by β-cells found within the pancreatic
Inflammation in the pancreatic Langerhans β-cell islets (insulitis) is a
islets of Langerhans. These cells play a vital role in regulating insulin
common pathway observed in different types of diabetes, regardless of
release through glucose-stimulated insulin secretion (GSIS), triggered by
the underlying cause. Insulitis leads to a decline in the function and
glucose stimulation. The function and quantity of β-cells are modulated
number of β-cells [110]. According to some theories, the "stressed" β-cell
by different transcription factors, which are regulated by pancreatic
may change the ratio of β-cell mass in Langerhans islets, resulting in
pericytes and macrophages. [109].
10
Fig. (5). Role of Adipose Tissue (WAT) & (BAT) in T2D related to inflammation.
localized inflammation in people with a hereditary predisposition. the islets in this condition. Free fatty acids (FFAs), endocannabinoids,
Numerous experimental models and observational human studies have and amyloid polypeptides are a few of the stimuli that induce islet
revealed that macrophages are the major cause of islet inflammation in macrophages to release IL-1 in human islets as shown in Fig. (6).
T2D patients [111]. The inflammasome/IL-1β signaling is the major and However, it has been hypothesized that the primary cause of hy
most common pathway that is active in the islets of various T2D models perglycemia is inflammation in pancreatic β-cells, which results in
and causes β-cell loss. Although it has also been suggested that islet apoptotic processes. In addition, after being initially produced, IL-1
autoimmunity contributes to the decline in β-cell activity throughout regulates the generation of insulin by activating the pancreatic β-cells
T2D, other immune cells could also be involved in the inflammation of on their own. This method also increases the synthesis of NO, which
Fig. (6). The Integral Role of Pancreatic β-Cells in the Pathogenesis of Type 2 Diabetes: Regulation, Dysfunction, and Inflammatory Mechanisms Leading to β-Cell
Loss and Hyperglycemia.
11
reduces the amount of ATP in the mitochondria [112]. Oxidative stress on by oxidative stress as well as insulin resistance [123].
may ↑ the β-cells’ production of ROS and other proinflammatory cyto
kines and chemokines, which would damage their blood supply and 4.2.3. Insulin production and secretion because of β-cell dysfunction
render them ineffective. Along with other inflammatory cytokines, IL-6 Normal glucose homeostasis requires healthy and functional
initiates pancreatic islet apoptosis, hence it acts as a pathologic marker pancreatic β-cells. Therefore, DM is associated with variable degrees of
for monitoring T2D [113]. By establishing a connection between islet β-cell malfunction [124]. A significant factor in the improvement of
inflammation, insulin resistance, and obesity, TNF-α is also thought to diabetes mellitus (DM) is the progressive loss of β-cell mass and function.
play a crucial role. β-cell inflammation and death appear to be fueled by This leads to impaired and reduced production of glucose-induced in
their overproduction in adipose tissue, and this leads to more insulin sulin, resulting in elevated postprandial glucose levels. The initial phase
resistance in peripheral tissues [112,114]. of insulin release is affected, followed by a decline in postprandial in
sulin secretion, leading to defects in steady-state and basal insulin
4.2.1. Manifestations of pancreatic Langerhans β-cell islets inflammation in release. Ultimately, this process culminates in total β-cell failure. The
people with T2D dysfunction or failure of β-cells is influenced by oxidative stress and
T2D incidence and development are closely correlated with immune various pathogenic mechanisms. Chronic hyperglycemia in islets trig
system activation, and inflammation of adipose tissue is mediated by gers the production of free radicals through biochemical processes, such
both innate and adaptive immunity [115]. A key factor in the beginning as elevated cytosolic calcium levels and activated protein kinase. β-cells
and intensification of islet inflammation is the phenotypic flip of mac are particularly susceptible to oxidative stress as they lack a specialized
rophages from primarily anti-inflammatory M2-type to higher pro antioxidant defense mechanism. Consequently, oxidative stress is a
portions of pro-inflammatory M1-type macrophages. Studies revealed common occurrence in both T1D and T2D, significantly contributing to
that activation of β-cell and T-cell recruitment is followed by macro the loss of function observed in these conditions [125]. Several
phage invasion to adipose tissue. Other organs, such as the liver, nervous biochemical pathways underlie the impairment of β-cell function by
system, and skeletal muscle, are also involved in the regulation of in oxidative stress. It leads to a substantial reduction in insulin synthesis
flammatory state and metabolic homeostasis in T2D. However, more and impairs the insertion of proinsulin vesicles into the plasma mem
studies are still required to support that claim [116]. brane. Additionally, it diminishes their exocytosis in response to changes
in blood glucose levels. Additionally, it can cause the pancreatic cells to
4.2.2. Oxidative stress and antioxidant defense system in β-cells undergo apoptotic processes that result in death and the loss of β-cells.
Active biomolecules known as free radicals are produced physio Several proapoptotic substances are extremely reactive to oxidative
logically during metabolic processes and/or by immune cells [117]. Free stress and can cause pancreatic cells to undergo apoptosis [126]. A
radicals play important physiological functions in a wide range of mo surplus of free radical species also affects β-cells’ metabolic processes
lecular processes, like cell-cell communication, synaptic plasticity, de negatively and damages KATP channels, which reduces insulin pro
fense against pathogen invasion, memory formation, cell-cell duction. According to studies showing that genetic knockout models of
interactions, apoptosis, cell proliferation, aging, and autophagy [118]. β-cell KATP channels protected them from oxidative stress, free radicals
However, oxidative stress is generated when free radical levels exceed damage KATP channels by attaching to their SH residues [127]. Higher
the natural antioxidant defense capacity. Catalase (CAT), glutathione levels of free radicals prevent Pdx-1 (the insulin promoter factor 1) and
(GLT), and superoxide dismutase (SOD) are just a few of the several MafA (a transcription factor) from regulating insulin gene expression,
enzymes that most biological cells use as part of their inherent defense which lowers insulin synthesis at the DNA level [128]. Wang showed in
system to shield them from free radical damage. Free radicals are 2017 that oxidative stress caused NF-κB, p38 MAPK, JNK/SAPK, and
reactive derivatives of either oxygen or nitrogen molecules, such as ROS: hexosamine pathways to be activated. These stress-activated signaling
hydrogen peroxide, hydroperoxyl, and hydroxyl radicals as well as su pathways are crucial in the malfunctioning of β-cells. TLRs (toll-like
peroxides [119]. Due to the unpaired electrons in the molecules that receptors) can also be activated by free radicals, which in turn impairs
make up the outer layer of these hyperactive components, they can bind β-cell activity [129]. Another potential biological link between β-cell
to and alter other biomolecules. They can oxidize nucleic acids, proteins, dysfunction and oxidative damage is oxidative stress-induced mito
and lipids, producing toxic byproducts that cause tissue malfunction chondrial malfunction [130].
[120]. Additionally, they change and sometimes even destroy the ar
chitecture of biological molecules. One well-known consequence of 4.2.4. Glucose transporter type 4 (GLUT-4) expression and/or localization
oxidative stress, which has an impact on gene expression in general and A GLUT-4 controls the amount of glucose that enters insulin-
cell survival, is DNA damage [121]. In addition to their harmful direct dependent cells including myocytes and adipocytes [131]. Any factor
effects, free radicals can also harm cells indirectly by activating several that lowers insulin sensitivity is mainly altered through GLUT-4
stress-sensitive intracellular signaling pathways, including the expression because it limits the amount of glucose that enters target
JNK/SAPK (stress-activated protein kinase/c-Jun NH (2)-terminal ki cells, which results in decreased insulin sensitivity in tissues. Clinical
nase), p38, mitogen-activated protein kinases (MAPK), NF-κB, PKC investigations demonstrate that T2D patients with insulin resistance
(protein kinase PKC (protein kinase C), AGE/RAGE (advanced glycation have reduced GLUT-4 expression and/or location. localization and
end product/receptor for AGE) interactions, hexosamine pathways, and Normal expression of GLUT-4 are important to control insulin sensitivity
sorbitol synthesis. Biomarkers such as total cholesterol, reactive hy in tissues because GLUT-4 controls glucose entry into insulin-dependent
droperoxides (ROOH), and malondialdehyde (MDA) are used to monitor cells including myocytes and adipocytes. Any factor that reduces the
oxidative stress in diabetic patients. Oxidative stress plays a crucial role expression of GLUT-4 has a considerable impact on the sensitivity of
in the pathogenesis of numerous problems of diabetes by altering lipid target tissues to insulin, as it restricts the amount of glucose that can
peroxidation and inducing mitochondrial malfunction and DNA damage enter the cells. The mechanisms listed below help oxidative stress to
[122]. Additionally, it plays various roles in pathological situations as produce this pathophysiologic condition; the mitochondria-targeted
well as age-related illnesses like cancer, chronic renal disease, chronic paraquat was used to cause mitochondrial oxidative stress in mouse
obstructive lung disease, and CVD. The steady loss of tissue function adipocytes and myotubes. It was noticed that GLUT-4 trafficking was
brought on by a variety of causes, including increasing free radical markedly suppressed and led to insulin resistance in tissues. The tran
species, is known as aging and the illnesses that it is associated with. The scriptional regulators of GLUT-4 expression, including NF-κB, PPAR-γ,
oxidative stress theory is widely accepted as the primary explanation for nuclear factor-1, p85, CEB/Ps (CCAAT enhancer-binding proteins),
aging and the difficulties associated with it. Therefore, maintaining a MEF2 (myocyte enhancer factor 2), and HIF-1 (hypoxia-inducible fac
normal state of redox biology is crucial to preventing difficulties brought tors alpha), can be suppressed by persistent oxidative stress.
12
Additionally, oxidative damage activates a variety of factors and occurs due to a reduction in the respiratory capacity of mitochondria,
byproducts that are caused by oxidative stress, including p38 MAPK, alteration in the normal function of the Mitochondrial Respiratory Chain
PKC, JNK/SAPK, hexosamine, and sorbitol, which can all inhibit GLUT-4 (MRC), increased levels of proton leak in the MRC, and alteration in the
expression. Therefore, localization and/or lowering expression of potential difference through the inner mitochondrial membrane result
GLUT-4 is the substantial molecular mechanism through which DM ing in disruption of mitochondrial membranes integrity [135]. These
could be developed due to insulin resistance resulting from oxidative processes can take place in either pancreatic islets (locally) or adipocytes
stress [127]. and muscle tissues (systemically). Healthy mitochondria generating the
energy required for glucose uptake are essential for maintaining normal
4.2.5. Insulin signaling pathways processes of glucose uptake in peripheral tissues via GLUT-4. As a result,
Malfunctioning of insulin signaling pathways may affect how quickly mitochondrial dysfunction significantly lowers the capacity of cells to
insulin resistance and diabetes develop. Insulin signal transduction (IST) produce ATP and inhibits the absorption of glucose caused by insulin in
regulation has been suggested as a potential therapeutic target for adipocytes and muscle cells [136]. Insulin resistance results from the
improving insulin sensitivity. Oxidative stress deteriorates the proper cells’ inability to take up blood glucose for insulin response under these
IST at several levels, including IRs, IRS-1 and IRS-2, Akt signaling circumstances. Furthermore, oxidative stress may adversely affect
pathways, and PI3K enzyme. When T2D-induced oxidative stress was mitochondrial function by promoting the synthesis of DAG (diac
created in diabetic rats, researchers found IST components in the brains ylglycerol) and fatty acid oxidation within the mitochondria. This pro
of those animals. They found that Nigella sativa oil might stop these cess can lead to the activation of additional serine/threonine kinases and
changes and return insulin signaling to normal [132]. In brain tissues, the impairment of insulin signal transduction (IST). As a consequence,
oxidative stress drastically reduced the expression of IST components oxidative stress-induced mitochondrial dysfunction presents another
such as p-IRS, p-AKT, and GSK-3. They can also disrupt normal IST via biological mechanism through which free radicals contribute to insulin
p38 MAPK-dependent molecular pathways; in vitro and in vivo models resistance [137].
of diabetes, blocking this pathway restored normal IST. The oxidative
stress brought on by hyperglycemia activates IKK-B, a stress-sensitive 4.3. Role of gut microbiota in T2D
serine/threonine (Ser/Thr) kinase, which then phosphorylates a vari
ety of substrates, including the IRs, IRS-1, and IRS-2 [127]. As a result, Studies have indicated that there are various factors involved in
there are negative knock-on effects such as insulin resistance and ↓ PI3K weight loss following bariatric surgery, apart from just malabsorption or
activation. In vitro, research has shown that the IKK-inhibitor salicylates physical limitations. Changes in gut hormones after bariatric surgery
can restore the normal IST in oxidative stress. Other serine/threonine have been found to have positive metabolic effects in the short- and
kinases that are vulnerable to oxidative stress that may impair insulin long-term and offer potential new therapeutic approaches for treating
signaling include Akt (or PKB), AMPK, mTOR, and GSK-3. By causing the insulin resistance and obesity [138]. Recent studies have also shown
proteins required for typical IST function to be downregulated, oxidative that there is a connection between the body’s energy balance and im
stress can also harm IST. Free radicals have an impact on the main IST mune system, and the bacteria in the gut. Transplanting gut bacteria
components, including GSK-3, IRS, IRS-1, and Akt, and are down from lean donors to insulin-resistant individuals has been found to have
regulated by oxidative stress. As a result, there will be an increase in DM beneficial metabolic effects. The composition of gut bacteria is influ
and insulin resistance. As a result, the disruption of the normal IST is due enced by metabolic status and diet and differs between obese and lean
to oxidative stress and insulin resistance [133] as shown in Fig. (7). individuals. The onset of obesity and diabetes is believed to be linked to
low-grade inflammation generated from a metabolic change in the body
4.2.6. Systemic mitochondrial dysfunction triggered by an interaction between the immune system and products
Mitochondria are double-membrane organelles that are responsible from gut microbiota [139].
for energy production, calcium storage, the creation of fatty acids and Lipopolysaccharides (LPS) can induce inflammation by triggering
heat, as well as cell survival. They also participate in cellular signaling the sensation of inflammatory cytokines. Conversely, Short-chain fatty
networks [134]. It has been established that insulin resistance and DM acids (SCFAs) have the opposite effect, as they can reduce the produc
have a pathogenesis that includes mitochondrial dysfunction. Most cases tion of pro-inflammatory cytokines and chemokines while promoting
of mitochondrial dysfunction result from oxidative stress, which dis the growth of regulatory T cells. Additionally, SCFAs inhibit the activity
rupts mitochondrial function. Disruption of mitochondrial function of inflammatory T cells and prevent the release of IFN-inducible protein
10 (IP-10) in human colonic sub-epithelial myofibroblasts. This in
dicates that SCFAs play a role in dampening the inflammatory response
and promoting immune regulation [140].
Organ impairment can result from a range of harmful compounds
that an unbalanced gut flora can create. The bacterial metabolites
imidazole propionate (ImP) and branched-chain amino acids (BCAA)
can develop insulin resistance by inhibiting insulin signaling [141].
Trimethylamine (TMA) is transformed by the liver into
trimethylamine-N-oxide (TMAO), which hastens the onset of diabetic
nephropathy. Furthermore, increased levels of some nephrotoxic me
tabolites such as indoxyl sulfate and P-cresyl sulfate could worsen kid
ney damage. Increased ethanol- and phenylacetate-producing bacteria
in the intestines encourage the growth of non-alcoholic fatty liver dis
ease (NAFLD) and further liver damage [142] as described in Fig. (8).
5. Complications associated with DM

Fig. (7). Insulin signal transduction (IST), insulin receptor substrate-1 (IRS-1),
an inhibitor of nuclear factor kappa B (IKK-B), glycogen synthase kinase 3 (GSK- 5.1. Liver cirrhosis
3), AMP-activated protein kinase (AMPK), mammalian target of rapamycin
(mTOR), and p38 mitogen-activated protein kinases are some of the molecular The liver plays a crucial role in carbohydrate metabolism because it
pathways that are damaged by oxidative stress (p38 MAPK). regulates blood glucose levels through the processes of glycogenesis and
13
Fig. (8). A schematic illustration shows how having more bacteria in the intestines causes NAFLD to proceed more quickly and cause more liver damage.
glycogenolysis [143]. However, diseases such as insulin resistance, 5.1.2. NASH

glucose intolerance, and diabetes can disrupt the metabolic balance of NASH is a complex manifestation of NAFLD [149]. NASH is predis
glucose in the liver. In cases of liver disease, both muscle and adipose posed by obesity in visceral, hypertriglyceridemia, and insulin resis
tissue exhibit insulin resistance, and along with hyperinsulinemia, these tance [150]. It is known that enlarged adipose tissue in a state of chronic
factors are believed to be key underlying causes of diabetes [144]. inflammation linked to obesity secretes more adipokines [151]. Cyto
Additionally, as hepatitis C virus (HCV), alcohol, hemochromatosis, and kines released from the liver can induce some systemic effects such as
NAFLD are frequently linked to DM, the liver disease etiology is signif hyperglycemia, hyperinsulinemia, and insulin resistance. These abnor
icant in determining the occurrence of the condition. Since FBG levels malities prevent the liver from properly metabolizing lipids [152]. The
may be normal in people with compensated liver cirrhosis, DM may be most studied cytokine (TNF) directly stimulates the liver stellate cells
subclinical in these cases. Hepatogenous diabetes is a condition of leading to fibrosis of the liver. Losing body weight aids in the treatment
impaired glucose regulation owing to loss of liver functions as a conse of metabolic syndrome disorders like hyperlipidemia and fatty liver
quence of cirrhosis which means DM develops after the cirrhosis onset. [153].
Hepatogenous diabetes has a distinct natural history than inherited T2D
because microangiopathy is less common. In contrast, patients with 5.1.3. Alcohol-related liver disease
diabetes and cirrhosis have cirrhosis consequences more frequently, In persons with alcoholic liver disease, diabetes is most likely to
which can be fatal. DM causes more severe liver failure by accelerating occur [154]. This risk is inversely correlated with the amount of alcohol
liver fibrosis and inflammation [145]. Secondly, DM may ↑ the incidence ingested, rising by a factor of two in patients who consume more than
of bacterial infections in individuals with cirrhosis, leading to higher 270 g of alcohol per week as opposed to those who consume lower than
mortality rates. One mechanism behind this is that insulin resistance 120 g/wk. After acute alcohol consumption, there is a considerable
increases the production of adipokines, including TNF-α and leptin, decrease in insulin-mediated glucose absorption. Contrarily, those who
which activate inflammatory pathways that worsen liver damage. Adi are chronic alcoholics frequently get chronic pancreatitis and lose their
ponectin is a different cytokine responsible for modulating insulin pancreatic islet cells, which leads to DM [155].
sensitivity and tissue inflammation. Reduced adiponectin levels are re
ported in cases with insulin resistance in the liver and peripheral tissues. 5.2. Diabetic kidney disease
Some theories suggest that the development of liver disease is linked to
low levels of adiponectin. The second pathway involves DM exacer DM may have a significant negative influence on the kidneys and
bating immunodepression in cirrhotic patients, which increases the urine system leading to end-stage renal failure in Western Europe and
likelihood of life-threatening infections that can damage liver function the US [156]. The underlying problem in about 40% of all patients who
[146]. consistently require dialysis is diabetes mellitus. Chronic renal insuffi
ciency is caused by glomerular damage brought on by diabetes, extra
5.1.1. NAFLD renal and intrarenal atherosclerosis, and other factors [157,158].
NAFLD refers to several liver conditions, such as cirrhosis, fibrosis, Diabetes also causes severe interstitial inflammation in the kidneys.
and simple steatosis [147]. Fatty liver, considered to be the most benign Individuals are more likely to develop contrast-induced nephropathy
form of NAFLD, is thought to affect one-third of adult Americans. The (CIN) and frequently encounter bacterial infections of the urinary sys
main fatty liver brought on by the buildup of fat is predominantly tem and renal tissue as described in Fig. (9). Acute kidney injury (AKI),
composed of triglycerides because of a metabolic syndrome caused by however, is still a significant problem for patients who are hospitalized
T2D, obesity, and dyslipidemia. Nonalcoholic steatohepatitis (NASH) is all over the world. The number of instances has steadily increased in
considered one of the severe manifestations of NAFLD that also causes recent years, reaching 20% in middle Europe. According to a 2013
tissue inflammation, cell death, and fibrosis. NASH is the most frequent meta-analysis of more than 300 studies, the average AKI incidence for
make of cryptogenic cirrhosis currently. It is categorized as a condition people worldwide is substantially more than 30% [159].
that can lead to liver failure and cirrhosis [148]. Despite efforts to control levels of blood glucose can still develop
14
Fig. (9). Diabetic nephropathy and renal long-term complications of DM.
kidney disease, suggesting that additional factors like lipotoxicity, including improved ketone body production, anti-inflammatory effects,
oxidative stress, and hyperglycemic memory play a role. Hyperglycemic decrease of oxidative stress, blood pressure lowering, and inhibition of
memory refers to the phenomenon where previous episodes of high kidney fibrosis [161,167].
blood glucose levels can have long-lasting effects on the development of
complications, even when glucose levels are subsequently well 5.3. Cardiovascular disease
controlled. The exact mechanisms underlying metabolic memory are not
fully understood but involve epigenetic, genetic, cellular, and tissue- Cardiovascular disease (CVD) stands as the primary cause of
level alterations that occur during periods of hyperglycemia [160,161]. morbidity and mortality among patients with diabetes., particularly T2D
Diabetic kidney disease is marked by significant changes in the [170]. Atherosclerosis, characterized by plaque formation in the ar
structure and function of the kidneys. These alterations include impaired teries, is a common form of CVD in diabetes [171]. Hyperglycemia plays
podocyte function, resulting in the detachment of podocytes from the a role in contributing to endothelial dysfunction and the activation of
glomerular basement membrane. Moreover, there is a thickening of the vascular smooth muscle cells (VSMCs) through the production of
glomerular basement membrane due to the accumulation of extracel advanced glycation end products (AGEs). Additionally, it contributes to
lular matrix components. These changes lead to tubule-interstitial the formation of fatty streaks in the arterial wall [172].
fibrosis, glomerular sclerosis, and a decline in kidney function, man Recently, novel signaling molecules have been linked to the patho
ifested as albuminuria and reduced glomerular filtration rate (GFR) genesis of CVD in individuals with T2D. QKI-7, an RNA-binding protein,
[162]. is elevated in the vessels of diabetic patients and promotes endothelial
Transforming growth factor-beta 1 (TGF-β1) plays a crucial role in dysfunction by degrading mRNAs essential for endothelial cell function.
promoting fibrogenesis in the kidney. It facilitates the accumulation of Inhibition of QKI-7 may hold promise for treating vascular complica
extracellular matrix, inhibits its breakdown, and triggers cell de- tions. Nitric oxide (NO) is a beneficial molecule in atherosclerosis, and
differentiation, all of which contribute to the development of fibrosis. its regulation involves signaling pathways that include PI3K/Akt,
Both hyperglycemia and insulin resistance enhance the signaling of TGF- Ca2 + /calmodulin-dependent protein kinase II (CaMKII), and PKA.
β1, further promoting its effects in the kidney. Additionally, abnormal Dysregulated calcium signaling in diabetic hearts, caused by AGEs and
signaling of Janus kinase-signal transducer and activator of transcrip hyperglycemia, disrupts the balance of calcium release and uptake,
tion (JAK-STAT) pathways also plays a role in the activation of TGF-β1, leading to reduced expression and activity of sarcoplasmic/endoplasmic
exacerbating its fibrogenic actions.[163,164]. Although therapies tar reticulum Ca2 + ATPase 2a (SERCA2a) and heart failure [173,174].
geting active TGF-β1 have shown limited efficacy, targeting the latent Epigenetic changes mediated by histone deacetylases (HDACs) and
form of TGF-β1 holds promise for future treatments [165]. Lipid other regulators play an important role in diabetic CVD. HDAC4, in
signaling and lipotoxicity are emerging as important factors in diabetic response to CaMKII and PKA signaling, regulates β-adrenergic signaling
kidney disease. Abnormal lipid metabolism and the excessive accumu and protects against diabetic heart failure. Sarcolipin, a negative regu
lation of lipids in the kidney lead to renal lipotoxicity and podocyte lator of SERCA2a, is increased in diabetic cardiomyocytes, further
dysfunction. Certain molecules and pathways that play a role in lipid impairing calcium regulation [175,176].
metabolism, such as sphingomyelin phosphodiesterase acid-like 3b Exophers, structures involved in cellular waste disposal, have been
(SMPDL3b) and junctional adhesion molecule-like protein (JAML), have discovered in the heart and play a key role in maintaining cardiac
been implicated in the development and progression of kidney disease. function. Cardiomyocytes utilize exophers to remove dysfunctional
These molecules and pathways are potential targets for interventions mitochondria, and their dysregulation may contribute to cardiomyop
aimed at improving kidney health. Inhibition of these targets shows athy and other diabetic complications [177] as shown in Fig. 10.
promise in ameliorating diabetic kidney injury [166].
VEGF-B and mTORC1 signaling have also been a critical role in 5.4. Complications associated with immune disease
diabetic kidney disease [165,167]. Inhibition of VEGF-B and mTORC1
signaling pathways has shown beneficial action in animal models, 5.4.1. Hyperglycemia and susceptibility to infection
reducing glomerular lipid content, insulin resistance, and renal damage. The human body has powerful defense mechanisms against various
SGLT2 inhibitors, commonly used antidiabetic drugs, have been shown microorganisms, such as bacteria, viruses, parasites, and fungi. Nor
to have dual benefits. They not only help in lowering blood glucose mally, these defense mechanisms make it difficult for viruses to pene
levels but also demonstrate the ability to slow down the progression of trate and cause illness. However, some diseases cause deterioration of
kidney disease associated with diabetes [168,169]. The protective ef the immune system. For example, an open wound can allow bacteria to
fects of SGLT2 inhibitors may be attributed to various mechanisms, enter and cause infection. Healthy skin, mucosal surfaces, ROS,
15
Fig. (10). Cardiovascular complications result from the hyperglycemia pathway that causes endothelial cell impairment by inducing VCAM-1 expression on the cell
membrane [109].
cytokines, and chemokines act as natural barriers and assist our defense monocytes from PBMCs emitted less IL-6 and IL-1. Anti-CD3 antibodies
mechanisms in preventing the infiltration of harmful pathogens as activated non-diabetic participants’ PBMCs, and when those cells were
described in Fig. (11). Unfortunately, diabetes disrupts the host’s then subjected to high glucose levels, the production of the cytokines
immunological response [178,179]. In addition to the possibility of IL-2, IL-6, and IL-10 was suppressed. Inhibition of cytokines may sup
natural barrier deterioration caused by neuropathy, cellular immunity is press the immune response in hyperglycemic patients because IL-6 is
suppressed due to T2D. Both a lack of insulin and high blood sugar are crucial for protection against pathogens as well as for the adaptive im
the main contributors. Infections are a concern for individuals with mune response through the induction of antibody production and
diabetes as their immune systems are unable to adequately defend development of effector T-cells. Studies revealed that dextrose
against foreign invaders. Numerous studies have investigated the octreotide-induced PBMCs from healthy patients showed lower IL-17A
mechanisms related to diabetes that compromise the defense mecha and IL-6 mainly in the CD16 + and CD14 + intermediate monocytes
nism of the host against infections [180,181]. expression, indicating compromised immunological responses due to
the elevated level of blood glucose. The increased glycation caused the
5.4.2. Impairment of cytokine production inhibition of IL-10 secretion by myeloid cells. Production of TNF-α and
Monocytes and Peripheral blood mononuclear cells (PBMCs) in T1D IFN-γ was also reduced by T cells [182]. In comparison to normal mice,
& T2D patients release less IL1β than LPS controls after stimulation with mice with high-fat diet-induced hyperglycemia and
LPS [178]. When compared to healthy donors, T1D participants’ leptin-receptor-deficient had decreased levels of the cytokine IL-22.
Fig. (11). Diabetes mellitus effects on the immune system and its major associated complications.
16
Following infection with Burkholderia pseudomallei, PBMC cultures crosstalk between glial cells and pericytes is crucial for preserving a
from individuals with diabetes produced a decrease in levels of IFN and healthy vascular system in the eye and preventing complications asso
IL-12 compared to PBMCs from healthy donors. The administration of ciated with diabetic retinopathy [190].
recombinant IFN-γ and IL-12 significantly reduced bacterial load in Src, a crucial signaling protein, is regulated by other factors,
PBMCs from individuals with diabetes, indicating that the reduced including angiopoietin 1 (Ang1) and Ang2. Pericytes release Ang1,
production of IFN-γ and IL-12 in diabetes decreases the ability of im which binds to the Tie2 receptor on endothelial cells, triggering
mune cells to control bacterial growth during infection [183]. Therefore, signaling pathways that enhance intercellular interactions and
diabetic hyperglycemia is suggested responsible for inhibiting leuko strengthen cell-cell junctions. In contrast, Ang2 acts as an antagonist to
cytes and macrophage activity against infections [184]. Diabetic mice Ang1/Tie2 signaling, promoting increased permeability of the blood-
have decreased expression of some proteins involved in pathogen retina barrier. [191].
recognition like the Toll/IL-1R domain-containing adaptor protein Crosstalk between pericytes and endothelial cells is essential for a
(TIRAP) and Toll-like receptor (TLR)− 2 [185]. Several investigations healthy retinal vasculature. Circular RNAs, such as cPWWP2A and
have revealed that diabetic subjects’ neutrophils and monocytes have cZNF532, have been identified as mediators of this crosstalk. They
higher TLR expression [178]. TLR expression increased in patients with regulate the expression of target microRNAs, Subsequently, these in
well-managed hyperglycemia but decreased in diabetic patients with teractions influence the expression of genes related to pericyte function
bad glycemic control besides other complications [186]. and vascularization. [192,193] as shown in Fig. (12).
Diabetic retinopathy is characterized by persistent inflammation,
5.5. Diabetic retinopathy marked by increased levels of oxidized lipoproteins, AGEs, and free
radicals. This ongoing inflammatory state significantly contributes to
Diabetic retinopathy is a major complication of diabetes, with the development of the condition. Proinflammatory cytokines like IL-6,
approximately 20% of patients at the time of diabetes diagnosis and IL-17A, IL-1β, TNFα, and MCP-1 play a crucial role in the pathogenesis of
approximately 40–45% during the disease. This condition is marked by diabetic retinopathy, leading to harmful effects such as vascular leakage,
the dysfunction of two key cell types present in the retina: endothelial apoptosis of endothelial cells, and capillary degeneration. Another
cells, responsible for forming blood vessels in the retinal microvascu contributing factor is Prostaglandin E2 and its receptor EP2, which
lature, and pericytes, which offer support and regulate the activities of induce the expression of IL-1β and NLRP3 signaling in diabetic reti
the endothelial cells. [187]. nopathy, further intensifying the inflammatory response and disease
Hyperglycemia, the presence of harmful substances like advanced progression. In summary, chronic inflammation and the involvement of
glycation end products (AGEs), and oxidative stress collectively various inflammatory molecules play a central role in the development
contribute to the disruption of tight junctions between endothelial cells and advancement of diabetic retinopathy, causing damage to the retinal
in the retina’s blood vessels. Consequently, pericytes, which support and vasculature and contributing to vision-related complications.
regulate these endothelial cells, become detached and undergo cell [194–196].
death (apoptosis). This early loss of pericytes is a significant factor in Lipids are emerging as important signaling molecules that contribute
diabetic retinopathy, a condition that affects the eyes in people with to the progression of diabetic retinopathy. One example is ceramide 6,
diabetes. The detachment and apoptosis of pericytes result in increased which triggers the expression of regulation in development and DNA
permeability of the blood-retina barrier, allowing harmful substances to damage responses 1 (REDD1). REDD1, in turn, helps prevent apoptosis
leak into the retina and contributing to the progression of the disease. by interfering with the function of JNK, a protein involved in cell death
Therefore, targeting pericytes for early interventions becomes crucial in pathways. Certain lipids, such as eicosapentaenoic acid (EPA), and do
preventing the advancement of diabetic retinopathy. [187,188]. cosahexaenoic acid (DHA) appear to have protective roles in diabetic
Various signaling pathways contribute to the loss of pericytes in retinopathy. These lipids may offer beneficial effects in mitigating the
diabetic retinopathy, and these pathways include Notch 1, Notch 3, disease’s progression and related complications. On the other hand,
hypoxia-inducible factor 1 alpha (HIF1α), and vascular endothelial some lipids can worsen the advancement of diabetic retinopathy. For
growth factor-1 (VEGF-1). VEGF-1 signaling plays a major role in the instance, 12-hydroxyeicosatrienoic acids (12-HETE) and 15S-HETE have
advancement of diabetic retinopathy by promoting abnormal and demonstrated that these factors worsen the progression of the disease.
disorganized growth of new blood vessels (neovascularization) from likely by promoting inflammatory processes and other detrimental ef
endothelial cells. While therapies targeting VEGF-1 have been effective fects on the retinal vasculature. The intricate interplay of these lipids as
in inhibiting the advancement of diabetic retinopathy, individual pa secondary messengers in diabetic retinopathy underscores the impor
tient responses to these treatments vary. Recent research indicates that tance of lipid metabolism in the disease’s pathogenesis and suggests
the levels of Semaphorin 4d (Sema4d) in body fluids can serve as a potential therapeutic targets for managing the condition effectively.
predictive biomarker for how patients will respond to anti-VEGF-1 [197].
therapy. Higher levels of Sema4d are associated with a poorer Dipeptidyl peptidase 4 inhibitors (DPP4i), mainly used to treat T2D,
response to anti-VEGF-1 treatment. Moreover, Sema4d itself plays a have been employed to treat diabetic retinopathy. However, their effects
significant role in the progression of diabetic retinopathy. Combining vary depending on the specific inhibitor used. For example, linagliptin
therapies that target both VEGF-1 and Sema4d may offer a more effec shows GLP1R-independent anti-angiogenic effects mediated by the
tive approach compared to using anti-VEGF-1 treatment alone. decrease of VEGFR signaling. Elevated levels of DPP4i can lead to
Addressing both these factors simultaneously could lead to better aggravated permeability and promote a proangiogenic response in dia
treatment outcomes for diabetic retinopathy patients. [189,190]. betic retinopathy [198].
Effective communication between pericytes and retinal glial cells is Overall, understanding the complex cellular and molecular mecha
vital for the proper function of blood vessels in the eye. This commu nisms involved in diabetic retinopathy opens possibilities for developing
nication involves the release of a membrane-bound protein called targeted interventions to prevent and treat this condition.
Sema4d by retinal glial cells. Once released, Sema4d triggers signaling
pathways in both pericytes and endothelial cells. As a result of this 5.6. Diabetic neuropathy
signaling, the vascular endothelial cadherin (VE-Cadherin), which helps
maintain tight junctions between cells, undergoes internalization and Diabetic neuropathy, a more common complication in approxi
phosphorylation. This process weakens the tight junctions between cells mately half of diabetic patients, affects both the autonomic and pe
and contributes to increased vascular permeability, leading to the ripheral nervous systems. It mainly affects the sensory nerve endings in
leakage of blood vessels in diabetic retinopathy. Maintaining the the hands and lower limbs, causing a range of symptoms like pain,
17
Fig. (12). Mechanisms of pericyte detachment and tight junction disruption in diabetic retinopathy [109].
burning sensations, tingling, and numbness. As the condition advances, diabetic neuropathy have links to genetic factors, particularly specific
it can also involve the motor nerve endings in the lower extremities, variations in genes related to inflammation and lipid metabolism. Some
leading to problems with balance and a loss of sensation in the feet. of these genes include APOE, NF-κB, nitric oxide synthase 3 (NOS3),
Moreover, diabetic neuropathy can also appear proximally in regions SREBP-1, Toll-like receptor 2 (TLR2), and TLR4. These genetic poly
such as the thighs or pelvic area, following a pattern of spreading from morphisms are associated with the improvement of T2D and diabetic
the more central parts of the body to the outermost areas. primarily neuropathy. Activation of Toll-like receptor 4 (TLR4) sets off a series of
impacts the sensory nerve endings in the hands and lower limbs, signaling processes that result in an increased production and release of
resulting in symptoms such as pain, burning, tingling, and numbness. As TNFα, which contributes to neuroinflammation. Inhibiting Notch1 or
the condition advances, motor nerve endings in the lower extremities TLR4 has been found to reduce TNFα levels, which in turn helps alleviate
can also be affected, leading to balance issues and loss of sensation in the mechanical allodynia (pain from non-painful stimuli) and improve
feet. Additionally, diabetic neuropathy can manifest proximally in re thermal hyperalgesia thresholds (increased sensitivity to heat). This
gions such as the thigh or pelvic area, following a pattern from proximal suggests that targeting these pathways could be a potential approach for
to distal [199,200]. managing pain and inflammation associated with diabetic neuropathy
The development of diabetic neuropathy is associated with the [204–207].
activation of the polyol pathway in diabetes, resulting in the accumu Both insulin deficiency and resistance in sensory nerves are believed
lation of substances such as methylglyoxal (MG) and advanced glycation to be significant contributors to the development of diabetic neuropa
end products (AGEs), which impair nerve function. MG specifically thy. Insulin plays a crucial role as a neurotrophic hormone, essential for
targets the voltage-gated sodium channel Na(v)1.8, leading to increased maintaining normal nerve function. In diabetes, insufficient insulin
pain sensitivity, or hyperalgesia, in individuals with diabetes. Na(v)1.8 signaling can lead to various issues, such as reduced nerve regeneration
is involved in heightening pain perception. cAMP and PKA are other capacity, impaired neurochemical synthesis, and mitochondrial
regulators of Na(v)1.8 that also elevate the levels of hyperpolarization- dysfunction. These factors collectively contribute to the development
activated cyclic nucleotide-gated 2 (HCN2) ion channels in nerve fibers and progression of diabetic neuropathy. Hyperglycemia in diabetes also
responsible for pain sensing. In mouse models of diabetic neuropathy, impacts Schwann cells, responsible for supporting and surrounding
the hyperactivation of HCN2 in Na(v)1.8-positive neurons is linked to sensory axons in the peripheral nervous system. This Schwann cell
pain, and inhibiting HCN2 has shown pain-relieving effects in both T1D dysfunction results in disrupted myelin, compromised axon conduction,
and T2D models. Diabetic neuropathy is also associated with mechanical and impaired nerve regeneration, further exacerbating diabetic neu
allodynia, where normally non-painful stimuli trigger pain. Recent ropathy. Several molecular targets, such as MAPK, p75 neurotrophin
research indicates that the CXCL12/CXCR4 signaling axis may play a receptor (NTR), neurotrophic factor-3 (NT-3), and β-nerve growth factor
significant role in the initiation of mechanical allodynia in diabetic (NGF), are deregulated due to this Schwann cell dysfunction, adding to
neuropathy. Additionally, MG modification of the ligand-gated ion the pathophysiology of diabetic neuropathy [208,209] as shown in
channel TRPA1 contributes to increased pain hypersensitivity in dia Fig. (13).
betic neuropathy. [201–203].
Neuronal oxidative/nitrosative stress triggers the stimulation of
pathways like nuclear factor "kappa-light-chain-enhancer" of activated 5.7. Other complications in DM
B-cells (NFκB), MAPK, and JNK promoting inflammation and cytokine
production that contribute to diabetic neuropathy. High-throughput In addition to the well-known complications mentioned earlier,
analyses have identified inflammation and lipid metabolism pathways, recent research suggests that individuals with diabetes may also develop
involving targets like PPARγ, Apolipoprotein E (ApoE), and leptin, as restrictive lung diseases, including lung fibrosis, although studies are
potentially critical in the development of this complication. T2D and needed to understand the underlying mechanisms [210]. Present find
ings indicate that elevated blood glucose levels and oxidative stress
18
Fig. (13). Mechanisms of hyperalgesia and mechanical allodynia in diabetic neuropathy: Insights into Notch, TLR4, cAMP/PKA signaling, and CXCL12/
CXCR4 pathways.
might have a role in causing DNA damage, which in turn contributes to 5.7.2. Type 1 diabetes and associated autoimmune conditions
the development of lung fibrosis in diabetes [211]. A protein called
RAGE, implicated in the repair of damaged DNA, is involved in this a) Coeliac disease: Coeliac disease is an autoimmune disorder in which
process. In animal studies, introducing a hyperactive form of RAGE the immune system reacts to gluten, a protein found in wheat, barley,
through a viral delivery system has shown promising results in reversing and rye. It is more common in individuals with T1D.
fibrosis in the kidneys and lungs of diabetic mice [212]. b) Rheumatoid arthritis: Rheumatoid arthritis is another autoimmune
Approximately 13–24% of individuals with diabetes suffer from disease that can co-occur with T1D. It primarily affects the joints and
different types of cognitive dysfunction, including dementia, reduced can cause inflammation and pain.
verbal memory, impaired attention, and deficits in executive func c) Addison’s disease: Addison’s disease is a rare autoimmune condition
tioning. One potential cause of impaired neural function in diabetes is that affects the adrenal glands, leading to a deficiency in hormones
insulin resistance within the brain. Besides insulin resistance, other like cortisol and aldosterone. It can coexist with T1D, as both are
factors like neuroinflammation, disrupted iron metabolism, and the autoimmune disorders.
accumulation of hyperphosphorylated tau protein, leading to protein d) Autoimmune thyroid disease: Autoimmune thyroid diseases, such as
buildup, may also play a role in cognitive dysfunction. Intriguingly, Hashimoto’s thyroiditis and Graves’ disease, involve the immune
there is a significant association between Alzheimer’s disease and T2D. system attacking the thyroid gland. These conditions are more
The two conditions appear to be connected, with individuals having common in individuals with T1D [219–221].
diabetes facing a higher risk of developing Alzheimer’s disease. These
findings suggest the existence of shared underlying mechanisms be It’s important to note that autoimmune diseases tend to share a
tween diabetes and Alzheimer’s, contributing to the cognitive deficits common underlying mechanism of the immune system mistakenly
observed in diabetic patients [213,214]. attacking the body’s tissues. This is why individuals with one autoim
mune condition may have a higher risk of developing another. Regular
5.7.1. Type 2 diabetes and conditions closely linked to it medical check-ups and monitoring are crucial for individuals with dia
betes to manage and address any associated conditions effectively.
a) Alzheimer’s disease: Some researchers refer to Alzheimer’s disease as
"type 3 diabetes" due to its close association with insulin resistance 6. Link to pathways and treatment options
and impaired glucose metabolism [215].
b) Polycystic ovary syndrome (PCOS): PCOS is a condition that affects Understanding the molecular pathways involved in diabetic com
women and is characterized by hormonal imbalances. It can impact plications is essential for developing targeted therapies. Some pathways
fertility and is closely linked with insulin resistance, often leading to that have shown potential in treatment are:
an increased risk of type 2 diabetes [216].
c) Cushing’s syndrome: Cushing’s syndrome is characterized by an • Inflammatory pathways:
excess production of the hormone cortisol. Elevated cortisol levels Targeting pro-inflammatory cytokines like TNF-α and IL-1β, using
can lead to insulin resistance, increasing the risk of type 2 diabetes drugs like Anakinra, Canakinumab, and Gevokizumab, can help
[217]. reduce inflammation and improve glycemic control.
d) Pancreatic cancer: There is a debated link between pancreatic cancer • Oxidative stress pathways:
and T2D. Some studies suggest that T2D may be both a consequence Antioxidant therapies that target ROS production and enhance
and a risk factor for pancreatic cancer, but the exact nature of this endogenous antioxidant defense, such as vitamin D analogs and
relationship is still being explored [218]. alpha-1 antitrypsin (AAT), may mitigate oxidative damage.
19
• Epigenetic pathways and metabolic memory: diagnostic tools can aid in identifying patients at risk of developing
Understanding the epigenetic changes involved in metabolic complications at an early stage, allowing for timely intervention.
memory can lead to novel therapies aimed at reversing or preventing f) Lifestyle interventions:
the long-term effects of hyperglycemia. While pharmacological treatments are essential, lifestyle modifi
• Personalized medicine: cations remain a cornerstone in diabetes management. Encouraging
Identifying genetic and phenotypic markers that predict an in a balanced diet, maintaining a healthy weight, and engaging in
dividual’s susceptibility to specific complications can guide person regular physical activity are beneficial for enhancing glycemic con
alized treatment strategies. trol and lowering the risk of complications.
• Lifestyle interventions: g) Combination therapies:
Encouraging lifestyle modifications, including healthy diet, exercise, Combining therapies that target different pathways implicated in
and weight management, remains fundamental in diabetes management diabetes and its complications may yield better outcomes than single-
and preventing complications. agent treatments. Combinations of anti-inflammatory agents, antioxi
Combining therapies that target multiple pathways, such as anti- dants, and drugs targeting metabolic pathways could have synergistic
inflammatory agents, antioxidants, and metabolic modulators, holds effects in reducing complications.
promise for reducing the burden of diabetic complications. Additionally,
advancements in diagnostics and early intervention can help detect CRediT authorship contribution statement
complications at an early stage and improve patient outcomes. Overall,
future research efforts should focus on developing personalized and Ahmed A. Al-Karmalawy: Conceptualization, Design, Construction
targeted treatments, leveraging advancements in diagnostics, and un of the conceptual framework of the review, Supervision. Samar A.
derstanding the intricate molecular pathways involved in diabetes and Antar, Nada A. Ashour, Marwa Sharaky, Muhammad Khattab,
its complications. This approach can pave the way for more effective Naira A. Ashour, Roaa T. Zaid, Ahmed A. Al-Karmalawy: Literature
management of diabetes and better outcomes for patients. search, Collection, Draft preparation. Samar A. Antar, Nada A.
Ashour, Ahmed A. Al-Karmalawy: Data interpretation. Samar A.
7. Conclusion and future perspectives Antar, Nada A. Ashour, Muhammad Khattab, Ahmed A. Al-Karma
lawy: Software. Eun Joo Roh, Ahmed Elkamhaw: Funding. Samar A.
DM is a complex metabolic disorder that affects multiple organ Antar, Nada A. Ashour, Marwa Sharaky, Muhammad Khattab,
systems and leads to various complications, including kidney disease, Naira A. Ashour, Roaa T. Zaid, Eun Joo Roh, Ahmed Elkamhaw,
cardiovascular disease, immune dysfunction, retinopathy, and neurop Ahmed A. Al-Karmalawy: Original draft writing. Nada A. Ashour,
athy. The knowledge of the underlying mechanisms and pathways Marwa Sharaky, Ahmed A. Al-Karmalawy: Review and editing of the
involved in these complications has opened new avenues for future manuscript. All authors have read and agreed to the submitted final
perspectives and potential treatments to inhibit the burden of diabetes version of the manuscript.
and its complications.
Declaration of Competing Interest

a) Targeting inflammation:
Inflammation plays a vital role in the development of diabetes and
We wish to confirm that there are no known conflicts of interest
its complications. Future research should focus on identifying spe
associated with this publication and there has been no significant
cific targets within the inflammatory pathways to develop more
financial support for this work that could have influenced its outcome.
effective anti-inflammatory therapies. Drugs that inhibit pro-
inflammatory cytokines, like TNF-α and IL-1β have shown promise
Data availability
in reducing inflammation and improving glycemic control in dia
betes patients.
No data was used for the research described in the article.
b) Oxidative stress and antioxidant therapies:
Oxidative stress is a main driver of diabetic complications. Future
studies should explore the potential of antioxidant therapies to Acknowledgments
decrease oxidative damage and inhibit or prevent the progression of
diabetic complications. Targeting pathways involved in reactive This research was supported by the National Research Council of
oxygen species (ROS) production and enhancing endogenous anti Science & Technology (NST) grant by the Korea government (MSIT) (No.
oxidant defense mechanisms could be beneficial. CAP23011–100), KIST Institutional programs (2E32333) from the KIST
c) Metabolic memory: and 2ME1650 from KDDF. Ahmed Elkamhawy extends his appreciation
Metabolic memory, where previous episodes of hyperglycemia to KIST for supporting this work through “2022 KIST School Partnership
have long-lasting effects on complications even with subsequent project” and in the accomplishment of this project, he would like to
glycemic control, requires further investigation. Understanding the thank the Technology Innovation Commercial Office (TICO) at Man
underlying epigenetic and cellular changes involved in metabolic soura University for their highly effective contribution.
memory can provide insights into novel therapeutic strategies to
mitigate complications. References
d) Personalized medicine:
1) A. Poznyak, A.V. Grechko, P. Poggio, V.A. Myasoedova, V. Alfieri, A.N. Orekhov,
Each individual’s response to diabetes and its treatments can vary. The diabetes mellitus–atherosclerosis connection: The role of lipid and glucose
Personalized medicine, based on genetic, epigenetic, and phenotypic metabolism and chronic inflammation, Int. J. Mol. Sci. 21 (5) (2020) 1835,
characteristics, holds great potential for tailoring treatment strate https://doi.org/10.3390/ijms21051835.
2) M.C. Rossi, A. Nicolucci, A. Ozzello, S. Gentile, A. Aglialoro, A. Chiambretti,
gies to individual patients. Precision medicine can help identify pa
F. Baccetti, F.M. Gentile, F. Romeo, G. Lucisano, Impact of severe and symptomatic
tients at higher risk of specific complications and target treatments hypoglycemia on quality of life and fear of hypoglycemia in type 1 and type 2
accordingly. diabetes. Results of the Hypos-1 observational study, Nutr., Metab. Cardiovasc.
e) Advancements in diagnostics: Dis. 29 (7) (2019) 736–743, https://doi.org/10.1016/j.numecd.2019.04.009.
3) WHO, Diabetes, 2019.
Early detection of diabetes and its complications is crucial for N.A. ElSayed, G. Aleppo, V.R. Aroda, R.R. Bannuru, F.M. Brown, D. Bruemmer, B.
effective management. Developing more sensitive and specific S. Collins, J.L. Gaglia, M.E. Hilliard, D. Isaacs, E.L. Johnson, 2. Classification and
20
diagnosis of diabetes: standards of care in diabetes—2023, Diabetes care 46 30) A.T. Kharroubi, Diabetes mellitus: The epidemic of the century, H. M. J. W. J. o. D.
(Supplement_1) (2023) S19–S40. Darwish 6 (6) (2015) 850, https://doi.org/10.4239/wjd.v6.i6.850.
5) L. Kahanovitz, P.M. Sluss, S.J.J.Poc Russell, Type 1 diabetes–a clinical perspective American Diabetes Association, 2021. 2. Classification and diagnosis of diabetes:
16 (1) (2017) 37, https://doi.org/10.1097%2FPOC.0000000000000125. standards of medical care in diabetes—2021. Diabetes care, 44(Supplement_1), pp.
S. Merger, R.D. Leslie, B.O. Boehm, The broad clinical phenotype of Type 1 diabetes at S15-S33.
presentation, Diabetic Medicine 30 (2) (2013) 170–178. N. Xu, H. Wu, D. Li, J.J.Dr Wang, c practice, Diagnostic accuracy of glycated hemoglobin
7) A. Imagawa, T.J.Ej Hanafusa, Fulminant type 1 diabetes mellitus 53 (5) (2006) compared with oral glucose tolerance test for diagnosing diabetes mellitus in
577–584, https://doi.org/10.1507/endocrj.KR-72. Chinese adults: a meta-analysis, 106(1), 2014: 11–18. https://doi.org/10.1016/j.
8) A. Imagawa, T.J.Dmr Hanafusa, Fulminant type 1 diabetes—an important subtype diabres.2014.04.010.
in East Asia, reviews 27 (8) (2011) 959–964, https://doi.org/10.1002/dmrr.1236. S. Sivaprasad, B. Gupta, M.C. Gulliford, H. Dodhia, M. Mohamed, D. Nagi, J.R.J.Po
9) U. Galicia-Garcia, A. Benito-Vicente, S. Jebari, A. Larrea-Sebal, H. Siddiqi, K. Evans, Ethnic variations in the prevalence of diabetic retinopathy in people with
B. Uribe, H. Ostolaza, C.J.Ijoms Martín, Pathophysiology of type 2 diabetes diabetes attending screening in the United Kingdom (DRIVE UK), 7(3), 2012:
mellitus 21 (17) (2020) 6275, https://doi.org/10.3390/ijms21176275. e32182. https://doi.org/10.1371/journal.pone.0032182.
10) Q. Dufurrena, F.M. Amjad, P.E. Scherer, L.M. Weiss, J. Nagajyothi, J. Roth, H. T. Grant, Y. Soriano, P.R. Marantz, I. Nelson, E. Williams, D. Ramirez, J. Burg, C.J.Ajopm
B. Tanowitz, R.J.Pr Kuliawat, Alterations in pancreatic β cell function and Nordin, Community-based screening for cardiovascular disease and diabetes using
Trypanosoma cruzi infection: evidence from human and animal studies 116 (3) HbA1c, 26(4), 2004: 271–275. https://doi.org/10.1016/j.amepre.2003.12.015.
(2017) 827–838, https://doi.org/10.1007/s00436-016-5350-5. 35) M.G. Bonini, R.M. Sargis, Environmental toxicant exposures and type 2 diabetes
11) C. Wysham, J.J.P.M. Shubrook, Beta-cell failure in type 2 diabetes: mechanisms, mellitus: two interrelated public health problems on the rise, Curr. Opin. Toxicol. 7
markers, and clinical implications 132 (8) (2020) 676–686, https://doi.org/ (2018) 52–59, https://doi.org/10.1016/j.cotox.2017.09.003.
10.1080/00325481.2020.1771047. 36) B. Mlinar, J. Marc, A. Janež, M. Pfeifer, Molecular mechanisms of insulin
12) M.L. Geurtsen, E.E. van Soest, E. Voerman, E.A. Steegers, V.W. Jaddoe, R.J. resistance and associated diseases, Clin. Chim. Acta 375 (1–2) (2007) 20–35,
D. Gaillard, High maternal early-pregnancy blood glucose levels are associated https://doi.org/10.1016/j.cca.2006.07.005.
with altered fetal growth and increased risk of adverse birth outcomes 62 (10) 37) A.K. Sikalidis, A.J.B. Maykish, The gut microbiome and type 2 diabetes mellitus:
(2019) 1880–1890, https://doi.org/10.1007/s00125-019-4957-3. discussing a complex relationship 8 (1) (2020) 8, https://doi.org/10.3390/
13) M.H. Hollander, K.M. Paarlberg, A.J.J.O. Huisjes, Gestational diabetes: a review of biomedicines8010008.
the current literature and guidelines, G. Surv. 62 (2) (2007) 125–136, https://doi. 38) Y.T. Eloutify, R.A. El-Shiekh, K.M. Ibrahim, A.R. Hamed, A.A. Al-Karmalawy, A.
org/10.1097/01.ogx.0000253303.92229.59. A. Shokry, Y.H. Ahmed, B. Avula, K. Katragunta, I.A. Khan, M.R. Meselhy,
14) J.F. Plows, J.L. Stanley, P.N. Baker, C.M. Reynolds, M.H.J.Ijoms Vickers, The Bioactive fraction from Plumeria obtusa L. attenuates LPS-induced acute lung
pathophysiology of gestational diabetes mellitus 19 (11) (2018) 3342, https://doi. injury in mice and inflammation in RAW 264.7 macrophages: LC/QToF-MS and
org/10.3390/ijms19113342. molecular docking, Inflammopharmacology (2023), https://doi.org/10.1007/
15) C.F. Chukwunyere, D.O. Awonuga, O.F. Adesina, I.C.J.D. Udenze, Gestational s10787-023-01144-w.
diabetes: Comparison of random and fasting plasma glucose as modalities of 39) S. Antar, A.A. Al-Karmalawy, A. Mourad, M. Mourad, M. Elbadry, S. Saber,
screening, 2020. https://www.emjreviews.com/wp-content/uploads/2020/11/ A. Khodir, Protective effects of mirazid on gentamicin-induced nephrotoxicity in
Gestational-Diabetes-Comparison-of-Random-and-Fasting-Plasma-Glucose-as- rats through antioxidant, anti-inflammatory, JNK1/iNOS, and apoptotic pathways;
Modalities-of-Screening.pdf. novel mechanistic insights, Pharm. Sci. (2022), https://doi.org/10.34172/
16) T. Reinehr, E. Schober, S. Wiegand, A. Thon, R. Holl, β-cell autoantibodies in PS.2022.4.
children with type 2 diabetes mellitus: subgroup or misclassification? Arch. Dis. 40) M.A. Atkinson, G.S. Eisenbarth, A.W. Michels, Type 1 diabetes, Lancet 383 (9911)
Child. 91 (6) (2006) 473–477, https://doi.org/10.1136/adc.2005.088229. (2014) 69–82, https://doi.org/10.1016/s0140-6736(13)60591-7.
17) G.M. Williams, A.E. Long, I.V. Wilson, R.J. Aitken, R.C. Wyatt, T.J. McDonald, F. 41) M.A. Atkinson, J.A. Bluestone, G.S. Eisenbarth, M. Hebrok, K.C. Herold, D. Accili,
S. Wong, A.T. Hattersley, A.J. Williams, P.J. Bingley, Beta cell function and M. Pietropaolo, P.R. Arvan, M. Von Herrath, D.S. Markel, How does type 1 diabetes
ongoing autoimmunity in long-standing, childhood onset type 1 diabetes, develop? Notion Homicide Or. β-Cell Suicide Revisit., Diabetes 60 (5) (2011)
Diabetologia 59 (2016) 2722–2726, https://doi.org/10.1007/s00125-016-4087-0. 1370–1379, https://doi.org/10.2337/db10-1797.
18) F. Mauvais-Jarvis, E. Sobngwi, R. Porcher, J.-P. Riveline, J.-P. Kevorkian, 42) G. Bottazzo, A. Florin-Christensen, D. Doniach, Islet-cell antibodies in diabetes
C. Vaisse, G. Charpentier, P.-J. Guillausseau, P. Vexiau, J.-F. Gautier, Ketosis-prone mellitus with autoimmune polyendocrine deficiencies, Lancet 304 (7892) (1974)
type 2 diabetes in patients of sub-Saharan African origin: clinical pathophysiology 1279–1283, https://doi.org/10.4049/jimmunol.1701303.
and natural history of β-cell dysfunction and insulin resistance, Diabetes 53 (3) 43) M.A. Atkinson, G.S. Eisenbarth, Type 1 diabetes: new perspectives on disease
(2004) 645–653, https://doi.org/10.2337/diabetes.53.3.645. pathogenesis and treatment, Lancet 358 (9277) (2001) 221–229, https://doi.org/
19) C.C. Thomas, L.H. Philipson, Update on diabetes classification, Med. Clin. 99 (1) 10.1016/s0140-6736(01)05415-0.
(2015) 1–16, https://doi.org/10.1016/j.mcna.2014.08.015. 44) H.D. Shin, B.L. Park, L.H. Kim, H.S. Jung, Y.M. Cho, M.K. Moon, Y.J. Park, H.
20) A.D. Association, Diagnosis and classification of diabetes mellitus. Diabetes Care K. Lee, K.S. Park, Genetic polymorphisms in peroxisome proliferator-activated
2010; 33 (Suppl. 1): S62-S69, Erratum in: Diabetes Care 33, 2010: e57. https://doi. receptor δ associated with obesity, Diabetes 53 (3) (2004) 847–851, https://doi.
org/10.2337/dc10-S062. org/10.2337/diabetes.53.3.847.
21) A.A. Kazi, L. Blonde, Classification of diabetes mellitus, Clin. Lab. Med. 21 (1) 45) M. La Noce, G.F. Nicoletti, G. Papaccio, V. Del Vecchio, F.J.C. Papaccio, Insulitis in
(2001) 1–13, https://doi.org/10.1002/hep4.1105. Human Type 1 Diabetic Pancreas: From Stem Cell Grafting to Islet Organoids for a
22) E.D. Rosenstein, S. Advani, R.E. Reitz, N. Kramer, The prevalence of insulin Successful Cell-Based Therapy 11 (23) (2022) 3941, https://doi.org/10.3390/
receptor antibodies in patients with systemic lupus erythematosus and related cells11233941.
conditions, JCR: J. Clin. Rheumatol. 7 (6) (2001) 371–373, https://doi.org/ 46) A.Z. Valdes, Immunological tolerance and autoimmunity. Translational
10.1097/00124743-200112000-00004. Autoimmunity, Elsevier,, 2022, pp. 325–345, https://doi.org/10.1007/
23) E. Ahlqvist, R.B. Prasad, L. Groop, Subtypes of Type 2 Diabetes Determined From bf02934736.
Clinical Parameters, Diabetes 69 (10) (2020) 2086–2093, https://doi.org/ C.P. Martins, L.A. New, E.C. O’Connor, D.M. Previte, K.R. Cargill, I.L. Tse, S. Sims-Lucas,
10.2337/dbi20-0001. J.D. Piganelli, Glycolysis inhibition induces functional and metabolic exhaustion of
24) A. Sarría-Santamera, B. Orazumbekova, T. Maulenkul, A. Gaipov, K. Atageldiyeva, CD4+ T cells in type 1 diabetes, Frontiers in immunology 12 (2021) 669456.
The identification of diabetes mellitus subtypes applying cluster analysis 48) S.A. Antar, N.A. Ashour, M.E. Marawan, A.A. Al-Karmalawy, Fibrosis: Types,
techniques: a systematic review, Int. J. Environ. Res. Public Health 17 (24) (2020) Effects, Markers, Mechanisms for Disease Progression, and Its Relation with
9523, https://doi.org/10.3390/ijerph17249523. Oxidative Stress, Immunity, and Inflammation, Int. J. Mol. Sci. 24 (4) (2023) 4004,
25) N. Omar, N.N. Nazirun, B. Vijayam, A.A. Wahab, H.A. Bahuri, Diabetes subtypes https://doi.org/10.3390/ijms24044004.
classification for personalized health care: A review, Artif. Intell. Rev. 56 (3) 49) A.A. Alzokaky, A.A. Al-Karmalawy, M.A. Saleh, W. Abdo, A.E. Farage, A. Belal, M.
(2023) 2697–2721, https://doi.org/10.1007/s10462-022-10202-8. A.S. Abourehab, S.A. Antar, Metformin ameliorates doxorubicin induced
26) S.B. Zaghlool, A. Halama, N. Stephan, V. Gudmundsdottir, V. Gudnason, L. cardiotoxicity targeting HMGB1/TLR4/NLRP3 signaling pathway in mice, Life Sci.
L. Jennings, M. Thangam, E. Ahlqvist, R.A. Malik, O.M.E. Albagha, A. (2023), 121390, https://doi.org/10.1016/j.lfs.2023.121390.
B. Abou‑Samra, K. Suhre, Metabolic and proteomic signatures of type 2 diabetes A. Giovenzana, D. Carnovale, B. Phillips, A. Petrelli, N. Giannoukakis, Neutrophils and
subtypes in an Arab population, Nat. Commun. 13 (1) (2022), 7121, https://doi. their role in the aetiopathogenesis of type 1 and type 2 diabetes, Diabetes/
org/10.1038/s41467-022-34754-z. Metabolism Research and Reviews 38 (1) (2022), e3483.
27) D.M. Aly, O.P. Dwivedi, R.B. Prasad, A. Käräjämäki, R. Hjort, M. Åkerlund, 51) Y. Yang, J. Day, F. Souza-Fonseca Guimaraes, I.P. Wicks, C.J.C. Louis,
A. Mahajan, M.S. Udler, J.C. Florez, M.I. McCarthy, R.G. Center, J. Brosnan, T. Immunology, Nat. Kill. Cells Inflamm. autoimmune Dis. 10 (2) (2021), e1250,
O. Melander, S. Carlsson, O. Hansson, T. Tuomi, L. Groop, E. Ahlqvist, Aetiological https://doi.org/10.1002/cti2.1250.
differences between novel subtypes of diabetes derived from genetic associations, 52) M.K. ElMahdy, M.O. Zaki, A.A. Al-Karmalawy, W. Abdo, S.M. Alnasser, S.A. Antar,
2020.09.29.20203935, medRxiv (2020), https://doi.org/10.1101/ Glimepiride ameliorates renal toxicity induced by cadmium in mice: Modulation of
2020.09.29.20203935. Jun N terminal kinase (JNK)/nuclear factor kappa B (NF-κB) and
28) T. Nakagami, M. Tominaga, R. Nishimura, N. Yoshiike, M. Daimon, T. Oizumi, N.J. phosphatidylinositol 3-kinases (PI3K)/protein kinase (AKT) pathways, Life Sci.
Dr Tajima, c practice, globin A1c alone an efficient screening test for undiagnosed (2022), 121184, https://doi.org/10.1016/j.lfs.2022.121184.
diabetes? Jpn. Is. Meas. glycated hemoNational Diabetes Surv. 76 (2) (2007) C.L. Yang, F. Sun, F.X. Wang, S.J. Rong, T.T. Yue, J.H. Luo, Q. Zhou, C.Y. Wang, S.W. Liu,
251–256, https://doi.org/10.1016/j.diabres.2006.09.015. The interferon regulatory factors, a double-edged sword, in the pathogenesis of type
S. Genuth, K.G.M.M. Alberti, P. Bennett, J. Buse, R. DeFronzo, R. Kahn, J. Kitzmiller, W. 1 diabetes, Cellular Immunology (2022) 104590.
C. Knowler, H. Lebovitz, A. Lernmark, D. Nathan, Follow-up report on the diagnosis 54) S.A. Antar, M.A. Saleh, A.A. Al-Karmalawy, Investigating the possible mechanisms
of diabetes mellitus, Diabetes care 26 (11) (2003) 3160–3167. of pirfenidone to be targeted as a promising anti-inflammatory, anti-fibrotic, anti-
21
oxidant, anti-apoptotic, anti-tumor, and/or anti-SARS-CoV-2, Life Sci. 309 (2022), 75) B.B. Duncan, M.I. Schmidt, Chronic activation of the innate immune system may
121048, https://doi.org/10.1016/j.lfs.2022.121048. underlie the metabolic syndrome, Sao Paulo Med. J. 119 (2001) 122–127, https://
55) J. Yu, M. Li, D. Zhan, C. Shi, L. Fang, C. Ban, W. Zheng, V. Veeraraghavan, S. doi.org/10.1590/s1516-31802001000300008.
Mohan, X.J.P.M. Tang, Inhibitory effects of triterpenoid betulin on inflammatory 76) F.B. Hu, J.B. Meigs, T.Y. Li, N. Rifai, J.E. Manson, Inflammatory markers and risk
mediators inducible nitric oxide synthase, cyclooxygenase-2, tumor necrosis of developing type 2 diabetes in women, Diabetes 53 (3) (2004) 693–700, https://
factor-alpha, interleukin-6, and proliferating cell nuclear antigen in 1, 2-dimeth doi.org/10.2337/diabetes.53.3.693.
ylhydrazine-induced rat colon carcinogenesis, 16(72) (2020). https://go.gale. 77) K. Ueki, T. Kadowaki, C.R. Kahn, Role of suppressors of cytokine signaling SOCS-1
com/ps/i.do?p=AONE&u=googlescholar&id=GALE| and SOCS-3 in hepatic steatosis and the metabolic syndrome, Hepatol. Res. 33 (2)
A652828218&v=2.1&it=r&sid=googleScholar&asid=0a1aef72. (2005) 185–192, https://doi.org/10.1016/j.hepres.2005.09.032.
J. Yong, J.D. Johnson, P. Arvan, J. Han, R.J. Kaufman, Therapeutic opportunities for 78) W. Aldhahi, O. Hamdy, Adipokines, inflammation, and the endothelium in
pancreatic β-cell ER stress in diabetes mellitus, Nature Reviews Endocrinology 17 (8) diabetes, Curr. Diabetes Rep. 3 (4) (2003) 293–298, https://doi.org/10.1007/
(2021) 455–467. s11892-003-0020-2.
S. Ly, D. Nedosekin, H.K. Wong, Review of an anti-CD20 monoclonal antibody for the 79) K.K. Koh, S.H. Han, M.J. Quon, Inflammatory markers and the metabolic
treatment of autoimmune diseases of the skin, American journal of clinical syndrome: insights from therapeutic interventions, J. Am. Coll. Cardiol. 46 (11)
dermatology 24 (2) (2023) 247–273. (2005) 1978–1985, https://doi.org/10.1016/j.jacc.2005.06.082.
58) M.I. Schmidt, B.B. Duncan, Diabesity: Inflamm. Metab. Cond. (2003), https://doi. 80) A. Chen, S. Mumick, C. Zhang, J. Lamb, H. Dai, D. Weingarth, J. Mudgett, H. Chen,
org/10.1515/cclm.2003.174. D.J. MacNeil, M.L. Reitman, Diet induction of monocyte chemoattractant protein-1
59) K. Alexandraki, C. Piperi, C. Kalofoutis, J. Singh, A. Alaveras, A. Kalofoutis, and its impact on obesity, Obes. Res. 13 (8) (2005) 1311–1320, https://doi.org/
Inflammatory process in type 2 diabetes: The role of cytokines, Ann. N. Y. Acad. 10.1038/oby.2005.159.
Sci. 1084 (1) (2006) 89–117, https://doi.org/10.1196/annals.1372.039. 81) K. Maedler, P. Sergeev, F. Ris, J. Oberholzer, H.I. Joller-Jemelka, G.A. Spinas,
C. Mignogna, E. Maddaloni, L. D’Onofrio, R. Buzzetti, Investigational therapies targeting N. Kaiser, P.A. Halban, M.Y. Donath, Glucose-induced β cell production of IL-1β
CD3 for prevention and treatment of type 1 diabetes, Expert Opinion on contributes to glucotoxicity in human pancreatic islets, J. Clin. Investig. 110 (6)
Investigational Drugs 30 (12) (2021) 1209–1219. (2002) 851–860, https://doi.org/10.1172/jci15318.
61) S. Tsalamandris, A.S. Antonopoulos, E. Oikonomou, G.-A. Papamikroulis, 82) H. Chen, M. Montagnani, T. Funahashi, I. Shimomura, M.J. Quon, Adiponectin
G. Vogiatzi, S. Papaioannou, S. Deftereos, D.J.Ecr Tousoulis, The role of stimulates production of nitric oxide in vascular endothelial cells, J. Biol. Chem.
inflammation in diabetes: current concepts and future perspectives 14 (1) (2019) 278 (45) (2003) 45021–45026, https://doi.org/10.1074/jbc.m307878200.
50, https://doi.org/10.15420/ecr.2018.33.1. 83) O. Ukkola, M. Santaniemi, Adiponectin: a link between excess adiposity and
62) M.D. Pescovitz, C.J. Greenbaum, H. Krause-Steinrauf, D.J. Becker, S.E. Gitelman, associated comorbidities? J. Mol. Med. 80 (2002) 696–702, https://doi.org/
R. Goland, P.A. Gottlieb, J.B. Marks, P.F. McGee, A.M. Moran, Rituximab, B- 10.1007/s00109-002-0378-7.
lymphocyte depletion, and preservation of beta-cell function, N. Engl. J. Med. 361 84) C.M. Steppan, J. Wang, E.L. Whiteman, M.J. Birnbaum, M.A. Lazar, Activation of
(22) (2009) 2143–2152, https://doi.org/10.1056/nejmoa0904452. SOCS-3 by resistin, Mol. Cell. Biol. 25 (4) (2005) 1569–1575, https://doi.org/
S.S. Park, R. Rodriguez Ortega, C.W. Agudelo, J. Perez Perez, B. Perez Gandara, I. Garcia- 10.1128/mcb.25.4.1569-1575.2005.
Arcos, C. McCarthy, P.J.M. Geraghty, Therapeutic potential of alpha-1 antitrypsin in 85) C.M. Steppan, S.T. Bailey, S. Bhat, E.J. Brown, R.R. Banerjee, C.M. Wright, H.
Type 1 and Type 2 diabetes mellitus, 57(4), 2021: 397. https://doi.org/10.3390/ R. Patel, R.S. Ahima, M.A. Lazar, The hormone resistin links obesity to diabetes,
medicina57040397. Nature 409 (6818) (2001) 307–312, https://doi.org/10.1038/35053000.
64) M.D. Pescovitz, C.J. Greenbaum, B. Bundy, D.J. Becker, S.E. Gitelman, R. Goland, 86) U. Scho¨nbeck, P. Libby, CD40 signaling and plaque instability, Circ. Res. 89 (12)
P.A. Gottlieb, J.B. Marks, A. Moran, P. Raskin, B-lymphocyte depletion with (2001) 1092–1103, https://doi.org/10.1161/hh2401.101272.
rituximab and β-cell function: two-year results, Diabetes care 37 (2) (2014) 87) M. Kong, K. Xie, M. Lv, J. Li, J. Yao, K. Yan, X. Wu, Y. Xu, D.J.B. Ye, Anti-
453–459, https://doi.org/10.2337/dc13-0626. inflammatory phytochemicals for the treatment of diabetes and its complications:
65) M. Berretta, V. Quagliariello, A. Bignucolo, S. Facchini, N. Maurea, R. Di Francia, Lessons learned and future promise, Pharmacotherapy 133 (2021), 110975,
F. Fiorica, S. Sharifi, S. Bressan, S.N.J.A. Richter, Mult. Eff. Vitam. D. Chronic Dis.: https://doi.org/10.1016/j.biopha.2020.110975.
Reduct. Lipid Peroxidation Update Evid. Clin. Stud. 11 (6) (2022) 1090, https:// 88) N. Roshanravan, A.N. Shabestari, N.M. Alamdari, A. Ostadrahimi, A. Separham,
doi.org/10.3390/antiox11061090. R. Parvizi, M.A. Jafarabadi, M. Ghodrat, M. Akbarzadeh, M.J.C. Naemi, A novel
66) A. Mohamed, A. Al-Karmalawy, A. El-Kholy, D. El-Damas, H. Abostate, S. Mostafa, inflammatory signaling pathway in patients with slow coronary flow: NF-κB/IL-
M. Hamada, M.K. Elkady, Y. Hassan, E. Al-Hussain, Effect of Vitamin D 1β/nitric oxide 143 (2021), 155511, https://doi.org/10.1016/j.cyto.2021.155511.
supplementation in patients with liver cirrhosis having spontaneous bacterial 89) D.M. Bannigida, B.S. Nayak, R.J.Aop Vijayaraghavan, Insulin resistance and
peritonitis: a randomized controlled study, Eur. Rev. Med. Pharmacol. Sci. 25 (22) oxidative marker in women with PCOS, biochemistry 126 (2) (2020) 183–186,
(2021) 6908–6919, https://doi.org/10.26355/eurrev_202111_27239. https://doi.org/10.1080/13813455.2018.1499120.
67) L. Mastrandrea, J. Yu, T. Behrens, J. Buchlis, C. Albini, S. Fourtner, T. Quattrin, 90) V.O. Gorbatenko, S.V. Goriainov, V.A. Babenko, E.Y. Plotnikov, M.G. Sergeeva, D.
Etanercept treatment in children with new-onset type 1 diabetes: pilot V.J.B. Chistyakov, Anti-Inflammatory Properties of Metformin During Cultivation
randomized, placebo-controlled, double-blind study, Diabetes care 32 (7) (2009) of Primary Rat Astrocytes in a Medium with High Glucose Concentration 87 (7)
1244–1249, https://doi.org/10.2337/dc09-0054. (2022) 577–589, https://doi.org/10.1134/s000629792207001x.
68) P.A. Gottlieb, A.K. Alkanani, A.W. Michels, E.C. Lewis, L. Shapiro, C.A. Dinarello, G.D. Lopaschuk, S. Verma, Mechanisms of cardiovascular benefits of sodium glucose co-
D. Zipris, α1-Antitrypsin therapy downregulates toll-like receptor-induced IL-1β transporter 2 (SGLT2) inhibitors: a state-of-the-art review, Basic to Translational
responses in monocytes and myeloid dendritic cells and may improve islet function Science 5 (6) (2020) 632–644.
in recently diagnosed patients with type 1 diabetes, J. Clin. Endocrinol. Metab. 99 92) P.C. van Poppel, E.J. van Asseldonk, J.J. Holst, T. Vilsbøll, M. Netea, C. Tack, The
(8) (2014) E1418–E1426, https://doi.org/10.1210/jc.2013-3864. interleukin-1 receptor antagonist anakinra improves first-phase insulin secretion
69) A. Ataie-Jafari, S.-C. Loke, A.B. Rahmat, B. Larijani, F. Abbasi, M.K. Leow, and insulinogenic index in subjects with impaired glucose tolerance, Diabetes,
Z. Yassin, A randomized placebo-controlled trial of alphacalcidol on the Obes. Metab. 16 (12) (2014) 1269–1273, https://doi.org/10.1111/dom.12357.
preservation of beta cell function in children with recent onset type 1 diabetes, 93) E.J. van Asseldonk, P.C. van Poppel, D.B. Ballak, R. Stienstra, M.G. Netea, C.
Clin. Nutr. 32 (6) (2013) 911–917, https://doi.org/10.1016/j.clnu.2013.01.012. J. Tack, One week treatment with the IL-1 receptor antagonist anakinra leads to a
70) B. Boucher, The effects of calcitriol and nicotinamide on residual pancreatic beta- sustained improvement in insulin sensitivity in insulin resistant patients with type
cell funtion in patients with recent-onset Type 1 diabetes (IMDIAB XI), author 1 diabetes mellitus, Clin. Immunol. 160 (2) (2015) 155–162, https://doi.org/
reply 219-20, Diabet. Med.: a J. Br. Diabet. Assoc. 24 (2) (2007) 219, https://doi. 10.1016/j.clim.2015.06.003.
org/10.1111/j.1464-5491.2007.2065_1.x. 94) C. Cavelti-Weder, A. Babians-Brunner, C. Keller, M.A. Stahel, M. Kurz-Levin,
71) M. Alhadj Ali, Y.-F. Liu, S. Arif, D. Tatovic, H. Shariff, V.B. Gibson, N. Yusuf, H. Zayed, A.M. Solinger, T. Mandrup-Poulsen, C.A. Dinarello, M.Y. Donath, Effects
R. Baptista, M. Eichmann, N. Petrov, Metabolic and immune effects of of gevokizumab on glycemia and inflammatory markers in type 2 diabetes,
immunotherapy with proinsulin peptide in human new-onset type 1 diabetes, Sci. Diabetes care 35 (8) (2012) 1654–1662, https://doi.org/10.2337/dc11-2219.
Transl. Med. 9 (402) (2017) eaaf7779, https://doi.org/10.1126/scitranslmed. 95) J. Hensen, C. Howard, V. Walter, T. Thuren, Impact of interleukin-1β antibody
aaf7779. (canakinumab) on glycaemic indicators in patients with type 2 diabetes mellitus:
72) B.O. Roep, N. Solvason, P.A. Gottlieb, J.R. Abreu, L.C. Harrison, G.S. Eisenbarth, results of secondary endpoints from a randomized, placebo-controlled trial,
L. Yu, M. Leviten, W.A. Hagopian, J.B. Buse, Plasmid-encoded proinsulin preserves Diabetes Metab. 39 (6) (2013) 524–531, https://doi.org/10.1016/j.
C-peptide while specifically reducing proinsulin-specific CD8+ T cells in type 1 diabet.2013.07.003.
diabetes, 191ra82-191ra82, Sci. Transl. Med. 5 (191) (2013), https://doi.org/ 96) B.M. Everett, M.Y. Donath, A.D. Pradhan, T. Thuren, P. Pais, J.C. Nicolau, R.
10.1126/scitranslmed.3006103. J. Glynn, P. Libby, P.M. Ridker, Anti-inflammatory therapy with canakinumab for
73) M.J. Haller, D.A. Schatz, J.S. Skyler, J.P. Krischer, B.N. Bundy, J.L. Miller, M. the prevention and management of diabetes, J. Am. Coll. Cardiol. 71 (21) (2018)
A. Atkinson, D.J. Becker, D. Baidal, L.A. DiMeglio, Low-dose anti-thymocyte 2392–2401, https://doi.org/10.1016/j.jacc.2018.03.002.
globulin (ATG) preserves β-cell function and improves HbA1c in new-onset type 1 97) E. Faghihimani, A. Aminorroaya, H. Rezvanian, P. Adibi, F. Ismail-Beigi, M. Amini,
diabetes, Diabetes care 41 (9) (2018) 1917–1925, https://doi.org/10.2337/dc18- Salsalate improves glycemic control in patients with newly diagnosed type 2
0494. diabetes, Acta Diabetol. 50 (2013) 537–543, https://doi.org/10.1007/s00592-
74) S. Tsalamandris, A.S. Antonopoulos, E. Oikonomou, G.-A. Papamikroulis, 011-0329-2.
G. Vogiatzi, S. Papaioannou, S. Deftereos, D. Tousoulis, The role of inflammation 98) A. Goldfine, P. Conlin, F. Halperin, J. Koska, P. Permana, D. Schwenke,
in diabetes: current concepts and future perspectives, Eur. Cardiol. Rev. 14 (1) S. Shoelson, P. Reaven, A randomised trial of salsalate for insulin resistance and
(2019) 50, https://doi.org/10.15420/ecr.2018.33.1. cardiovascular risk factors in persons with abnormal glucose tolerance,
Diabetologia 56 (2013) 714–723, https://doi.org/10.1007/s00125-012-2819-3.
22
99) T.L. Stanley, M.V. Zanni, S. Johnsen, S. Rasheed, H. Makimura, H. Lee, V.K. Khor, Z. Chen, R. Tian, Z. She, J. Cai, H. Li, Role of oxidative stress in the pathogenesis of
R.S. Ahima, S.K. Grinspoon, TNF-α antagonism with etanercept decreases glucose nonalcoholic fatty liver disease, Free Radical Biology and Medicine 152 (2020)
and increases the proportion of high molecular weight adiponectin in obese 116–141.
subjects with features of the metabolic syndrome, J. Clin. Endocrinol. Metab. 96 M.E.J.M. Cerf, Beta cell physiological dynamics and dysfunctional transitions in response
(1) (2011) E146–E150, https://doi.org/10.1210/jc.2010-1170. to islet inflammation in obesity and diabetes, 10(11), 2020: 452. https://doi.org/
100) D.N. Kiortsis, A.K. Mavridis, S. Vasakos, S.N. Nikas, A.A. Drosos, Effects of 10.3390/metabo10110452.
infliximab treatment on insulin resistance in patients with rheumatoid arthritis I.A. Anastasiou, I. Eleftheriadou, A. Tentolouris, C. Koliaki, O.A. Kosta, N.J.Cmc
and ankylosing spondylitis, Ann. Rheum. Dis. 64 (5) (2005) 765–766, https:// Tentolouris, The effect of oxidative stress and antioxidant therapies on pancreatic
doi.org/10.1136/ard.2004.026534. β-cell dysfunction: results from in vitro and in vivo studies, 28(7), 2021: 1328–1346.
101) M.G. Ramos-Zavala, M. González-Ortiz, E. Martínez-Abundis, J.A. Robles- https://doi.org/10.2174/0929867327666200526135642.
Cervantes, R. González-López, N.J. Santiago-Hernández, Effect of diacerein on J.S. Bhatti, A. Sehrawat, J. Mishra, I.S. Sidhu, U. Navik, N. Khullar, S. Kumar, G.K. Bhatti,
insulin secretion and metabolic control in drug-naive patients with type 2 P.H. Reddy, Oxidative stress in the pathophysiology of type 2 diabetes and related
diabetes: a randomized clinical trial, Diabetes care 34 (7) (2011) 1591–1594, complications: Current therapeutics strategies and future perspectives, Free Radical
https://doi.org/10.2337/dc11-0357. Biology and Medicine 184 (2022) 114–134.
102) P.M. Ridker, B.M. Everett, A. Pradhan, J.G. MacFadyen, D.H. Solomon, 127) H. Yaribeygi, T. Sathyapalan, S.L. Atkin, A.J.Om Sahebkar, c longevity, Mol. Mech.
E. Zaharris, V. Mam, A. Hasan, Y. Rosenberg, E. Iturriaga, Low-dose methotrexate Link. Oxid. Stress Diabetes Mellit. 2020 (2020), https://doi.org/10.1155/2020/
for the prevention of atherosclerotic events, N. Engl. J. Med. 380 (8) (2019) 8609213.
752–762, https://doi.org/10.1056/nejmoa1809798. M. Soleimani-Dodran, R. Alipanah-Moghadam, F. Jeddi, M. Babaei, R. Salimnejad, E.J.N.
103) M.C. De Rotte, P.H. De Jong, E. Den Boer, S.M. Pluijm, B. Özcan, A.E. Weel, Bahreini, Metabolism, Effect of hydroalcoholic seed extract of Nigella sativa on
J. Lindemans, J.M. Hazes, R. De Jonge, Effect of methotrexate use and hepatic and pancreatic factors of Nrf2 and FGF21 in the regulation of insulin
erythrocyte methotrexate polyglutamate on glycosylated hemoglobin in transcription factors of MafA and PDX-1 in streptozotocin-treated diabetic rats, 19
rheumatoid arthritis, Arthritis Rheumatol. 66 (8) (2014) 2026–2036, https://doi. (1), 2022: 1–12. https://doi.org/10.1186/s12986–022-00699–9.
org/10.1002/art.38652. 129) Y. Li, S.-L. Deng, Z.-X. Lian, K.J.C. Yu, Roles toll- Recept. nitroxidative Stress
104) D. Erkan, M.J. Harrison, R. Levy, M. Peterson, M. Petri, L. Sammaritano, Mamm. 8 (6) (2019) 576, https://doi.org/10.3390/cells8060576.
A. Unalp-Arida, V. Vilela, Y. Yazici, M.D. Lockshin, Aspirin for primary A. Andreadi, A. Bellia, N. Di Daniele, M. Meloni, R. Lauro, D. Della-Morte, D. Lauro, The
thrombosis prevention in the antiphospholipid syndrome: A randomized, double- molecular link between oxidative stress, insulin resistance, and type 2 diabetes: A
blind, placebo-controlled trial in asymptomatic antiphospholipid target for new therapies against cardiovascular diseases, Current opinion in
antibody–positive individuals, Arthritis Rheum.: Off. J. Am. Coll. Rheumatol. 56 pharmacology 62 (2022) 85–96.
(7) (2007) 2382–2391, https://doi.org/10.1002/art.22663. H. Cabrera-Cruz, L. Oróstica, F. Plaza-Parrochia, I. Torres-Pinto, C. Romero, M.J.Ajop-e
105) B. Ahmed, R. Sultana, M.W.J.B. Greene, Adipose tissue and insulin resistance in Vega, metabolism, The insulin-sensitizing mechanism of myo-inositol is associated
obese, Pharmacotherapy 137 (2021), 111315, https://doi.org/10.1016/j. with AMPK activation and GLUT-4 expression in human endometrial cells exposed to
biopha.2021.111315. a PCOS environment, 318(2), 2020: E237-E248. https://doi.org/10.1152/
106) M. Roden, G.I.J.N. Shulman, The integrative biology of type 2 diabetes 576 ajpendo.00162.2019.
(7785) (2019) 51–60, https://doi.org/10.1038/s41586-019-1797-8. H.H. Shen, S.J. Peterson, L. Bellner, A. Choudhary, L. Levy, L. Gancz, A. Sasson, J.
107) A. Chait, L.J.J.Ficm Den Hartigh, Adipose tissue distribution, inflammation and Trainer, R. Rezzani, A.J.A. Resnick, Cold-pressed Nigella sativa oil standardized to
its metabolic consequences, including diabetes and cardiovascular disease 7 3% thymoquinone potentiates omega-3 protection against obesity-induced oxidative
(2020), 22, https://doi.org/10.3389/fcvm.2020.00022. stress, inflammation, and markers of insulin resistance accompanied with conversion
M. Singh, F. Benencia, Inflammatory processes in obesity: focus on endothelial of white to beige fat in mice, 9(6), 2020: 489. https://doi.org/10.3390/
dysfunction and the role of adipokines as inflammatory mediators: We reviewed antiox9060489.
obesity-induced metabolic and immunological changes at the level of vasculature L.E. Tebay, H. Robertson, S.T. Durant, S.R. Vitale, T.M. Penning, A.T. Dinkova-Kostova,
and emphasize on the importance of adipokines, International reviews of J.D. Hayes, Mechanisms of activation of the transcription factor Nrf2 by redox
immunology 38 (4) (2019) 157–171. stressors, nutrient cues, and energy status and the pathways through which it
109) S. Demir, P.P. Nawroth, S. Herzig, B. Ekim Üstünel, Emerging targets in type 2 attenuates degenerative disease, Free Radical Biology and Medicine 88 (2015)
diabetes and diabetic complications, Adv. Sci. 8 (18) (2021), 2100275, https:// 108–146.
doi.org/10.1002/advs.202100275. 134) L.D. Osellame, T.S. Blacker, M.R.J.Bp Duchen, rC. endocrinology, metabolism,
110) Q. Ling, L. Shen, W. Zhang, D. Qu, H. Wang, B. Wang, Y. Liu, J. Lu, D. Zhu, Y.J.M. Cell. Mol. Mech. mitochondrial Funct. 26 (6) (2012) 711–723, https://doi.org/
M. Bi, Increased plasmablasts enhance T cell-mediated beta cell destruction and 10.1016/j.beem.2012.05.003.
promote the development of type 1 diabetes 28 (1) (2022), 18, https://doi.org/ 135) M.T.J.Nr Islam, Oxid. Stress mitochondrial Dysfunct. -linked Neurodegener.
10.1186/s10020-022-00447-y. Disord. 39 (1) (2017) 73–82, https://doi.org/10.1080/01616412.2016.1251711.
C. Cosentino, R. Regazzi, Crosstalk between macrophages and pancreatic β-cells in islet 136) C.M. Kusminski, P.E.J.Tie Scherer, metabolism, Mitochondrial Dysfunct. White
development, homeostasis and disease, International Journal of Molecular Sciences Adipose Tissue 23 (9) (2012) 435–443, https://doi.org/10.1016/j.
22 (4) (2021) 1765. tem.2012.06.004.
112) P.V. Dludla, S.E. Mabhida, K. Ziqubu, B.B. Nkambule, S.E. Mazibuko-Mbeje, 137) A.P. Rolo, C.M.J.T. Palmeira, a pharmacology, Diabetes mitochondrial Funct.: role
S. Hanser, A.K. Basson, C. Pheiffer, A.P. Kengne, Pancreatic β-cell dysfunction in hyperglycemia Oxid. Stress 212 (2) (2006) 167–178, https://doi.org/10.1016/j.
type 2 diabetes: Implications of inflammation and oxidative stress, World J. taap.2006.01.003.
Diabetes 14 (3) (2023) 130, https://doi.org/10.4239/wjd.v14.i3.130. 138) N.K. Davies, J.M. O’Sullivan, L.D. Plank, R.J.Sf.O. Murphy, R. Diseases, Alter. gut
113) V. Rani, G. Deep, R.K. Singh, K. Palle, U.C. Yadav, Oxidative stress and metabolic Micro Bariatr. Surg. its Assoc. Metab. Benefit.: A Syst. Rev. 15 (4) (2019) 656–665,
disorders: Pathogenesis and therapeutic strategies, Life Sci. 148 (2016) 183–193, https://doi.org/10.1016/j.soard.2019.03.011.
https://doi.org/10.1016/j.lfs.2016.02.002. 139) A. Nogal, A.M. Valdes, C.J.Gm Menni, role Short. -chain Fat. Acids Inter. gut Micro
114) A. Kuryłowicz, K.J.M. Koźniewski, Anti-inflammatory strategies targeting Diet. cardio-Metab. Health 13 (1) (2021) 1897212, https://doi.org/10.1080/
metaflammation in type 2 diabetes 25 (9) (2020) 2224, https://doi.org/10.3390/ 19490976.2021.1897212.
molecules25092224. A. Schwarz, R. Philippsen, T. Schwarz, Induction of regulatory T cells and correction of
115) J.C. Pickup, Inflammation and activated innate immunity in the pathogenesis of cytokine disbalance by short-chain fatty acids: implications for psoriasis therapy,
type 2 diabetes, Diabetes care 27 (3) (2004) 813–823, https://doi.org/10.2337/ Journal of Investigative Dermatology 141 (1) (2021) 95–104.
diacare.27.3.813. 141) G. Yang, J. Wei, P. Liu, Q. Zhang, Y. Tian, G. Hou, L. Meng, Y. Xin, X.J.M. Jiang,
116) Z. Huang, A.J.Fii Xu, Adipose extracellular vesicles in intercellular and inter- Role gut Micro Type 2 Diabetes Relat. Dis. 117 (2021), 154712, https://doi.org/
organ crosstalk in metabolic health and diseases 12 (2021), 608680, https://doi. 10.1016/j.metabol.2021.154712.
org/10.3389/fimmu.2021.608680. 142) R. Wang, R. Tang, B. Li, X. Ma, B. Schnabl, H.J.C. Tilg, m immunology, Gut Micro,
117) M. Valko, K. Jomova, C.J. Rhodes, K. Kuča, K. Musílek, Redox-and non-redox- liver Immunol., liver Dis. 18 (1) (2021) 4–17, https://doi.org/10.1038/s41423-
metal-induced formation of free radicals and their role in human disease, Arch. 020-00592-6.
Toxicol. 90 (2016) 1–37, https://doi.org/10.1007/s00204-015-1579-5. 143) D. Garcia-Compean, J.O. Jaquez-Quintana, J.A. Gonzalez-Gonzalez, H.J.
118) V. Chavda, B. Chaurasia, K. Garg, H. Deora, G.E. Umana, P. Palmisciano, G. Scalia, WjogW. Maldonado-Garza, Liver cirrhosis Diabetes.: risk Factors, Pathophysiol.,
B.J.B.D. Lu, Molecular mechanisms of oxidative stress in stroke and cancer 5 Clin. Implic. Manag. 15 (3) (2009) 280, https://doi.org/10.3748/wjg.15.280.
(2022), 100029, https://doi.org/10.1016/j.dscb.2021.100029. 144) E. Bugianesi, A.J. McCullough, G.J.H. Marchesini, Insul. Resist.: a Metab. Pathw.
O. Morris, H. Jasper, Reactive Oxygen Species in intestinal stem cell metabolism, fate and Chronic liver Dis. 42 (5) (2005) 987–1000, https://doi.org/10.1002/hep.20920.
function, Free Radical Biology and Medicine 166 (2021) 140–146. 145) M. Elsahar, N.M. Elwan, S. El-Nakeep, M. Naguib, H.H. Soliman, A.A. Aboubakr,
G. Martemucci, C. Costagliola, M. Mariano, L. D’andrea, P. Napolitano, A.G.J.O. A. AbdelMaqsod, H. Sedrak, S.N. Assaad, R.J.Ajog Elwakil, Manag. Diabetes liver
D’Alessandro, Free radical properties, source and targets, antioxidant consumption Dis. Assoc. 19 (4) (2018) 166–179, https://doi.org/10.1016/j.ajg.2018.08.003.
and health, 2(2), 2022: 48–78. https://doi.org/10.3390/oxygen2020006. 146) J. Helenius-Hietala, J.H. Meurman, K. Höckerstedt, C. Lindqvist, H.J.T.I. Isoniemi,
I.P. Tirado-Ballestas, N. Alvarez-Ortega, W. Maldonado-Rojas, J. Olivero-Verbel, Eff. Aetiol. Sev. liver Dis. Oral. Health Dent. Treat. Transplant. 25 (2) (2012)
K. Caballero-Gallardo, Oxidative stress and alterations in the expression of genes 158–165, https://doi.org/10.1111/j.1432-2277.2011.01381.x.
related to inflammation, DNA damage, and metal exposure in lung cells exposed to a 147) K. Mehta, D.H. Van Thiel, N. Shah, S.J.Nr Mobarhan, Nonalcoholic Fat. liver Dis.:
hydroethanolic coal dust extract, Molecular Biology Reports 49 (6) (2022) Pathog. role Antioxid. 60 (9) (2002) 289–293, https://doi.org/10.1301/
4861–4871. 002966402320387224.
122) Q. Kang, C.J.R.B. Yang, Oxid. Stress Diabet. Retin.: Mol. Mech., Pathog. role Ther.
Implic. 37 (2020), 101799, https://doi.org/10.1016/j.redox.2020.101799.
23
148) P. Dietrich, C.J.Bp Hellerbrand, rC. gastroenterology, Non-Alcohol. Fat. liver Dis., endothelial cell function in diabetes, Nat. Commun. 11 (1) (2020), 3812, https://
Obes. Metab. Syndr. 28 (4) (2014) 637–653, https://doi.org/10.1016/j. doi.org/10.1038/s41467-020-17468-y.
bpg.2014.07.008. 174) K. Park, A. Mima, Q. Li, C. Rask-Madsen, P. He, K. Mizutani, S. Katagiri, Y. Maeda,
149) E. Hashimoto, M. Taniai, K.J.Jog Tokushige, hepatology, Charact. Diagn. NAFLD/ I.-H. Wu, M. Khamaisi, Insulin decreases atherosclerosis by inducing endothelin
NASH 28 (2013) 64–70, https://doi.org/10.1111/jgh.12271. receptor B expression, JCI Insight 1 (6) (2016), https://doi.org/10.1172/jci.
150) S. Chitturi, S. Abeygunasekera, G.C. Farrell, J. Holmes-Walker, J.M. Hui, C. Fung, insight.86574.
R. Karim, R. Lin, D. Samarasinghe, C.J.H. Liddle, NASH Insul. Resist.: Insul. 175) Z. Liu, Y. Zhang, C. Qiu, H. Zhu, S. Pan, H. Jia, H. Kang, G. Guan, R. Hui, L. Zhu,
hypersecretion Specif. Assoc. Insul. Resist. Syndr. 35 (2) (2002) 373–379, https:// Diabetes mellitus exacerbates post-myocardial infarction heart failure by reducing
doi.org/10.1053/jhep.2002.30692. sarcolipin promoter methylation, ESC Heart Fail. 7 (4) (2020) 1935–1948, https://
151) P. Trayhurn, I.S.J.Bjon Wood, Adipokines: Inflamm. pleiotropic role White Adipose doi.org/10.1002/ehf2.12789.
Tissue 92 (3) (2004) 347–355, https://doi.org/10.1079/bjn20041213. 176) M. Kronlage, M. Dewenter, J. Grosso, T. Fleming, U. Oehl, L.H. Lehmann, I. Falcão-
K. Qureshi, G.A.J.WjogW. Abrams, Metabolic liver disease of obesity and role of adipose Pires, A.F. Leite-Moreira, N. Volk, H.-J. Gröne, O-GlcNAcylation of histone
tissue in the pathogenesis of nonalcoholic fatty liver disease, 13(26), 2007: 3540. deacetylase 4 protects the diabetic heart from failure, Circulation 140 (7) (2019)
https://doi.org/10.3748/wjg.v13.i26.3540. 580–594, https://doi.org/10.1161/circulationaha.117.031942.
153) I. Copaci, L. Micu, M.J.Jo.G. Voiculescu, L. Diseases, The role of cytokines in non- 177) J.A. Nicolás-Ávila, A.V. Lechuga-Vieco, L. Esteban-Martínez, M. Sánchez-Díaz,
alcoholic steatohepatitis, A Syst. Rev. 15 (4) (2006) 363. 〈https://pubmed.ncbi. E. Díaz-García, D.J. Santiago, A. Rubio-Ponce, J.L. Li, A. Balachander, J.
nlm.nih.gov/17205149/〉. A. Quintana, A network of macrophages supports mitochondrial homeostasis in the
154) R.W. Thomsen, P. Jepsen, H.T.J.Cid Sørensen, Diabetes Mellit. pyogenic liver heart, e23, Cell 183 (1) (2020) 94–109, https://doi.org/10.1016/j.
abscess: risk Progn. 44 (9) (2007) 1194–1201, https://doi.org/10.1086/521170. cell.2020.08.031.
155) J.Y. Kim, D.Y. Lee, Y.J. Lee, K.J. Park, K.H. Kim, J.W. Kim, W.-H.J.Wjobc Kim, 178) A. Berbudi, N. Rahmadika, A.I. Tjahjadi, R.J.Cdr Ruslami, Type 2 Diabetes its
Chronic Alcohol Consum. potentiates Dev. Diabetes Pancreat. β-Cell Dysfunct. 6 Impact Immune Syst. 16 (5) (2020) 442, https://doi.org/10.3390/
(1) (2015) 1, https://doi.org/10.4331/wjbc.v6.i1.1. antiox11030462.
156) D. Patschan, G.J.Ijon Müller, Acute Kidney Inj. Diabetes Mellit. 2016 (2016), 179) M.A. Salem, R.A. El-Shiekh, N.M. Aborehab, A.A. Al-Karmalawy, S.M. Ezzat,
https://doi.org/10.1155/2016/6232909. S. Alseekh, A.R. Fernie, Metabolomics driven analysis of Nigella sativa seeds
M.C. Thomas, M. Brownlee, K. Susztak, K. Sharma, K.A. Jandeleit-Dahm, S. Zoungas, identifies the impact of roasting on the chemical composition and
P. Rossing, P.-H. Groop, M.E. Cooper, Diabetic kidney disease, Nature reviews immunomodulatory activity, Food Chem. (2022), 133906, https://doi.org/
Disease primers 1 (1) (2015) 1–20. 10.1016/j.foodchem.2022.133906.
158) R.M. Hazem, S.A. Antar, Y.K. Nafea, A.A. Al-Karmalawy, M.A. Saleh, M.F. El-Azab, M.E. Ryan, O. Carnu, A. Kamer, The influence of diabetes on the periodontal tissues, The
Pirfenidone and vitamin D mitigate renal fibrosis induced by doxorubicin in mice Journal of the American Dental Association 134 (2003) 34S–40S.
with Ehrlich solid tumor, Life Sci. 288 (2022), 120185, https://doi.org/10.1016/j. 181) M.F. El-Azab, A.A. Al-Karmalawy, S.A. Antar, P.A. Hanna, K.M. Tawfik, R.
lfs.2021.120185. M. Hazem, A novel role of Nano selenium and sildenafil on streptozotocin-induced
M. Akhtar, N.M. Taha, A. Nauman, I.B. Mujeeb, A.D.M. Al-Nabet, Diabetic kidney diabetic nephropathy in rats by modulation of inflammatory, oxidative, and
disease: Past and present, Advances in anatomic pathology 27 (2) (2020) 87–97. apoptotic pathways, Life Sci. 303 (2022), 120691, https://doi.org/10.1016/j.
160) R. Natarajan, Epigenetic mechanisms in diabetic vascular complications and lfs.2022.120691.
metabolic memory: The 2020 Edwin Bierman Award Lecture, Diabetes 70 (2) C.L. Price, S.C. Knight, Methylglyoxal: possible link between hyperglycaemia and
(2021) 328–337, https://doi.org/10.2337/dbi20-0030. immune suppression? Trends in Endocrinology & Metabolism 20 (7) (2009)
161) A. Falkevall, A. Mehlem, I. Palombo, B.H. Sahlgren, L. Ebarasi, L. He, A. 312–317.
J. Ytterberg, H. Olauson, J. Axelsson, B. Sundelin, Reducing VEGF-B signaling P. Meenakshi, S. Ramya, J. Lavanya, V. Vijayalakshmi, G.J.C. Sumanlatha, Effect of IFN-
ameliorates renal lipotoxicity and protects against diabetic kidney disease, Cell γ, IL-12 and IL-10 cytokine production and mRNA expression in tuberculosis patients
Metab. 25 (3) (2017) 713–726, https://doi.org/10.1016/j.cmet.2017.01.004. with diabetes mellitus and their household contacts, 81, 2016: 127–136. https://doi.
162) T.A. Zelniker, E. Braunwald, Mechanisms of cardiorenal effects of sodium-glucose org/10.1016/j.cyto.2016.03.009.
cotransporter 2 inhibitors: JACC state-of-the-art review, J. Am. Coll. Cardiol. 75 184) G.H. Tesch, Macrophages and diabetic nephropathy. Seminars in nephrology,
(4) (2020) 422–434, https://doi.org/10.1016/j.jacc.2019.11.031. Elsevier,, 2010, pp. 290–301, https://doi.org/10.1016/j.semnephrol.2010.03.007.
163) K.R. Tuttle, F.C. Brosius III, S.G. Adler, M. Kretzler, R.L. Mehta, J.A. Tumlin, 185) J.B. Frazao, P.R. Errante, A.J.Aiete Condino-Neto, Toll- receptors’ Pathw. Disturb.
Y. Tanaka, M. Haneda, J. Liu, M.E. Silk, JAK1/JAK2 inhibition by baricitinib in are Assoc. Increase susceptibility Infect. Hum. 61 (2013) 427–443, https://doi.
diabetic kidney disease: results from a Phase 2 randomized controlled clinical trial, org/10.1007/s00005-013-0243-0.
Nephrol. Dial. Transplant. 33 (11) (2018) 1950–1959, https://doi.org/10.1093/ N. Rojo-Botello, A. García-Hernández, L.J.Jopr Moreno-Fierros, Expression of toll-like
ndt/gfx377. receptors 2, 4 and 9 is increased in gingival tissue from patients with type 2 diabetes
164) L. Zhao, Y. Zou, F. Liu, Transforming growth factor-beta1 in diabetic kidney and chronic periodontitis, 47(1), 2012: 62–73. https://doi.org/10.1111/
disease, Front. Cell Dev. Biol. 8 (2020), 187, https://doi.org/10.3389/ j.1600–0765.2011.01405.x.
fcell.2020.00187. 187) K. Miloudi, M. Oubaha, C. Ménard, A. Dejda, V. Guber, G. Cagnone, A.M. Wilson,
165) Q. Lu, W.W. Wang, M.Z. Zhang, Z.X. Ma, X.R. Qiu, M. Shen, X.X. Yin, ROS induces N. Tétreault, G. Mawambo, F. Binet, NOTCH1 signaling induces pathological
epithelial‑mesenchymal transition via the TGF‑β1/PI3K/Akt/mTOR pathway in vascular permeability in diabetic retinopathy, Proc. Natl. Acad. Sci. 116 (10)
diabetic nephropathy, Exp. Ther. Med. 17 (1) (2019) 835–846, https://doi.org/ (2019) 4538–4547, https://doi.org/10.1073/pnas.1814711116.
10.3892/etm.2018.7014. 188) H. Liu, W. Zhang, B. Lilly, Evaluation of Notch3 deficiency in diabetes-induced
166) X. Meng, P. Tang, J. Li, H. Lan, TGF-ß/Smad signaling in renal fibrosis, Front pericyte loss in the retina, J. Vasc. Res. 55 (5) (2018) 308–318, https://doi.org/
Physiol. 6 (2015) 82, https://doi.org/10.3389/fphys.2015.00082. 10.1159/000493151.
167) I. Tomita, S. Kume, S. Sugahara, N. Osawa, K. Yamahara, M. Yasuda-Yamahara, 189) Jh Wu, Yn Li, Aq Chen, Cd Hong, Cl Zhang, Hl Wang, Yf Zhou, P.C. Li, Y. Wang,
N. Takeda, M. Chin-Kanasaki, T. Kaneko, E. Mayoux, SGLT2 inhibition mediates L. Mao, Inhibition of Sema4D/PlexinB1 signaling alleviates vascular dysfunction in
protection from diabetic kidney disease by promoting ketone body-induced diabetic retinopathy, EMBO Mol. Med. 12 (2) (2020), e10154, https://doi.org/
mTORC1 inhibition, e6, Cell Metab. 32 (3) (2020) 404–419, https://doi.org/ 10.15252/emmm.201810154.
10.1016/j.cmet.2020.06.020. 190) M. Whitehead, A. Osborne, P.S. Widdowson, P. Yu-Wai-Man, K.R. Martin,
168) V. Perkovic, M.J. Jardine, B. Neal, S. Bompoint, H.J. Heerspink, D.M. Charytan, Angiopoietins in diabetic retinopathy: current understanding and therapeutic
R. Edwards, R. Agarwal, G. Bakris, S. Bull, Canagliflozin and renal outcomes in potential, J. Diabetes Res. 2019 (2019), https://doi.org/10.1155/2019/5140521.
type 2 diabetes and nephropathy, N. Engl. J. Med. 380 (24) (2019) 2295–2306, 191) D. Ferland-McCollough, S. Slater, J. Richard, C. Reni, G. Mangialardi, Pericytes, an
https://doi.org/10.1056/nejmoa1811744. overlooked player in vascular pathobiology, Pharmacol. Ther. 171 (2017) 30–42,
169) B.L. Neuen, T. Young, H.J. Heerspink, B. Neal, V. Perkovic, L. Billot, K. https://doi.org/10.1016/j.pharmthera.2016.11.008.
W. Mahaffey, D.M. Charytan, D.C. Wheeler, C. Arnott, SGLT2 inhibitors for the 192) C. Liu, H.-M. Ge, B.-H. Liu, R. Dong, K. Shan, X. Chen, M.-D. Yao, X.-M. Li, J. Yao,
prevention of kidney failure in patients with type 2 diabetes: a systematic review R.-M. Zhou, Targeting pericyte–endothelial cell crosstalk by circular RNA-
and meta-analysis, Lancet Diabetes Endocrinol. 7 (11) (2019) 845–854, https:// cPWWP2A inhibition aggravates diabetes-induced microvascular dysfunction,
doi.org/10.1016/s2213-8587(19)30256-6. Proc. Natl. Acad. Sci. 116 (15) (2019) 7455–7464, https://doi.org/10.1073/
170) C.C. Low Wang, C.N. Hess, W.R. Hiatt, A.B. Goldfine, Clinical update: pnas.1814874116.
cardiovascular disease in diabetes mellitus: atherosclerotic cardiovascular disease 193) Q. Jiang, C. Liu, C.-P. Li, S.-S. Xu, M.-D. Yao, H.-M. Ge, Y.-N. Sun, X.-M. Li, S.-
and heart failure in type 2 diabetes mellitus–mechanisms, management, and J. Zhang, K. Shan, Circular RNA-ZNF532 regulates diabetes-induced retinal
clinical considerations, Circulation 133 (24) (2016) 2459–2502, https://doi.org/ pericyte degeneration and vascular dysfunction, J. Clin. Investig. 130 (7) (2020)
10.1161/circulationaha.116.022194. 3833–3847, https://doi.org/10.1172/jci123353.
171) T.R. Einarson, A. Acs, C. Ludwig, U.H. Panton, Prevalence of cardiovascular 194) S.I. Lindstrom, S. Sigurdardottir, T.E. Zapadka, J. Tang, H. Liu, B.E. Taylor, D.
disease in type 2 diabetes: a systematic literature review of scientific evidence from G. Smith, C.A. Lee, J. DeAngelis, T.S. Kern, Diabetes induces IL-17A-Act1-FADD-
across the world in 2007–2017, Cardiovasc. Diabetol. 17 (1) (2018) 1–19, https:// dependent retinal endothelial cell death and capillary degeneration, J. Diabetes its
doi.org/10.1186/s12933-018-0728-6. Complicat. 33 (9) (2019) 668–674, https://doi.org/10.1016/j.
172) M.A. Reddy, S. Das, C. Zhuo, W. Jin, M. Wang, L. Lanting, R. Natarajan, Regulation jdiacomp.2019.05.016.
of vascular smooth muscle cell dysfunction under diabetic conditions by miR-504, 195) S.W. Jung, J.-Y. Moon, The role of inflammation in diabetic kidney disease, Korean
Arterioscler., Thromb., Vasc. Biol. 36 (5) (2016) 864–873, https://doi.org/ J. Intern. Med. 36 (4) (2021) 753, https://doi.org/10.3904/kjim.2021.174.
10.1161/atvbaha.115.306770. 196) M. Wang, Y. Wang, T. Xie, P. Zhan, J. Zou, X. Nie, J. Shao, M. Zhuang, C. Tan,
173) C. Yang, M. Eleftheriadou, S. Kelaini, T. Morrison, M.V. González, R. Caines, J. Tan, Prostaglandin E 2/EP 2 receptor signalling pathway promotes diabetic
N. Edwards, A. Yacoub, K. Edgar, A. Moez, Targeting QKI-7 in vivo restores
24
retinopathy in a rat model of diabetes, Diabetologia 62 (2019) 335–348, https:// Nat. Rev. Neurol. 13 (3) (2017) 135–147, https://doi.org/10.1038/
doi.org/10.1007/s00125-018-4755-3. nrneurol.2016.201.
197) K. Elmasry, A.S. Ibrahim, S. Abdulmoneim, M. Al-Shabrawey, Bioactive lipids and 210) S. Kopf, J.B. Groener, Z. Kender, T. Fleming, M. Brune, C. Riedinger, N. Volk,
pathological retinal angiogenesis, Br. J. Pharmacol. 176 (1) (2019) 93–109, E. Herpel, D. Pesta, J. Szendrödi, Breathlessness and restrictive lung disease: an
https://doi.org/10.1111/bph.14507. important diabetes-related feature in patients with type 2 diabetes, Respiration 96
198) M. Kolibabka, N. Dietrich, T. Klein, H.-P. Hammes, Anti-angiogenic effects of the (1) (2018) 29–40, https://doi.org/10.1159/000488909.
DPP-4 inhibitor linagliptin via inhibition of VEGFR signalling in the mouse model 211) J.B. Groener, D. Oikonomou, R. Cheko, Z. Kender, J. Zemva, L. Kihm,
of oxygen-induced retinopathy, Diabetologia 61 (2018) 2412–2421, https://doi. M. Muckenthaler, V. Peters, T. Fleming, S. Kopf, Methylglyoxal and advanced
org/10.1007/s00125-018-4701-4. glycation end products in patients with diabetes–what we know so far and the
199) M. Pham, D. Oikonomou, B. Hornung, M. Weiler, S. Heiland, P. Bäumer, missing links, Exp. Clin. Endocrinol. Diabetes 127 (08) (2019) 497–504, https://
J. Kollmer, P.P. Nawroth, M. Bendszus, Magnetic resonance neurography detects doi.org/10.1055/s-0043-106443.
diabetic neuropathy early and with proximal predominance, Ann. Neurol. 78 (6) 212) V. Kumar, R. Agrawal, A. Pandey, S. Kopf, M. Hoeffgen, S. Kaymak, O.
(2015) 939–948, https://doi.org/10.1002/ana.24524. R. Bandapalli, V. Gorbunova, A. Seluanov, M.A. Mall, Compromised DNA repair is
200) D. Schwarz, A.S. Hidmark, V. Sturm, M. Fischer, D. Milford, I. Hausser, F. Sahm, M. responsible for diabetes-associated fibrosis, EMBO J. 39 (11) (2020), e103477,
O. Breckwoldt, N. Agarwal, R. Kuner, Characterization of experimental diabetic https://doi.org/10.15252/embj.2019103477.
neuropathy using multicontrast magnetic resonance neurography at ultra high 213) V. Kumar, T. Fleming, S. Terjung, C. Gorzelanny, C. Gebhardt, R. Agrawal, M.
field strength, Sci. Rep. 10 (1) (2020), 7593, https://doi.org/10.1038/s41598-020- A. Mall, J. Ranzinger, M. Zeier, T. Madhusudhan, Homeostatic nuclear RAGE–ATM
64585-1. interaction is essential for efficient DNA repair, Nucleic Acids Res. 45 (18) (2017)
201) A. Bierhaus, T. Fleming, S. Stoyanov, A. Leffler, A. Babes, C. Neacsu, S.K. Sauer, 10595–10613, https://doi.org/10.1093/nar/gkx705.
M. Eberhardt, M. Schnölzer, F. Lasitschka, Methylglyoxal modification of Nav1. 8 214) H.J. Lee, H.I. Seo, H.Y. Cha, Y.J. Yang, S.H. Kwon, S.J. Yang, Diabetes and
facilitates nociceptive neuron firing and causes hyperalgesia in diabetic Alzheimer’s disease: mechanisms and nutritional aspects, Clin. Nutr. Res. 7 (4)
neuropathy, Nat. Med. 18 (6) (2012) 926–933, https://doi.org/10.1038/nm.2750. (2018) 229–240, https://doi.org/10.1093%2Fnar%2Fgkx705.
C. Tsantoulas, S. Laínez, S. Wong, I. Mehta, B. Vilar, P.A. McNaughton, 215) X. Li, D. Song, S.X. Leng, Link between type 2 diabetes and Alzheimer’s disease:
Hyperpolarization-activated cyclic nucleotide–gated 2 (HCN2) ion channels drive from epidemiology to mechanism and treatment, Clin. Inter. Aging 10 (2015)
pain in mouse models of diabetic neuropathy, Sci. Transl. Med. 9 (409) (2017), 549–560, https://doi.org/10.2147/cia.s74042.
eaam6072, https://doi.org/10.1126/scitranslmed.aam6072. [216] M.A. Hossain, M. Al Amin, M.I. Hasan, M. Sohel, M.A. Ahammed, S.M.
203) N.D. Jayaraj, B.J. Bhattacharyya, A.A. Belmadani, D. Ren, C.A. Rathwell, H. Mahmud, M.R. Rahman, M.H. Rahman, Bioinformatics and system biology
S. Hackelberg, B.E. Hopkins, H.R. Gupta, R.J. Miller, D.M. Menichella, Reducing approaches to identify molecular pathogenesis of polycystic ovarian syndrome,
CXCR4-mediated nociceptor hyperexcitability reverses painful diabetic type 2 diabetes, obesity, and cardiovascular disease that are linked to the
neuropathy, J. Clin. Investig. 128 (6) (2018) 2205–2225, https://doi.org/10.1172/ progression of female infertility, Inform. Med. Unlocked 30 (2022), 100960,
jci92117. https://doi.org/10.1016/j.imu.2022.100960.
204) D.A. Andersson, C. Gentry, E. Light, N. Vastani, J. Vallortigara, A. Bierhaus, [217] B. Catargi, V. Rigalleau, A. Poussin, N. Ronci-Chaix, V. Bex, V. Vergnot, H. Gin,
T. Fleming, S. Bevan, Methylglyoxal evokes pain by stimulating TRPA1, PloS One 8 P. Roger, A. Tabarin, Occult Cushing’s Syndrome in Type-2 Diabetes, J. Clin.
(10) (2013), e77986, https://doi.org/10.1371/journal.pone.0077986. Endocrinol. Metab. 88 (12) (2003) 5808–5813, https://doi.org/10.1210/jc.2003-
205) I.-I. Witzel, H.F. Jelinek, K. Khalaf, S. Lee, A.H. Khandoker, H. Alsafar, Identifying 030254.
common genetic risk factors of diabetic neuropathies, Front. Endocrinol. 6 (2015) [218] J. Wu, L. Tang, F. Zheng, X. Chen, L. Li, A review of the last decade: pancreatic
88, https://doi.org/10.3389/fendo.2015.00088. cancer and type 2 diabetes, Archives of Physiology and Biochemistry 1–9. https://
206) E.L. Feldman, K.-A. Nave, T.S. Jensen, D.L. Bennett, New horizons in diabetic doi.org/10.1080/13813455.2023.2252204.
neuropathy: mechanisms, bioenergetics, and pain, Neuron 93 (6) (2017) [219] M.O. Goodarzi, J.I. Rotter, Genetics Insights in the Relationship Between Type 2
1296–1313, https://doi.org/10.1016/j.neuron.2017.02.005. Diabetes and Coronary Heart Disease, Circ. Res. 126 (11) (2020) 1526–1548,
207) T. Chen, H. Li, Y. Yin, Y. Zhang, Z. Liu, H. Liu, Interactions of Notch1 and TLR4 https://doi.org/10.1161/circresaha.119.316065.
signaling pathways in DRG neurons of in vivo and in vitro models of diabetic [220] N. Bottini, T. Vang, F. Cucca, T. Mustelin, Role of PTPN22 in type 1 diabetes and
neuropathy, Sci. Rep. 7 (1) (2017), 14923, https://doi.org/10.1038/s41598-017- other autoimmune diseases, Semin. Immunol. 18 (4) (2006) 207–213, https://
15053-w. doi.org/10.1016/j.smim.2006.03.008.
208) C. Grote, D. Wright, A role for insulin in diabetic neuropathy, Front Neurosci. 10 [221] K. Kakleas, A. Soldatou, F. Karachaliou, K. Karavanaki, Associated autoimmune
(2016) 581, https://doi.org/10.3389/fnins.2016.00581. diseases in children and adolescents with type 1 diabetes mellitus (T1DM),
209) N.P. Gonçalves, C.B. Vægter, H. Andersen, L. Østergaard, N.A. Calcutt, T.S. Jensen, Autoimmun. Rev. 14 (9) (2015) 781–797, https://doi.org/10.1016/j.
Schwann cell interactions with axons and microvessels in diabetic neuropathy, autrev.2015.05.002.
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Biomedicine & Pharmacotherapy 168 (2023) 115734

Contents lists available at ScienceDirect

Biomedicine & Pharmacotherapy

Diabetes mellitus: Classification, mediators, and complications; A gate to

1. Introduction dysglycemia. Alteration in glucose and C-peptide levels can be utilized

individuals. Table (1)

in determining how the autoimmune process proceeds. The harmful

3.1.3. Anti-inflammatory trials on T1D

3.2. Inflammation in T2D

Various pathophysiological studies have provided significant in

3.2.1. Mediators of inflammation T2D

Fig. (4). The key Mediators of inflammation in type 2 diabetes.

5. Complications associated with DM

glycogenolysis [143]. However, diseases such as insulin resistance, 5.1.2. NASH

Fig. (9). Diabetic nephropathy and renal long-term complications of DM.

Declaration of Competing Interest

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Biomedicine & Pharmacotherapy 168 (2023) 115734

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Biomedicine & Pharmacotherapy

Diabetes mellitus: Classification, mediators, and complications; A gate to

1. Introduction dysglycemia. Alteration in glucose and C-peptide levels can be utilized

individuals. Table (1)

in determining how the autoimmune process proceeds. The harmful

3.1.3. Anti-inflammatory trials on T1D

3.2. Inflammation in T2D

Various pathophysiological studies have provided significant in­

3.2.1. Mediators of inflammation T2D

Fig. (4). The key Mediators of inflammation in type 2 diabetes.

5. Complications associated with DM

glycogenolysis [143]. However, diseases such as insulin resistance, 5.1.2. NASH

Fig. (9). Diabetic nephropathy and renal long-term complications of DM.

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Various pathophysiological studies have provided significant in