See discussions, stats, and author profiles for this publication at: https://www.researchgate.

net/publication/374388621

A Review on the Mode of Action of the Gluconeogeic Enzyme,

Phosphoenolpyruvate Carboxykinase (PEPCK) and Its Regulation of Diabetes
Induced Hyperglycaemia With Special Emphasis on...

Article · October 2023

CITATIONS READS
0 105

1 author:

Asim Dutta
Institute of Advanced Study in Science and Technology
10 PUBLICATIONS 33 CITATIONS

SEE PROFILE

All content following this page was uploaded by Asim Dutta on 03 October 2023.

The user has requested enhancement of the downloaded file.

Annals of Multidisciplinary Research, Innovation and Technology (AMRIT), 1(2), 2022, 23-34 ISSN: 2583-4657

REVIEW ARTICLE

A Review on the Mode of Action of the Gluconeogeic Enzyme, Phosphoenolpyruvate

Carboxykinase (PEPCK) and Its Regulation of Diabetes Induced Hyperglycaemia With
Special Emphasis on Plant Derived PEPCK Modulators
1 2 1 1˜
Asim Kumar Dutta , Partha P. Dutta Josef Yakin, Jagat C. Borah , Narayan C. Talukdar

1
Life Science Division, Institute of Advanced Study in Science and Technology, Paschim Boragaon, Guwahati,
Assam-781035, India
1
Assam down town University, Panikhaiti, Guwahati, Assam-781026, India
˜
Corresponding author: Narayan Chandra Talukdar, Email: talukdar narayan@rediffmail.com
Article Chronicle: Received: 12/10/2022 Accepted: 16/12/2022 Published: 30/12/2022

Abstract
Phosphoenol pyruvatecarboxykinase (PEPCK) is the key rate-limiting enzyme in gluconeogenic pathway, which
helps to regulate blood glucose homeostasis. Over expression of this enzyme results in pre-diabetes and diabetes and
its expression is predominantly regulated by insulin. Insulin levels of diabetic subjects are insufficient to adequately
inhibit PEPCK. Thus, inhibition of PEPCK is a promising new therapeutic approach for treatment of diabetes. Specific
inhibitors of either PEPCK gene expression or PEPCK enzyme activity might decrease hepatic glucose overproduction
and substantially decrease hyperglycemia in diabetic patients. Phytochemicals from medicinal plants have been used
against many diseases including malaria, diabetes, cancer, etc. There are numerous medicinal plants whose extract
modulate glycolysis, Kreb’s cycle, gluconeogenesis, HMP shunt pathway, glycogen synthesis and their degradation,
cholesterol synthesis, metabolism and absorption of carbohydrates, and synthesis and release of insulin. In this review,
various reported activity on PEPCK by plant derived bioactive compounds are studied. This review will provide a
guide for researchers in the field, to develop candidates into environment-friendly effective, yet safe anti-diabetics.
Keywords: Phosphoenolpyruvate Carboxykinase, Diabetes Mellitus, Medicinal Plants, Anti-diabetic Drugs, Phyto-
chemicals, Regulation, Inhibitors

1 Introduction
Glucose is the primary metabolic fuel and major energy
supply for most living cells i.e., the main substrate for en-
ergy metabolism. Thus, maintaining its levels in an optimal
range is crucial for health and survival, and is regulated by a
complex interplay of metabolic processes controlling glucose
utilization and glucose production(1). The key metabolic
pathways involved in utilization of glucose are glycolysis and
the Krebs cycle or Citric acid cycle. Metabolic pathways in-
volved in glucose production during fasting are glycogenol-
ysis (breakdown of glycogen), gluconeogenesis (glucose syn-
thesis from non-glycosidic substrates) and lipolysis (release
free fatty acids)(2; 3) (Figure 1). In diabetic individuals, al- Figure 1: The Biosynthetic Pathway of Gluconeogenesis
tered rates of gluconeogenesis are responsible for increased Showing Highlighting the Position of the Enzyme, PEPCK
hepatic glucose output (HGO) and, therefore, sustained hy-
perglycemia observed in both insulin-dependent diabetes Expression from the gene for Phosphoenol pyruvatecar-
mellitus (IDDM) and non-insulin-dependent diabetes mel- boxykinase (PEPCK) is induced during diabetes, both
litus (NIDDM)(4; 5). in animals and in human patients(2). The mechanism

- 23 -
Annals of Multidisciplinary Research, Innovation and Technology (AMRIT), 1(2), 2022, 23-34 ISSN: 2583-4657

of action of current drugs for the treatment of diabetes, On the other hand, increase in insulin during high glucose
biguanides (e.g., metformin) and thiazolidinediones (e.g., levels lead to suppression of PEPCK gene expression(20).
rosiglitazone)(6; 7), induces an increase in insulin sensitivity The promoter region of PEPCK has more than 15 response
in peripheral tissues and the liver. The antihyperglycemic elements that can be recognized by many transcription fac-
action of rosiglitazone is a direct result of activation of the tors (FKHR1, HNF3, C/EBP) and other signalling pathway
nuclear receptor peroxisome proliferator-activated receptor- proteins (FOXO1, FOXO2, PGC1α, SIRT1, TRB3) for its
g (PPAR-g)(8) (11), whereas metformin has been linked di- regulation(3). Dysregulation of PEPCK has been found to
rectly to inhibition of liver gluconeogenesis(9; 10). However, be related to hyperglycaemia (abnormally high blood glu-
these drugs activate upstream regulators (e.g., PPAR-g or cose) in type 2 diabetes (T2DM) patients(21; 22) (Table 1,
AMP-K) that are involved in a broad range of physiological Figure 2).
functions(8; 11; 12; 13; 14). Over the past decades, there
has been an increasing body of literature related to the ef- 3 Role of PEPCK in Diabetes
fects of secondary metabolites from botanical sources on di- Diabetes mellitus (DM) is a complex metabolic disorder
abetes. Plants-derived metabolites including alkaloids, phe- characterized by overproduction of glucose by the liver and
nols, anthocyanins, flavonoids, stilbenoids, saponins, tan- underutilization by other organs. There are two principle
nins, polysaccharides, coumarins, and terpenes can tar- forms of diabetes: Type 1 diabetes or IDDM, caused by au-
get cellular and molecular mechanisms involved in carbo- toimmune destruction of the insulin secreting β- cells in the
hydrate metabolism(15). There are numerous medicinal pancreas. Type 2 diabetes (T2DM) or NIDDM, on the other
plants whose extract modulate glycolysis, Kreb’s cycle, glu- hand, results from the body’s inability to respond properly
coneogenesis, HMP shunt pathway, glycogen synthesis and to insulin. T2DM accounts for around 90% of all diabetes
their degradation, cholesterol synthesis, metabolism and cases worldwide(23). Because insulin is unresponsive, the
absorption of carbohydrates, and synthesis and release of entry of glucose into cells is impaired. The liver becomes
insulin(16). This review summarizes the current knowledge stuck in a gluconeogenic and ketogenic state. Hence, an
compiled from the latest studies published during the past excessive amount of glucose (hyperglycemia) is produced
decade on the mechanism-based action of plants-derived by the liver and released into the blood. Dysregulation of
secondary metabolites that can target the enzyme PEPCK gluconeogenesis is critically responsible for hyperglycemia
and various other metabolic pathways in humans against during fasting in T2DM patients(21). Insulin insensitivity
diabetes. leads to a decrease in the inhibition of gluconeogenic genes
including PEPCK, leading to an increase in blood glucose
2 Regulation of PEPCK
levels(24; 25). Overexpression of the PEPCK gene leads to
PEPCK gene expression is controlled by various biological insulin resistance and altered glucose tolerance, which are
agents consisting of dietary carbohydrate, hormones, and features of NIDDM(26). It is reported that diabetic induced
cellular intermediates. In mammalian liver and white adi- hyperglycemia can be controlled by PEPCK gene silencing
pose tissue, the enzyme is stimulated by starvation and in diabetic mice(27). The transcription factors, CREB(28),
reduced by a high-carbohydrate diet(17). The hormones, C/EBPα(29) and Foxo1(30; 31) are important in stimu-
insulin, glucagon, glucocorticoids regulate expression and lation of hepatic PEPCK expression in response to fast-
activity of a variety of proteins to maintain blood glucose ing or stress and its attenuation during feeding as reflected
within normal limits. PEPCK expression is induced by by changes in circulating levels of glucose metabolism hor-
the hormones, glucagon, catecholamines and glucocorticoids mones. Accordingly, the enzyme is overexpressed in all
during periods of fasting and on the other hand, inhibited forms of diabetes, in which gluconeogenesis is inappropri-
by the hormone, insulin upon feeding(18; 19). ately high and a 7-fold overexpression of PEPCK results in
hyperglycemia as observed in mice models(32). Insulin re-
sistance has been shown to be correlated with free fatty acid
levels in the blood during glyceroneogensis where PEPCK
plays a key role in control of free fatty acid re-esterification
in adipose tissue. Thus, for T2DM patients, elevated ac-
tivity of PEPCK should be down regulated to limit glucose
production.

4 PEPCK as Drug Target

The current therapies for T2DM includes mainly oral
anti-diabetic drugs, such as sulfonylureas, biguanides, α-
glucosidase inhibitors, thiazolidinediones, and dipeptidyl
peptidase-4 (DPP-4) inhibitors etc., which are used as
mono-therapy or in combination(6; 7). The mechanism of
action of most of these drugs involves increase in insulin
Figure 2: Biochemical Functionality and Role of PEPCK sensitivity. Anti-hyperglycemic action of the drug, thiazo-
lidinediones is a direct result of activation of the PPAR-
When glucagon levels are high during starvation, it acts whereas metformin inhibits gluconeogenesis pathway(8; 9).
through a secondary messenger, cyclic adenosine monophos- However, these drugs also activate upstream regulators or
phate (cAMP) to increase PEPCK gene expression. pathways involved in other various physiological functions

- 24 -
Annals of Multidisciplinary Research, Innovation and Technology (AMRIT), 1(2), 2022, 23-34 ISSN: 2583-4657

Table 1: Summary of Transcription Factors Involved in the Regulation of Cytosolic PEPCK Gene Expression

Transcription factor Function in PCK gene expression

Basal transcription
C/EBPα
cAMP-induced gene expression
Basal transcription
C/EBPβ
cAMP-induced gene expression
DBP Basal transcription
NF-1 Inhibits cAMP induced gene expression
HNF-1 Renal gene expression
HNF-3 Glucocorticoid-induced gene expression
CREB cAMP-induced gene expression
GR Glucocorticoid-induced gene expression
THR Thyroid hormone-induced gene expression
PPARy 2 Adipose tissue specific expression

like PPAR-, AMPK etc(11; 12; 13; 14). It is also ob- Arg87, Arg405, and the Na ion. The carboxylate group of
served that these medicines leads to drug resistance at cer- PEP is held by interactions with the main-chain NH groups
tain stages and has high rates of decreased response to of Arg87 and Gly417 and the side-chain amide group of
the drug after initial response. Previous attempts to con- Asn403. The un-liganded enzyme contains a bound Mn
trol hepatic glucose production (HGP) through inhibition ion and no bound Mg2+. The cysteine residue at posi-
of gluconeogenesis were limited to biguanides such as met- tion 288 is known to be very reactive and essential for cat-
formin. Metformin has many side effects such as gastroin- alytic activity as it lies between two putative phosphoryl
testinal disturbances and lactic acidosis (overproduction of binding domains and within a hydrophobic sequence(37).
lactic acid,)(4; 5). Inhibition of PEPCK provides supe- Under conditions where GTP is present as the Mg-GTP
rior efficacy and, coupled with reduced side effects, repre- complex and free Mg2+ is present in excess that Mn2+,
sents a novel treatment for T2DM considering its role dur- activation of PEPCK depends upon the degree of oxidation
ing hyperglycemia(25). One way to alleviate the diabetes- of cysteine sulfhydryl(38). PEPCK is known to be sensitive
induced hyperglycemia would be to lower the activity of to thiol reagents, and free sulfhydryl groups are essential
PEPCK. With this rationale, there have been efforts to for its catalytic activity and its modulation by sulfhydryl
identify the key amino acid residues that have major but reagents leads to its inhibition(39). PEPCK has 52 argi-
not essential roles in enzyme catalysis. Specific inhibitors nine residues, out of which, only one or two of the arginines
of either PEPCK gene expression or its enzymatic activity, are located at the active site and involved in CO; binding
might decrease hepatic glucose overproduction and substan- and activation(40). One of the 15 histidine residues in the
tially decrease hyperglycemia in diabetic patients(26). PEPCK is at or near the binding site and is involved in
catalysis.
5 Mechanism of PEPCK Inhibition
5.1 Known PEPCK Modulators
Structural analysis of PEPCK has also given new ideas on
its regulation and suggested to be a target for drug dis- Structural data suggest that molecules having phosphoryl-
covery. The structure of PEPCK has been solved exper- and phosphono-mono-carboxylates can attain correct po-
imentally by previous workers; captured in various active larity in the active site via the phosphoryl/phosphono
site conformations, such as holo-enzyme, GTP bound con- group of PEPCK. The phosphorus containing moiety
formation, and product bound conformation(33). PEPCK, can orient toward the manganese centre and position
like other kinases, is probably a bilobular enzyme with its the carboxylate toward the end of the pocket (Ta-
catalytic site at the base of the groove(34). One way of ble 2). (41) has thoroughly studied various substrate
PEPCK degradation is an inactivation reaction involving (PEP and OAA) analogues of PEPCK; oxalate1, succi-
oxidized thiol compounds. Loss of PEPCK activity was nate2, maleate3, phosphonoformate4, phosphoglycolate5, 3-
caused by modification of both thiol and vicinal dithiol phosphonopropionate6, 1,2-ethanediphosphonate7, sulfoac-
groups in the substrate binding region(35). Maxwell and etate8, 2,2-dimethylsulfoacetate9, 3-sulfopropionate10, sul-
Ray observed that PEPCK is not activated by Fe2+ but is fosuccinate11, 1,2-ethanedisulfonate12, pyrophosphate13,
inhibited by quinolinate18 (a dicarboxylic acid with a pyri- methanediphosphonate14, methanedisulfonate15. Out of
dine backbone)(36) . In the complex of human PEPCK these, phosphono formate and oxalate shows competitive
with PEP, no Magnesium (Mg) ion is present, and the Mn inhibition with a Ki value of 231 µM and 82 µM respec-
ion is found to be interacting with Lys244, His264, Asp311 tively. Pyrophosphate, Methane diphosphonate, Methane
residues, and three water molecules. Two molecules of wa- disulfonate belonging to the group of Diphosphoryls and
ter forms a bridge between Mn2+ and the terminal oxy- Diphosphonates, shows non-competitive inhibition towards
gen atoms of PEP’s phosphate moiety. PEP binds as a PEPCK. Methane diphosphonate and Methane disulfonate,
1:1 complex with a sodium (Na) ion. The negative charge being compounds of similar size and configuration as py-
on the phosphate is counterbalanced by the side-chains of rophosphate are reported to be non-competitive inhibitors

- 25 -
Annals of Multidisciplinary Research, Innovation and Technology (AMRIT), 1(2), 2022, 23-34 ISSN: 2583-4657

given that the -phosphate of GTP, acts a bridging ligand

between the active site and nucleotide metals. This site
also has been observed to bind anions like sulphate(42).
Putative OAA analogues are poor inhibitors which suggest
that the enzyme is relatively intolerant of changes in the
bi-carboxylate structure and two planar cis-carbonyl groups
for binding of ligands to its active site.β-sulfopyruvate16 are
sulfonyl mono-carboxylates are good inhibitors of PEPCK,
suggesting that the β-sulfo group effectively mimics the Figure 4: Non-substrate (GTP/GDP) Analogues.
C1 carboxylate of OAA and therefore binds to the en- 1-Allyl-3-butyl-8-methylxanthine (18), 5-Chloro-1,3-
zyme with a Ki similar to the Km of OAA (Ki=19-138 dimethylpyrazole (19), N-4-[3-Cyclopropylmethyl-
µM)(43). Phosphoglycolate is a well-studied competitive 1-(2-fluorobenzyl)-2,6 dioxo-2,3,6,7- tetrahydro-
inhibitor of PEPCK, with an inhibition constant (Ki) value 1H-purin-8-ylmethyl]-phenyl acetamide (20), N1-
of 1.04 mM. Because of its structural similarity to PEP, cyclohexyl-2-1-[4-methyl-2-(2-thienyl)-1,3-thiazol-5-
this analogue is used as an alternative substrate or re- yl]ethylidenehydrazine-1-carbothiamide (21), N’1-
versible inhibitor of PEPCK(41). It appears that PEP ob- (5-[1-methyl-5-(trifluoromethyl)-1H-pyrazol-3-yl]-2-
tains its higher affinity compared to its analogues like phos- thienylmethylidene)-2,4- dichlorobenzene-1-carbohydrazide
phoglycolate and 3-phosphonopropionoate -due to its aro- (22)
matic interactions with Y235 and F333 residues. Both PGA
and 3-phosphonopropionate lack the C3 methylene group, There are two binding sites of 3-MPA: one in the ac-
which appears to make a favourable aromatic interaction tive site that was responsible for the competitive inhibi-
with F333 residue. Studies have shown that R-hydroxyl tion and the other one close to the active site, able to
and R-sulfhydryl carboxylic acids are poor substrates for influence allosterically, the binding of substrates and in-
phosphoryl transfer reaction of PEPCK(43). There are two hibitors to the active site. The first report of non-susbtrate
PPAR binding sites in the PEPCK promoter, thus offer- competitive GTP inhibitors of PEPCK is 1-allyl-3-butyl-
ing potential sites through which known anti-hyperglycemic 8-methylxanthine18(39). The tri substituted xanthines
drugs like Thiazolidinediones (TZDs) (also targets PPAR (3-alkyl-1,8-dibenzylxanthines) are novel xanthenes which
site) could inhibit transcription of this gene. There is a are among the first inhibitors of human PEPCK to com-
definite role of extended binding site in PEPCK. Not only pete with the natural GTP substrate. Modifications at
extended site seems to play an important role in PEPCK’s xanthine’s C-8 aminobenzyl moiety shows a 5-membered
catalytic mechanism, non-competitive known inhibitors like heteroaromatic N-benzylsulfonamides providing a new -
3-Mercaptopicolinic acid (3-MPA)17 also seem to exploit interaction which increased the inhibitory activity of the
this site to inhibit the functional activity of PEPCK. xanthine class of PEPCK inhibitors. An analogue of the
sulphonamide class i.e. 5-chloro-1,3-dimethylpyrazole19 is
reported to be the most active inhibitor in both in vitro and
in vivo studies(44).
The use of and search for drugs and dietary supplements
derived from plants have accelerated in recent years. With
the rapid advancement of novel technologies and the in-
creased research on anti-diabetic natural products, many
new plants, extracts or active compounds have been found
to exhibit anti-diabetic effects particularly in its action
against PEPCK. These may provide us with valuable leads
to develop novel anti-diabetic agents to supplement the cur-
rent therapies (Table 3).
5.1.1 Plant Phenolic Compounds
Recent research strongly supports the concept that con-
sumption of fruits and plant-derived foods is beneficial for
treatment of T2DM and other metabolic complications(46).
The beneficial health effects of plant-derived products have
been largely attributed to its polyphenolic compounds(47).
Figure 3: Substrate (PEP/OAA) Analogues. Ox- These are the secondary metabolites produced in the plants
alate (1), Succinate (2), Maleate (3), Phosphonofor- by shikimic acid and pentose phosphate pathway (PPP)
mate (4), Phosphoglycolate (5), 3-Phosphonopropionate through phenylpropanoid metabolism(48). They range
(6), 1,2- ethanediphosphonate (7), Sulfoacetate (8), 2,2- from simple phenolic molecules to highly polymerized com-
Dimethylsulfoacetate (9), 3-Sulfopropionate (10), Sul- pounds containing benzene ring with one or more hydroxyl
fosuccinate (11), 1,2-Ethanedisulfonate (12), Pyrophos- substituent(49). Phenolics are the most distinct secondary
phate (13), Methanediphosphonate (14), Methanedisul- metabolites found in plants, and their distribution is re-
fonate (15), β-sulfopyruvate (16),3-Mercaptopicolinic acid ported throughout different metabolic process. It contains
(17), Quinolinate (18). numerous varieties of compounds: simple flavonoids, pheno-

- 26 -
Annals of Multidisciplinary Research, Innovation and Technology (AMRIT), 1(2), 2022, 23-34 ISSN: 2583-4657

Table 2: PEPCK Inhibition Pattern of Some Substrate and Non-substrate Analogues

Sl.No. Compound Name Pattern of Inhibition

Substrate (PEP/OAA) Analogues
1. Oxalate 1 Competitive
2. Succinate 2 Not Defined
3. Maleate 3 Not Defined
4. Phosphonoformate 4 Competitive
5. Phosphoglycolate 5 Competitive
6. 3-Phosphonopropionate 6 Competitive
7. 1,2-ethanediphosphonate 7 Competitive
8. Sulfoacetate 8 Competitive
9. 2,2-Dimethylsulfoacetate 9 Competitive
10. 3-Sulfopropionate 10 Competitive
11. Sulfosuccinate 11 Not defined
12. 1,2-Ethanedisulfonate 12 Not defined
13. Pyrophosphate 13 Noncompetitive
14. Methanediphosphonate 14 Noncompetitive
15. Methanedisulfonate 15 Noncompetitive
16. β-sulfopyruvate 16 Noncompetitive
17. 3-Mercaptopicolinic acid 17 Non-Competitive
18. Quinolinate 17 Competitive
Non-substrate (GTP/GDP) Analogues
19. 1-Allyl-3-butyl-8-methylxanthine 18 Competitive
20. 5-Chloro-1,3-dimethylpyrazole 19 Competitive
21. N-{4-[3-Cyclopropylmethyl-1-(2-fluorobenzyl)-2,6 dioxo- Competitive
2,3,6,7- tetrahydro-1H-purin-8-ylmethyl]-phenyl} ac-
etamide 20
22. N1-cyclohexyl-2-{1-[4-methyl-2-(2-thienyl)-1,3-thiazol-5- Competitive
yl]ethylidene}hydrazine-1-carbothiamide 21
23. N’1-({5-[1-methyl-5-(trifluoromethyl)-1H-pyrazol- Competitive
3-yl]-2-thienyl}methylidene)-2,4-dichlorobenzene-1-
carbohydrazide 22

lic acids, complex flavonoids and colored anthocyanins(50).

Several antioxidants from plants polyphenols have been
shown to possess potential regulators of blood glucose. Di-
etary plant polyphenols modulate carbohydrate and lipid
metabolism, attenuate hyperglycemia, dyslipidemia and in-
sulin resistance, improve β-cell function and stimulate in-
sulin secretion(47).Polyphenols have been suggested to en-
rich important hallmarks of T2DM (e.g. fasting and post-
prandial hyperglycemia) by inhibiting di-saccharidases (α-
amylase and α -glucosidase) in the intestinal lumen and also
improve glucose uptake in muscle and adipocytes(47).

Figure 5: PEPCK modulators by plant derived phenolic

compounds. Resveratrol (23), Oxyresveratrol (24), Pteros-
tilbene (25), Curcumin (26), Phloroglucinol (27), Caf-
feoylquinic acid (28), Rosmarinic acid (29), Octaphlorethol
A (30), Ferulic acid (31), Fisetin (32), Quercetin (33), Lu-
teolin (34), Apigenin (35), Dihydromyricetin (36)

These compounds also have been found to decrease PEPCK

expression and the rate of gluconeogenesis in streptozotocin
induced diabetic rats and in the hepatocyte cell line(51; 52)
(Figure 5). Resveratrol23, a polyphenol abundant in grapes

- 27 -
Annals of Multidisciplinary Research, Innovation and Technology (AMRIT), 1(2), 2022, 23-34 ISSN: 2583-4657

and cranberry, has been shown to directly up regulate nia fruit, cocoa beans, grape skin) conjugated with cate-
SIRT1 and AMPK signalling pathways in vivo and ex- chins, have been shown to possess insulin mimetic proper-
ert calorie restriction-like benefits(53). It is also shown ties which stimulate glucose uptake in adipocytes(72). They
to significantly decrease PEPCK protein level via PI3K- are oligomeric structures exclusively formed by polymeriza-
Akt-signaling pathway. Treatment of STZ-diabetic rats tion of 2 to 10 subunits of the monomeric flavanolscatechin
with 23 (3.0 mg/kg), significantly decreased PEPCK pro- and epicatechin. (73) reported that Areca nut procyani-
tein level from 1.15 ± 0.02 to 0.92 ± 0.01 in liver(54). dins (ANP) has the potential to control hyperglycemia by
Other stilbene derivatives like, oxyresveratrol24 and pteros- regulating PEPCK in diabetic mice. Continuous feeding of
tilbene25 is also reported to suppress hepatic gluconeogenic ANP 10 mg/kg for 4 weeks in diabetes induced mice re-
gene expression and glucose production via AMPK activa- sulted in 40% reduction in PEPCK expression and a 31%
tion in H4IIE cells(55). Curcumin26, the active compo- reduction in blood glucose levels(73). Antihyperglycemic
nent of Curcuma longa (turmeric) have shown inhibitory effect of procyanidins is also reviewed previously. Increase
activity against PEPCK that result in improved insulin in AMPK phosphorylation in hepatic, adipose, and muscle
sensitivity. The level of expression of PEPCK was de- tissues was also found in vivo in diabetic induced mice along
creased significantly with treatment of 15-60 mg/kg of 26 with the upregulation of GLUT-4(74; 75). A flavonoid of
in rat models(56). In primary hepatocytes, curcumin26 strawberries, onion, persimmon; fistetin32 improves glucose
and phloroglucinol27 (found in Ecklonia cava, an edible homeostasis through the inhibition of hepatic gluconeogene-
brown algae) has been shown to inhibit gluconeogenesis sis which is evident from altered expression of PEPCK(76).
by activating AMPK, which diminishes PEPCK activity Quercetin33, structurally similar to 32, is universally dis-
in an insulin-independent manner. Treatment of isolated tributed in the plant kingdom and the most abundant
mice hepatocyte with 25 M of 26 for 120 min inhibited flavonoid in the human diet which is also known to inhibit
activity of PEPCK by about 30%. Western blot analysis PEPCK(77). Treatment with 50 M of 33 stimulated AMPK
also showed decrease in expression of 3 or 6 h of treat- and increased GLUT4 translocation and protein content in
ment with 50 µM of phloroglucinol27 compared with the cultured rat L6 skeletal muscle cells. It positively influences
control group(57; 58). Polyphenols form Syzygium aro- glucose metabolism and therefore appear to be a promis-
maticum (clove) and Artemisia dracunculus (tarragon), 5- ing therapeutic candidate for the treatment of T2DM. Lu-
caffeoylquinic acid 28 acid found in Coffea arabica (coffee) teolin34 is another most common polyphenolic flavonoids
and Cichorium intybus (chicory) were also shown to reduce present in many edible plants such as carrots, peppers,
expression levels of PEPCK(59; 60). Rosmarinic acid 29 is a celery, olive oil, peppermint, thyme, rosemary, oregano,
potent antioxidant present in many common culinary herbs lettuce, pomegranate, artichoke, cucumber, lemon, beets,
belonging to Lamiaceae, Boraginaceae, and Anthocero- cabbage, cauliflower, spinach, parsley, and green tea(71).
taceae families and was first isolated from rosemary (Ros- Structurally similar to 34, apigenin35 is a natural plant
marinus officinalis)(61). Treatment of HFD rats with ros- flavone abundant in chamomile, parsley, onions, grapefruit,
marinic acid 29 (200 mg/kg) via intra-peritoneal injection oranges and plant derived beverages with antioxidant and
for 7 days reduces hyperglycaemia and ameliorates insulin anti-proliferative effects(78). Apigenin35 having three phe-
sensitivity by decreasing PEPCK expression (from 1.9 to nolic hydroxyl groups has a lower antioxidant activity than
1.3 fold) and increasing GLUT-4 (insulin-regulated glucose luteolin34 bearing four phenolic OH-groups including an
transporter) expression(62). Octaphlorethol-A (OPA)30, a ortho-dihydroxy structure in the B ring and 2,3-double bond
type of phlorotannin found in Ishige foliacea (marine al- in conjugation with the 4-oxo function in the C ring and
gae) is reported to inhibit PEPCK activity by increas- the 5- and 7-OH groups in ring A for effective free rad-
ing GLUT4-mediated glucose utilization via activation of ical scavenging by dissociation of hydroxyl functions(79).
AMPK(63). Ferulic acid 31 is one of the most bioavail- PEPCK mRNA expression was down-regulated by flavones
able compounds found in many staple foods such as grain in a dose dependent manner after 2 h with an IC50 of 3.2
bran, whole grain food, citrus fruits, banana, coffee, or- mM for apigenin and 5.2 mM for luteolin. PKB/AKT-,
ange juice, eggplant, bamboo shoots, beetroot, cabbage, PRAS40-, p70S6K-, and S6-phosphorylation are reported
spinach and broccoli(64). Ferulic acid 31 is recognized for to be the target signaling pathway(80). A major Chi-
its anti-diabetic property by improving insulin signalling nese drug constituent, dihydro-myricetin (ampelopsin)36
molecules and reducing the negative regulators of insulin found in Ampelopsis grossedentata is reported to regulate
action. The mRNA levels of PEPCK and the interaction be- PEPCK via the IRS/PI3K/Akt signalling pathways to de-
tween the Foxo1 signalling protein and promoters of gluco- crease glucose production(81; 82). Another major group
neogenic genes were reported to be reduced significantly by of flavonoids, anthocyanins are the group of polyphenols
31(65). Flavonoids, the major class of polyphenols are con- generally found in bilberries and berries are known to reg-
sidered as prospective therapeutic compounds in the treat- ulate glucose metabolism. Anthocyanins of different origin
ment of TD2M. Flavonoids from medicinal plants are known have shown to affect glucose absorption, insulin secretion
to have beneficial hypoglycemic effects as reported earlier and lipid metabolism in both in vitro and in vivo models.
in soybean(66), buckwheat leaf(67), mulberry leaf(68), Mo- (83; 84) have reported the decrease in enzyme activities of
mordica grosvenori fruit(69), and Lithocarpus polystachyus PEPCK due to inhibition of important signalling pathway
leaf(70). They are large heterogeneous group of phytochem- proteins like PPAR coactivator 1α (PGC-1α) and Foxo1 by
icals found in plant-based foods (tea, soy, coffee, cocoa, anthocyanian extract of Morus alba (white mulberry).
cereal grains, cinnamon, ginger, fruits, and berries)(71).
Procyanidins (flavonoid found in apple, cinnamon, aro-

- 28 -
Annals of Multidisciplinary Research, Innovation and Technology (AMRIT), 1(2), 2022, 23-34 ISSN: 2583-4657

5.1.2 Alkaloids 5.1.3 Terpenoids and Steroids

Alkaloids are the plant derived heterocyclic nitrogenous Terpenoids and steroids constitute the largest known group
compounds most common in herbaceous plants, but some of plant secondary metabolites. Triterpenes are specific to
occur in woody tropical species also. Plant alkaloids pre- the plant kingdom and like steroids, arise via squalene(a
dominate in four families of plants viz. Asteraceae, Apoc- biochemical intermediate), from mevalonate pathway (iso-
ynaceae, Boraginaceae and Fabaceae(84). This large group prenoid pathway or HMG-CoA reductase pathway). Ter-
of secondary metabolites with approximately 20,000 com- penoids and steroids are formed by units of 5-carbon derived
pounds identified till date representing huge structural from 2-methylbutadiene and oxygen.
biosynthetic diversity(85). Based on their biosynthetic ori-
gin, alkaloids are classified into different classes; indole al-
kaloids derived from tryptophan, pyrrolizidine alkaloids de-
rived from ornithine or arginine, and quinolizidine alkaloids
derived from lysine(86). Alkaloids are known for poten-
tial treatment for disorders related to diabetes, such as
hyperglycemia, hyperlipidemia, insulin resistance etc.(87).
Berberine37 an isoquinoline alkaloid originally obtained
from root and stem bark of extracts of the Chinese herb,
Coptischinensis (Chinese goldthread) is reported to regulate
PEPCK through decreased expression of FoxO1, SREBP1,
ChREBP and AMPK signalling pathway in the liver(88; 89) Figure 7: PEPCK modulators by plant derived terpenoids
(Figure 6). and steroids. Pterosin A (44), Tormentic acid (45), eburi-
coic acid (46), 3-Deacetyl-3-cinnamoyl-azadirachtin (47),
Ergostatrien-3β-ol (48), 20-Hydroxyecdysone (49).

Pterosins, a class of terpenes are abundant in ferns (eg. Hy-

polepispunctata), and pterosin A is considered a novel ac-
tivator of AMPK, which is crucial for regulating blood glu-
cose homeostasis(94) (Figure 7). PterosinA44 (100 mg/kg)
is reported to inhibit PEPCK expression in cultured liver
cells by triggering phosphorylations of AMPK in the liv-
ers of STZ induced diabetic mice. It also enhanced glu-
cose uptake and AMPK phosphorylation in cultured human
muscle cells(95). Similar mechanism of inhibition are also
observed in tormentic acid 45 (bioactive compound of the
Figure 6: PEPCK modulators by plant derived alkaloids. leaf extract of loquat (Eriobotrya japonica)(96) eburicoic
Berberine (37), Isonitramine (38), Lycoricidine (39), Lyco- acid46 (bioactive compound of the edible fungus, Antro-
ricidinol (40), Rutaecarpine (41), Evodiamine (42), Arecol- dia camphorata)(97) in both in vivo and in vitro studies.3-
ine (43). Deacetyl-3-cinnamoyl-azadirachtin47 present in the neem
leaf extract has also been reported to exhibit perfect bind-
ing with PEPCK based on molecular docking studies and
Isonitramine38 is a synthesized Nitraria alkaloid (a genus structural data information. In a computational study, 47
of flowering plants belonging to Nitrariaceae family) and was found to bound deep into the binding cavity of PEPCK
has structural similarity to amino alcohol group of acar- making interactions with the residues Asn292, Met 295,
bose, an oral α-glucosidase inhibitor known for its use in the Leu293, Asn297, Gly289, Thr343, Pro528, Phe530, and
treatment of T2DM. Isonitramine38 is reported to increase Gly531 and with a good binding affinity of -37.57 Kcal(98).
insulin secretion as well as decrease PEPCK expression, re- Ergostatrien-3-β-ol48 derived from Antrodia camphorata is
sulting in normalization of glucose metabolism(90). Alka- also reported to increase expression levels of GLUT-4 and
loids derived from the extract of the bulbs of Lycoris san- AMPK possibly by down-regulations of PEPCK to inhibit
guinea (lily), lycoricidine39 and lycoricidinol40 suppresses hepatic glucose production. The most common ecdysteroid,
PEPCK expression by more than 80% at the concentra- 20-hydroxyecdysone (20E) 49 is found in many plants such
tion of 0.1M by inhibiting the phosphorylation of CREB as quinoa is reported to down regulate of liver PEPCK ex-
pathway(91). Rutaecarpine41 (10 and 25 M) and evodi- pression and also reduced the expression of PEPCK in adi-
amine42 (1 and 5 M), derived from Evodia rutaecarpa, in- pose tissue, suggesting a decreased glycerogenesis(99)
hibits PEPCK gene expression through regulation of sig-
nalling proteins Foxo1 and HNF4α (92). Arecoline43 (1.5 5.1.4 Glycoside
mg/kg), a nicotinic acid-based alkaloid found in the areca Glycosides are a group of naturally occurring compounds
nut (Areca catechu) improved hepatic insulin resistance in found in a variety of plant families, studied for their an-
T2DM rat models by increasing the mRNA levels of liver tibacterial, antifungal, anti-inflammatory, antioxidant, an-
nuclear receptors; constitutive and rostane receptor (CAR) tiviral and anticancer activities. There are more than
and pregnane X receptor (PXR) leading to the reduced glu- 11 distinguished classes, consisting of anthraquinone, car-
cose metabolism and PEPCK expression(93). diac, chromone, coumarin, cyanogenic, flavonoid, saponin,

- 29 -
Annals of Multidisciplinary Research, Innovation and Technology (AMRIT), 1(2), 2022, 23-34 ISSN: 2583-4657

steroidal and steviol glycosides(100). triterpenoid and steroidal glycosides collectively referred to
as saponins consist of polycyclic aglycones attached to one
or more sugar side chains. The a glycone part (sapogenin)
is either steroid (C27) or a triterpene (C30). These bioac-
tive compounds are present naturally in many plants and
known to possess potent hypoglycemic activity(106). Gin-
seng (Panax) is considered as one of the most important
alternative medicine for diabetes treatment(107). Phar-
macological properties of ginseng are mainly attributed to
the compound, ginsenoside Rg5 57(108). Ginsenoside Rg5
57 (50 mg/kg) decreases PEPCK expression by regulating
CREB activity in HFD-fed mice(109). The major prospec-
tive metabolite of protopanaxadiol-type ginsenoside, Gin-
senoside compound K58 (30 mg/kg dose per day), is re-
ported to show potent hypoglycemic effects which sup-
presses PEPCK activity via AMPK activation in the liver
after 4 weeks of administration. This is also supported by
in vitro experiments where alteration of PEPCK level con-
sists of the alteration of hepatic glucose production in a
dose-dependent manner after Compound K58 treatment in
HepG2 cells(68). Similar mechanism of inhibition are also
observed in Geniposide59 (active compound of Gardenia
jasminoides)(110) total saponins from box bean, Entada
phaseoloides(69) total saponins from Dioscorea nipponica
Figure 8: PEPCK modulators by plant derived glycosides. Makino(111) in both in vivo and in vitro studies.
Trans-2,3,5,4- tetrahydroxystilbene 2-O-β glucopyranoside
(50), Baicalin (51), Marein (52), Diosmin (53), Swertia- 6 Conclusion
marin (54), Salidroside (55), Amarogentin (56), Ginseno-
Diabetes is possibly the world’s fastest growing metabolic
side Rg5 (57), Ginsenoside compound K (58), Geniposide
disease and as its knowledge of heterogeneity increases, so
(58).
does the need for more appropriate disease control. Despite
the presence of anti-diabetic drugs in the pharmaceutical
Glycosides molecules are formed when the hydroxyl group market, the treatment of diabetes with medicinal plants
on the anomeric carbon of a sugar and the hydroxyl group is often successful. Herbal medicines and plant compo-
of another molecule condense to form an acetal or ke- nents with limited toxicity and no side effects are notable
tal linkage, known as a glycosidic bond(101). Several therapeutic options for the treatment of this disease. The
kinds of glycosides including hederagenin, phenolics, fla- existence of various beneficial plant secondary metabolites
vanone, and steroidal glycosides reported to possess anti- implies the importance of the anti-diabetic properties of
diabetic properties(102; 103) (Figure 8). Trans-2,3,5,4- these plants. The mechanisms of actions of hypoglycaemic
tetrahydroxystilbene 2-O-β glucopyranoside (trans-THSG) plants include: increasing of insulin secretion, increasing
50 a major bioactive phytochemical found in Polygonum of glucose absorption by muscle and fat tissues, prevention
multiflorum (tuber fleece flower), is a stilbene deriva- of glucose absorption from the intestine, and prevention
tive. The only difference between structures of trans- of glucose production from liver cells. These factors are
THSG50 and resveratrol23 is an extra 2-O-glycoside group mostly responsible for the reduction or elimination of dia-
in trans-THSG50. In HepG2 cells, cis-THSG50 (5 µM) betes complications. Most of the compounds reviewed here
demonstrated potent activity in suppressing transcription regulate PEPCK through inhibition of key signalling path-
of PEPCK. The main bioactive component of Scutel- ways viz AMPK, FOXO1, PGC1α, CREB etc. to control
laria baicalensis (traditional Chinese herbal medicine), glucose overproduction. Changes in PEPCK content alone
baicalin (5,6,7-trihydroxyflavone -7-b-D-glucuronide)51 and may not be sufficient to modulate gluconeogenesis. Con-
marein52, a major compound of Coreopsis tinctoria (gar- sidering the exquisite regulation of this enzyme, it seems
den tickseed) is found to inhibit expression of PEPCK via likely that PEPCK expression must coordinate with other
activation of the AMPK pathway(104). Diosmin53 com- mechanisms to regulate gluconeogenesis including key sig-
monly found in citrus fruits, has also been indicated to im- nalling proteins of cellular energy homeostasis. Further
prove glucose metabolism in diabetic disorders by regulating studies need to be carried out to see whether some of these
PEPCK(95). Swertiamarin54, a bitter secoiridoid glycoside compounds also bind to the active site of the enzyme to
and a known antidiabetic drug is also found to modulate control its rate of reaction. As the cytotoxic levels of many
PPAR-α which in turn, decreases the levels of PEPCK(105). of these compounds are much within the approved limits,
Salidroside55 (a phenylpropanoid glycoside) an active com- it would be reasonable to take these compounds for further
pound in Rhodiola rosea (rose root) and amarogentin56 (0.5 studies for its regulation of PEPCK. Computational studies
mg/kg), an active compound in Gentiana lutea (great yel- would also help to develop new pharmacophore regions in
low gentian), is reported to supress activity of PEPCK by these compounds which would fit perfectly inside the sub-
stimulating AMPK pathway in STZ-diabetic rats(69). The strate or nucleotide binding site of the enzyme. Along with

- 30 -
Annals of Multidisciplinary Research, Innovation and Technology (AMRIT), 1(2), 2022, 23-34 ISSN: 2583-4657

these, combination therapies to control glucose production [14] M. Stumvoll, N. Nurjhan, G. Perriello, G. Dailey, and
could be developed using two or more compounds. This re- J. E. Gerich, “Metabolic effects of metformin in non-insulin-
dependent diabetes mellitus,” New England Journal of
view provides insight into the current available compounds Medicine, vol. 333, no. 9, pp. 550–554, 1995.
against PEPCK, its mode of action and future directions
to develop novel anti-diabetic drugs. [15] R. A. Dar, M. Shahnawaz, S. Rasool, and P. H. Qazi, “Natural
product medicines: A literature update,” J phytopharmacol,
vol. 6, no. 6, pp. 349–351, 2017.
Conflict of Interest
[16] P. K. Prabhakar and M. Doble, “A target based therapeutic
approach towards diabetes mellitus using medicinal plants,”
The authors declare no conflict of Interest in this reported Current Diabetes Reviews, vol. 4, no. 4, pp. 291–308, 2008.
communication.
[17] S. M. Tilghman, R. Hanson, L. Reshef, M. Hopgood, and
F. Ballard, “Rapid loss of translatable messenger rna of phos-
Acknowledgments We are thankful to Department of phoenolpyruvate carboxykinase during glucose repression in
Science and Technology (Government of India), New Delhi, liver,” Proceedings of the National Academy of Sciences,
for providing financial support through a project sanc- vol. 71, no. 4, pp. 1304–1308, 1974.
tioned to AD (DST SERB NPDF project sanction no. [18] R. W. Hanson and Y. M. Patel, “Phosphoenolpyruvate car-
PDF/2016/002702). Thanks are also due to the Director, boxykinase (gtp): the gene and the enzyme,” Advances in en-
IASST for providing infrastructural facilities. zymology and related areas of molecular biology, vol. 69, pp.
203–203, 1994.

[19] R. K. Hall, X. L. Wang, L. George, S. R. Koch, and D. K.

References Granner, “Insulin represses phosphoenolpyruvate carboxyki-
[1] R. Rognstad, “Rate-limiting steps in metabolic pathways,” nase gene transcription by causing the rapid disruption of an
Journal of Biological Chemistry, vol. 254, p. 18751878, 1979. active transcription complex: a potential epigenetic effect,”
Molecular Endocrinology, vol. 21, no. 2, pp. 550–563, 2007.
[2] R. W. Hanson and L. Reshef, “Regulation of phosphoenolpyru-
vate carboxykinase (gtp) gene expression,” Annual Review of [20] C. Ramnanan, D. S. Edgerton, and A. Cherrington, “The role
Biochemistry, vol. 66, p. 581611, 1997. of insulin in the regulation of pepck and gluconeogenesis in
vivo,” US Endocrinology, vol. 5, pp. 34–39, 2010.
[3] D. L. Nelson and M. M. Cox, “Lehninger principles of biochem-
istry,” WH Freeman and Company, no. 6, 2012. [21] H. Cao, E. van der Veer, M. R. Ban, A. J. Hanley, B. Zin-
man, S. B. Harris, T. K. Young, J. G. Pickering, and R. A.
[4] R. A. Defronzo and E. Ferrannini, “Insulin resistance: a multi- Hegele, “Promoter polymorphism in pck1 (phosphoenolpyru-
faceted syndrome responsible for niddm, obesity, hypertension, vate carboxykinase gene) associated with type 2 diabetes mel-
dyslipidemia, and atherosclerotic cardiovascular disease,” Di- litus,” The Journal of Clinical Endocrinology & Metabolism,
abetes Care, vol. 14, p. 173194, 1991. vol. 89, no. 2, pp. 898–903, 2004.
[5] A. Consoli, N. Nurjhan, F. Capani, and J. Gerich, “Predomi-
[22] S. D. Rees, A. C. Britten, S. Bellary, J. P. O’Hare, S. Kumar,
nant role of gluconeogenesis in increased hepatic glucose pro-
A. H. Barnett, and M. Kelly, “The promoter polymorphism-
duction in niddm,” Diabetes, vol. 38, no. 5, pp. 550–557, 1989.
232c/g of the pck1 gene is associated with type 2 diabetes in a
uk-resident south asian population,” BMC Medical Genetics,
[6] C. J. Bailey, “Biguanides and niddm,” Diabetes Care, vol. 15,
vol. 10, no. 1, pp. 1–7, 2009.
p. 755772, 1992.

[7] B. J. Goldstein, “Rosiglitazone,” International Journal of [23] W. K. Ward, J. C. Beard, J. B. Halter, M. A. Pfeifer, and
Clinical Practice, vol. 54, no. 3, p. 33337, 2000. D. Porte Jr, “Pathophysiology of insulin secretion in non-
insulin-dependent diabetes mellitus,” Diabetes care, vol. 7,
[8] K. Schoonjans and J. Auwerx, “Thiazolidinediones: an up- no. 5, pp. 491–502, 1984.
date,” The Lancet, vol. 355, no. 9208, pp. 1008–1010, 2000.
[24] Y. Sun, S. Liu, S. Ferguson, L. Wang, P. Klepcyk, J. S.
[9] R. S. Hundal, M. Krssak, S. Dufour, D. Laurent, V. Lebon, Yun, and J. E. Friedman, “Phosphoenolpyruvate carboxyki-
V. Chandramouli, S. E. Inzucchi, W. C. Schumann, K. F. nase overexpression selectively attenuates insulin signaling and
Petersen, B. R. Landau et al., “Mechanism by which met- hepatic insulin sensitivity in transgenic mice,” Journal of Bi-
formin reduces glucose production in type 2 diabetes.” Dia- ological Chemistry, vol. 277, no. 26, pp. 23 301–23 307, 2002.
betes, vol. 49, no. 12, pp. 2063–2069, 2000.
[25] S. Wall, J. Chow, J. Huang, M. Jiang, A. Yang, and K. Jones,
[10] G. Zhou, R. Myers, Y. Li, Y. Chen, X. Shen, J. Fenyk-Melody, “Phosphoenolpyruvate carboxykinase: Possible therapeutic
M. Wu, J. Ventre, T. Doebber, N. Fujii et al., “Role of amp- targets for insulin resistant type-ii diabetes,” The FASEB
activated protein kinase in mechanism of metformin action,” Journal, vol. 29, p. LB67, 2015.
The Journal of clinical investigation, vol. 108, no. 8, pp. 1167–
1174, 2001.
[26] A. Valera, A. Pujol, M. Pelegrin, and F. Bosch, “Transgenic
mice overexpressing phosphoenolpyruvate carboxykinase de-
[11] A.-M. Lefebvre, I. Chen, P. Desreumaux, J. Najib, J.-C.
velop non-insulin-dependent diabetes mellitus.” Proceedings of
Fruchart, K. Geboes, M. Briggs, R. Heyman, and J. Auw-
the National Academy of Sciences, vol. 91, no. 19, pp. 9151–
erx, “Activation of the peroxisome proliferator-activated recep-
9154, 1994.
tor γ promotes the development of colon tumors in c57bl/6j-
apcmin/+ mice,” Nature medicine, vol. 4, no. 9, pp. 1053–
1057, 1998. [27] A. G. Gómez-Valadés, A. Vidal-Alabró, M. Molas, J. Boada,
J. Bermúdez, R. Bartrons, and J. C. Perales, “Overcoming
[12] P. Sarraf, E. Mueller, D. Jones, F. J. King, D. J. DeAngelo, diabetes-induced hyperglycemia through inhibition of hepatic
J. B. Partridge, S. A. Holden, L. B. Chen, S. Singer, C. Fletcher phosphoenolpyruvate carboxykinase (gtp) with rnai,” Molecu-
et al., “Differentiation and reversal of malignant changes in lar Therapy, vol. 13, no. 2, pp. 401–410, 2006.
colon cancer through pparγ,” Nature medicine, vol. 4, no. 9,
pp. 1046–1052, 1998. [28] P. Leahy, D. R. Crawford, G. Grossman, R. M. Gronosta-
jski, and R. W. Hanson, “Creb binding protein coordinates
[13] E. Saez, P. Tontonoz, M. C. Nelson, J. G. Alvarez, S. M. Baird, the function of multiple transcription factors including nuclear
V. A. Thomazy, R. M. Evans et al., “Activators of the nu- factor i to regulate phosphoenolpyruvate carboxykinase (gtp)
clear receptor pparγ enhance colon polyp formation,” Nature gene transcription,” Journal of Biological Chemistry, vol. 274,
medicine, vol. 4, no. 9, pp. 1058–1061, 1998. no. 13, pp. 8813–8822, 1999.

- 31 -
Annals of Multidisciplinary Research, Innovation and Technology (AMRIT), 1(2), 2022, 23-34 ISSN: 2583-4657

[29] W. Roesler, G. Vandenbark, and R. W. Hanson, “Identification [43] D. E. Ash, F. A. Emig, S. A. Chowdhury, Y. Satoh, and
of multiple protein binding domains in the promoter-regulatory V. L. Schramm, “Mammalian and avian liver phosphoenolpyru-
region of the phosphoenolpyruvate carboxykinase (gtp) gene,” vate carboxykinase. alternate substrates and inhibition by ana-
Journal of Biological Chemistry, vol. 264, no. 16, pp. 9657– logues of oxaloacetate.” Journal of Biological Chemistry, vol.
9664, 1989. 265, no. 13, pp. 7377–7384, 1990.

[30] D. Schmoll, K. S. Walker, D. R. Alessi, R. Grempler, [44] S. L. Pietranico, L. H. Foley, N. Huby, W. Yun, P. Dunten,
A. Burchell, S. Guo, R. Walther, and T. G. Unterman, “Regu- J. Vermeulen, P. Wang, K. Toth, G. Ramsey, M.-L. Gubler
lation of glucose-6-phosphatase gene expression by protein ki- et al., “C-8 modifications of 3-alkyl-1, 8-dibenzylxanthines as
nase bα and the forkhead transcription factor fkhr: evidence inhibitors of human cytosolic phosphoenolpyruvate carboxyk-
for insulin response unit-dependent and-independent effects of inase,” Bioorganic & medicinal chemistry letters, vol. 17,
insulin on promoter activity,” Journal of Biological Chem- no. 14, pp. 3835–3839, 2007.
istry, vol. 275, no. 46, pp. 36 324–36 333, 2000.
[45] J. Hidalgo, P. Latorre, J. A. Carrodeguas, A. Velázquez-
Campoy, J. Sancho, and P. López-Buesa, “Inhibition of
[31] W. Zhang, S. Patil, B. Chauhan, S. Guo, D. R. Powell, J. Le,
pig phosphoenolpyruvate carboxykinase isoenzymes by 3-
A. Klotsas, R. Matika, X. Xiao, R. Franks et al., “Foxo1 regu-
mercaptopicolinic acid and novel inhibitors,” PLoS One,
lates multiple metabolic pathways in the liver: effects on gluco-
vol. 11, no. 7, p. e0159002, 2016.
neogenic, glycolytic, and lipogenic gene expression,” Journal
of Biological Chemistry, vol. 281, no. 15, pp. 10 105–10 117,
[46] F. Bauer, J. W. Beulens, D. L. Van Der A, C. Wijmenga, D. E.
2006.
Grobbee, A. M. Spijkerman, Y. T. Van Der Schouw, N. C.
Onland-Moret et al., “Dietary patterns and the risk of type 2
[32] C. Veneziale, J. Donofrio, and H. Nishimura, “The concentra- diabetes in overweight and obese individuals,” European jour-
tion of p-enolpyruvate carboxykinase protein in murine tissues nal of nutrition, vol. 52, no. 3, pp. 1127–1134, 2013.
in diabetes of chemical and genetic origin.” Journal of Biolog-
ical Chemistry, vol. 258, no. 23, pp. 14 257–14 262, 1983. [47] K. Hanhineva, R. Törrönen, I. Bondia-Pons, J. Pekkinen,
M. Kolehmainen, H. Mykkänen, and K. Poutanen, “Impact
[33] S. M. Sullivan and T. Holyoak, “Structures of rat cytosolic of dietary polyphenols on carbohydrate metabolism,” Interna-
pepck: insight into the mechanism of phosphorylation and tional journal of molecular sciences, vol. 11, no. 4, pp. 1365–
decarboxylation of oxaloacetic acid,” Biochemistry, vol. 46, 1402, 2010.
no. 35, pp. 10 078–10 088, 2007.
[48] R. Randhir, Y.-T. Lin, K. Shetty, and Y.-T. Lin, “Phenolics,
[34] C. Anderson, F. Zucker, and T. Steitz, “Space-filling models their antioxidant and antimicrobial activity in dark germinated
of kinase clefts and conformation changes: Comparison of the fenugreek sprouts in response to peptide and phytochemical
surface structures of kinase enzymes implicates closing clefts elicitors.” Asia Pacific journal of clinical nutrition, vol. 13,
in their mechanism.” Science, vol. 204, no. 4391, pp. 375–380, no. 3, 2004.
1979.
[49] G. Velderrain-Rodrı́guez, H. Palafox-Carlos, A. Wall-
[35] E. Cardemil, M. V. Encinas, and A. M. Jabalquinto, “Reactive Medrano, J. Ayala-Zavala, C. O. Chen, M. Robles-Sánchez,
sulfhydryl groups in saccharomyces cerevisae phosphoenolpyru- H. Astiazaran-Garcı́a, E. Alvarez-Parrilla, and G. González-
vate carboxykinase,” Biochimica et Biophysica Acta (BBA)- Aguilar, “Phenolic compounds: their journey after intake,”
Protein Structure and Molecular Enzymology, vol. 1040, no. 1, Food & function, vol. 5, no. 2, pp. 189–197, 2014.
pp. 71–76, 1990.
[50] N. Babbar, H. S. Oberoi, S. K. Sandhu, and V. K. Bhargav,
“Influence of different solvents in extraction of phenolic com-
[36] J. R. Maxwell and P. D. Ray, “Responses of hepatic phos- pounds from vegetable residues and their evaluation as natural
phoenolpyruvate carboxykinase activities from normal and dia- sources of antioxidants,” Journal of food science and technol-
betic rats to quinolinate inhibition and ferrous ion activation,” ogy, vol. 51, no. 10, pp. 2568–2575, 2014.
Biochimica et Biophysica Acta (BBA)-Enzymology, vol. 614,
no. 1, pp. 163–172, 1980. [51] D. Ribnicky, A. Poulev, M. Watford, W. Cefalu, and I. Raskin,
“Antihyperglycemic activity of tarralin, an ethanolic extract
[37] C. T. Lewis, B. E. Haley, and G. M. Carlson, “Forma- of artemisia dracunculus l.” Phytomedicine, vol. 13, no. 8, pp.
tion of an intramolecular cystine disulfide during the reaction 550–557, 2006.
of 8-azidoguanosine 5’-triphosphate with cytosolic phospho-
enolpyruvate carboxykinase (gtp) causes inactivation without [52] D. Govorko, S. Logendra, Y. Wang, D. Esposito, S. Komarnyt-
photolabeling,” Biochemistry, vol. 28, no. 24, pp. 9248–9255, sky, D. Ribnicky, A. Poulev, Z. Wang, W. T. Cefalu, and
1989. I. Raskin, “Polyphenolic compounds from artemisia dracuncu-
lus l. inhibit pepck gene expression and gluconeogenesis in an
[38] R. I. Brinkworth, R. W. Hanson, F. A. Fullin, and V. L. h4iie hepatoma cell line,” American Journal of Physiology-
Schramm, “Mn2+-sensitive and-insensitive forms of phos- Endocrinology and Metabolism, vol. 293, no. 6, pp. E1503–
phoenolpyruvate carboxykinase (gtp).” Journal of Biological E1510, 2007.
Chemistry, vol. 256, no. 21, pp. 10 795–10 802, 1981.
[53] D. Beher, J. Wu, S. Cumine, K. W. Kim, S.-C. Lu, L. Atangan,
[39] A. Makinen and T. Nowak, “3-mercaptopicolinate. a reversible and M. Wang, “Resveratrol is not a direct activator of sirt1 en-
active site inhibitor of avian liver phosphoenolpyruvate car- zyme activity,” Chemical biology & drug design, vol. 74, no. 6,
boxykinase.” Journal of Biological Chemistry, vol. 258, no. 19, pp. 619–624, 2009.
pp. 11 654–11 662, 1983.
[54] T.-C. Chi, W.-P. Chen, T.-L. Chi, T.-F. Kuo, S.-S. Lee, J.-
T. Cheng, and M.-J. Su, “Phosphatidylinositol-3-kinase is in-
[40] K.-C. Cheng and T. Nowak, “Arginine residues at the active
volved in the antihyperglycemic effect induced by resveratrol
site of avian liver phosphoenolpyruvate carboxykinase,” Jour-
in streptozotocin-induced diabetic rats,” Life sciences, vol. 80,
nal of Biological Chemistry, vol. 264, no. 6, pp. 3317–3324,
no. 18, pp. 1713–1720, 2007.
1989.
[55] G. Ren, A. M. Rimando, and S. T. Mathews, “Ampk acti-
[41] R. M. Stiffin, S. M. Sullivan, G. M. Carlson, and T. Holyoak, vation by pterostilbene contributes to suppression of hepatic
“Differential inhibition of cytosolic pepck by substrate ana- gluconeogenic gene expression and glucose production in h4iie
logues. kinetic and structural characterization of inhibitor cells,” Biochemical and biophysical research communications,
recognition,” Biochemistry, vol. 47, no. 7, pp. 2099–2109, 2008. vol. 498, no. 3, pp. 640–645, 2018.

[42] S. M. Sullivan and T. Holyoak, “Enzymes with lid-gated active [56] J.-D. Shen, Y. Wei, Y.-J. Li, J.-Y. Qiao, and Y.-C. Li, “Cur-
sites must operate by an induced fit mechanism instead of con- cumin reverses the depressive-like behavior and insulin resis-
formational selection,” Proceedings of the National Academy tance induced by chronic mild stress,” Metabolic brain disease,
of Sciences, vol. 105, no. 37, pp. 13 829–13 834, 2008. vol. 32, no. 4, pp. 1163–1172, 2017.

- 32 -
Annals of Multidisciplinary Research, Innovation and Technology (AMRIT), 1(2), 2022, 23-34 ISSN: 2583-4657

[57] H. Fujiwara, M. Hosokawa, X. Zhou, S. Fujimoto, K. Fukuda, [73] P.-L. Huang, C.-W. Chi, and T.-Y. Liu, “Areca nut procyani-
K. Toyoda, Y. Nishi, Y. Fujita, K. Yamada, Y. Yamada et al., dins ameliorate streptozocin-induced hyperglycemia by regu-
“Curcumin inhibits glucose production in isolated mice hepato- lating gluconeogenesis,” Food and chemical toxicology, vol. 55,
cytes,” Diabetes research and clinical practice, vol. 80, no. 2, pp. 137–143, 2013.
pp. 185–191, 2008.
[74] H.-Y. Tsai, L.-Y. Wu, and L. S. Hwang, “Effect of a
[58] J.-Y. Yoon, H. Choi, and H.-S. Jun, “The effect of phloroglu- proanthocyanidin-rich extract from longan flower on markers of
cinol, a component of ecklonia cava extract, on hepatic glucose metabolic syndrome in fructose-fed rats,” Journal of Agricul-
production,” Marine Drugs, vol. 15, no. 4, p. 106, 2017. tural and Food Chemistry, vol. 56, no. 22, pp. 11 018–11 024,
2008.
[59] Z. Zhao and M. H. Moghadasian, “Bioavailability of hydrox-
ycinnamates: a brief review of in vivo and in vitro studies,” [75] Y. Kurimoto, Y. Shibayama, S. Inoue, M. Soga, M. Takikawa,
Phytochemistry Reviews, vol. 9, no. 1, pp. 133–145, 2010. C. Ito, F. Nanba, T. Yoshida, Y. Yamashita, H. Ashida et al.,
“Black soybean seed coat extract ameliorates hyperglycemia
[60] K. M. P. Jackson, T. Rathinasabapathy, D. Esposito, and and insulin sensitivity via the activation of amp-activated pro-
S. Komarnytsky, “Structural constraints and importance of tein kinase in diabetic mice,” Journal of agricultural and food
caffeic acid moiety for anti-hyperglycemic effects of caf- chemistry, vol. 61, no. 23, pp. 5558–5564, 2013.
feoylquinic acids from chicory,” Molecular nutrition food re-
search, vol. 61, no. 9, 2017. [76] G. S. Prasath, S. I. Pillai, and S. P. Subramanian, “Fisetin
improves glucose homeostasis through the inhibition of gluco-
[61] M. Petersen, “Rosmarinic acid: new aspects,” Phytochemistry neogenic enzymes in hepatic tissues of streptozotocin induced
Reviews, vol. 12, no. 1, pp. 207–227, 2013. diabetic rats,” European journal of pharmacology, vol. 740,
pp. 248–254, 2014.
[62] J. Runtuwene, K.-C. Cheng, A. Asakawa, H. Amitani, M. Ami-
tani, A. Morinaga, Y. Takimoto, B. H. R. Kairupan, and [77] H. M. Eid, A. Nachar, F. Thong, G. Sweeney, and P. S.
A. Inui, “Rosmarinic acid ameliorates hyperglycemia and in- Haddad, “The molecular basis of the antidiabetic action of
sulin sensitivity in diabetic rats, potentially by modulating the quercetin in cultured skeletal muscle cells and hepatocytes,”
expression of pepck and glut4,” Drug design, development and Pharmacognosy magazine, vol. 11, no. 41, p. 74, 2015.
therapy, vol. 10, p. 2193, 2016.
[78] S. Shukla and S. Gupta, “Apigenin: a promising molecule for
[63] S.-H. Lee, S.-C. Ko, M.-C. Kang, D. H. Lee, and Y.-J. Jeon, cancer prevention,” Pharmaceutical research, vol. 27, no. 6,
“Octaphlorethol a, a marine algae product, exhibits antidi- pp. 962–978, 2010.
abetic effects in type 2 diabetic mice by activating amp-
activated protein kinase and upregulating the expression of [79] E. J. Lien, S. Ren, H.-H. Bui, and R. Wang, “Quantita-
glucose transporter 4,” Food and Chemical Toxicology, vol. 91, tive structure-activity relationship analysis of phenolic antiox-
pp. 58–64, 2016. idants,” Free Radical Biology and Medicine, vol. 26, no. 3-4,
pp. 285–294, 1999.
[64] Z. Zhao and M. H. Moghadasian, “Chemistry, natural sources,
dietary intake and pharmacokinetic properties of ferulic acid: [80] C. Bumke-Vogt, M. A. Osterhoff, A. Borchert, V. Guzman-
A review,” Food Chemistry, vol. 109, no. 4, pp. 691–702, 2008. Perez, Z. Sarem, A. L. Birkenfeld, V. Bähr, and A. F. Pfeiffer,
“The flavones apigenin and luteolin induce foxo1 translocation
[65] A. Narasimhan, M. Chinnaiyan, and B. Karundevi, “Fer- but inhibit gluconeogenic and lipogenic gene expression in hu-
ulic acid exerts its antidiabetic effect by modulating insulin- man cells,” PloS one, vol. 9, no. 8, p. e104321, 2014.
signalling molecules in the liver of high-fat diet and fructose-
induced type-2 diabetic adult male rat,” Applied physiology,
[81] L. Le, B. Jiang, W. Wan, W. Zhai, L. Xu, K. Hu, and P. Xiao,
nutrition, and metabolism, vol. 40, no. 8, pp. 769–781, 2015.
“Metabolomics reveals the protective of dihydromyricetin on
glucose homeostasis by enhancing insulin sensitivity,” Scien-
[66] W.-H. Huang, P.-Y. Chien, C.-H. Yang, and A.-R. Lee,
tific Reports, vol. 6, no. 1, pp. 1–11, 2016.
“Novel synthesis of flavonoids of scutellaria baicalensis g eorgi,”
Chemical and pharmaceutical bulletin, vol. 51, no. 3, pp. 339–
[82] H. Radhakrishnakartha, A. P. Appu, and M. Indira, “Ascorbic
340, 2003.
acid supplementation enhances recovery from ethanol induced
inhibition of leydig cell steroidogenesis than abstention in male
[67] Z.-L. Zhang, M.-L. Zhou, Y. Tang, F.-L. Li, Y.-X. Tang, J.-
guinea pigs,” European journal of pharmacology, vol. 723, pp.
R. Shao, W.-T. Xue, and Y.-M. Wu, “Bioactive compounds
73–79, 2014.
in functional buckwheat food,” Food research international,
vol. 49, no. 1, pp. 389–395, 2012.
[83] F. Yan, G. Dai, and X. Zheng, “Mulberry anthocyanin extract
[68] L. Wei, L. Tao, and T. Keji, “Flavonoids from mulberry ameliorates insulin resistance by regulating pi3k/akt pathway
leaves by microwave-assisted extract and anti-fatigue activity,” in hepg2 cells and db/db mice,” The Journal of Nutritional
African Journal of Agricultural Research, vol. 4, no. 9, pp. Biochemistry, vol. 36, pp. 68–80, 2016.
898–902, 2009.
[84] T. Haig, Allelochemicals in Plants. New York, NY: Springer
[69] C. Zheng, J. Tang, D. Yang, and L. Tang, “Effects of total New York, 2008, p. 63104.
flavonoids in momordica grosvenori on hyperglycemia rat dur-
ing streptoaotocin diabetes,” Chinese Journal of Experimen- [85] L. Yang and J. Stöckigt, “Trends for diverse production strate-
tal Traditional Medical Formulae, vol. 17, no. 22, pp. 194–197, gies of plant medicinal alkaloids,” Natural product reports,
2011. vol. 27, no. 10, pp. 1469–1479, 2010.

[70] S.-z. Hou, S.-x. Chen, S. Huang, D.-x. Jiang, C.-J. Zhou, C.-q. [86] D. S. Seigler, Plant secondary metabolism. Springer Science
Chen, Y.-m. Liang, and X.-p. Lai, “The hypoglycemic activity & Business Media, 1998.
of lithocarpus polystachyus rehd. leaves in the experimental
hyperglycemic rats,” Journal of Ethnopharmacology, vol. 138, [87] S. B Gaikwad, G. Krishna Mohan, and M. Sandhya Rani, “Phy-
no. 1, pp. 142–149, 2011. tochemicals for diabetes management,” Pharmaceutical Crops,
vol. 5, no. 1, 2014.
[71] K. B. Pandey and S. I. Rizvi, “Plant polyphenols as dietary an-
tioxidants in human health and disease,” Oxidative medicine [88] X. Xia, J. Yan, Y. Shen, K. Tang, J. Yin, Y. Zhang, D. Yang,
and cellular longevity, vol. 2, no. 5, pp. 270–278, 2009. H. Liang, J. Ye, and J. Weng, “Berberine improves glucose
metabolism in diabetic rats by inhibition of hepatic gluconeo-
[72] G. Montagut, C. Bladé, M. Blay, J. Fernández-Larrea, G. Pu- genesis,” PLoS one, vol. 6, no. 2, p. e16556, 2011.
jadas, M. J. Salvadó, L. Arola, M. Pinent, and A. Ardévol,
“Effects of a grapeseed procyanidin extract (gspe) on insulin [89] W. Jiang, W. Wei, M. A. Gaertig, S. Li, and X.-J. Li, “Ther-
resistance,” The Journal of nutritional biochemistry, vol. 21, apeutic effect of berberine on huntingtons disease transgenic
no. 10, pp. 961–967, 2010. mouse model,” PLoS One, vol. 10, no. 7, p. e0134142, 2015.

- 33 -
 Annals of Multidisciplinary Research, Innovation and Technology (AMRIT), 1(2), 2022, 23-34 ISSN: 2583-4657

[90] J. Kim, J.-H. Yu, E. Ko, K.-W. Lee, A. Song, S. Park, I. Shin, [104] T. Wang, H. Jiang, S. Cao, Q. Chen, M. Cui, Z. Wang, D. Li,
W. Han, and D. Noh, “The alkaloid berberine inhibits the J. Zhou, F. Qiu, and N. Kang, “Baicalin and its metabolites
growth of anoikis-resistant mcf-7 and mda-mb-231 breast can- suppresses gluconeogenesis through activation of ampk or akt
cer cell lines by inducing cell cycle arrest,” Phytomedicine, in insulin resistant hepg-2 cells,” European Journal of Medic-
vol. 17, no. 6, pp. 436–440, 2010. inal Chemistry, vol. 141, pp. 92–100, 2017.

[91] Y. S. Yun, M. Tajima, S. Takahashi, Y. Takahashi, [105] T. P. Patel, K. Rawal, S. Soni, and S. Gupta, “Swertiamarin
M. Umemura, H. Nakano, H. S. Park, and H. Inoue, “Two al- ameliorates oleic acid induced lipid accumulation and oxida-
kaloids from bulbs of lycoris sanguinea maxim. suppress pepck tive stress by attenuating gluconeogenesis and lipogenesis in
expression by inhibiting the phosphorylation of creb,” Phy- hepatic steatosis,” Biomedicine & Pharmacotherapy, vol. 83,
totherapy Research, vol. 30, no. 10, pp. 1689–1695, 2016. pp. 785–791, 2016.
[92] H. Lu, D. Samanta, L. Xiang, H. Zhang, H. Hu, I. Chen, [106] A. Rao and D. Gurfinkel, “The bioactivity of saponins: triter-
J. W. Bullen, and G. L. Semenza, “Chemotherapy triggers hif- penoid and steroidal glycosides,” Drug metabolism and drug
1–dependent glutathione synthesis and copper chelation that interactions, vol. 17, no. 1-4, pp. 211–236, 2000.
induces the breast cancer stem cell phenotype,” Proceedings
of the National Academy of Sciences, vol. 112, no. 33, pp. [107] J.-T. Xie, S. Mehendale, and C.-S. Yuan, “Ginseng and dia-
E4600–E4609, 2015. betes,” The American journal of Chinese medicine, vol. 33,
no. 03, pp. 397–404, 2005.
[93] H.-Y. Ling, Q.-X. Yao, Z.-Q. Qi, S.-S. Yang, J.-Q. He, K.-F.
Zhang, and B. Hu, “The role of arecoline on hepatic insulin re- [108] L.-W. Qi, C.-Z. Wang, and C.-S. Yuan, “Ginsenosides from
sistance in type 2 diabetes rats,” Zhongguo Ying Yong Sheng li american ginseng: chemical and pharmacological diversity,”
xue za zhi= Zhongguo Yingyong Shenglixue Zazhi= Chinese Phytochemistry, vol. 72, no. 8, pp. 689–699, 2011.
Journal of Applied Physiology, vol. 30, no. 3, pp. 208–212,
2014. [109] N. Xiao, M.-D. Lou, Y.-T. Lu, L.-L. Yang, Q. Liu, B. Liu, L.-
W. Qi, and P. Li, “Ginsenoside rg5 attenuates hepatic glucagon
[94] C.-Y. Chen, F.-Y. Chiu, Y. Lin, W.-J. Huang, P.-S. Hsieh,
response via suppression of succinate-associated hif-1α induc-
and F.-L. Hsu, “Chemical constituents analysis and antidia-
tion in hfd-fed mice,” Diabetologia, vol. 60, no. 6, pp. 1084–
betic activity validation of four fern species from taiwan,” In-
1093, 2017.
ternational journal of molecular sciences, vol. 16, no. 2, pp.
2497–2516, 2015.
[110] C. Guo, F. Liang, W. S. Masood, and X. Yan, “Hydrogen sul-
[95] F.-L. Hsu, C.-F. Huang, Y.-W. Chen, Y.-P. Yen, C.-T. Wu, fide protected gastric epithelial cell from ischemia/reperfusion
B.-J. Uang, R.-S. Yang, and S.-H. Liu, “Antidiabetic effects injury by keap1 s-sulfhydration, mapk dependent anti-
of pterosin a, a small-molecular-weight natural product, on di- apoptosis and nf-κb dependent anti-inflammation pathway,”
abetic mouse models,” diabetes, vol. 62, no. 2, pp. 628–638, European journal of pharmacology, vol. 725, pp. 70–78, 2014.
2013.
[111] H. Yu, L. Zheng, L. Xu, L. Yin, Y. Lin, H. Li, K. Liu, and
[96] J.-B. Wu, Y.-H. Kuo, C.-H. Lin, H.-Y. Ho, and C.-C. Shih, J. Peng, “Potent effects of the total saponins from dioscorea
“Tormentic acid, a major component of suspension cells of nipponica makino against streptozotocin-induced type 2 dia-
eriobotrya japonica, suppresses high-fat diet-induced diabetes betes mellitus in rats,” Phytotherapy Research, vol. 29, no. 2,
and hyperlipidemia by glucose transporter 4 and amp-activated pp. 228–240, 2015.
protein kinase phosphorylation,” Journal of agricultural and
food chemistry, vol. 62, no. 44, pp. 10 717–10 726, 2014.

[97] C.-H. Lin, Y.-H. Kuo, and C.-C. Shih, “Eburicoic acid, a triter-
penoid compound from antrodia camphorata, displays antidia-
betic and antihyperlipidemic effects in palmitate-treated c2c12
myotubes and in high-fat diet-fed mice,” International Jour-
nal of Molecular Sciences, vol. 18, no. 11, p. 2314, 2017.

[98] A. Jalil, U. A. Ashfaq, S. Shahzadi, M. R. Javed, I. Rasul, S.-u.

Rehman, M. Shah, and M. S. Masoud, “Screening and design
of anti-diabetic compounds sourced from the leaves of neem
(azadirachta indica),” Bioinformation, vol. 9, no. 20, p. 1031,
2013.

[99] A.-S. Foucault, V. Mathé, R. Lafont, P. Even, W. Dioh, S. Veil-

let, D. Tomé, J.-F. Huneau, D. Hermier, and A. Quignard-
Boulangé, “Quinoa extract enriched in 20-hydroxyecdysone
protects mice from diet-induced obesity and modulates
adipokines expression,” Obesity, vol. 20, no. 2, pp. 270–277,
2012.

[100] R. Shah, L. S. De Jager, and T. H. Begley, “Simultane-

ous determination of steviol and steviol glycosides by liquid
chromatography-mass spectrometry,” Food Additives & Con-
taminants: Part A, vol. 29, no. 12, pp. 1861–1871, 2012.

[101] J. W. Pelley, “Structure and properties of biologic molecules,”

Elseviers Integrated Review Biochemistry (Second Edition),
WB Saunders, pp. 7–18, 2012.

[102] J. D. Park, Y. H. Lee, and S. I. Kim, “Ginsenoside rf2, a

new dammarane glycoside from korean red ginseng (panax gin-
seng),” Archives of pharmacal research, vol. 21, no. 5, pp.
615–617, 1998.

[103] M. Yoshikawa, T. Murakami, K. Yashiro, J. YAMAHARA,

H. MATSUDA, R. SAIJOH, and O. TANAKA, “Bioactive
saponins and glycosides. xi. structures of new dammarane-type
triterpene oligoglycosides, quinquenosides i, ii, iii, iv, and v,
from american ginseng, the roots of panax quinquefolium l.”
Chemical and pharmaceutical bulletin, vol. 46, no. 4, pp. 647–
654, 1998.

- 34 -

View publication stats