PATHOPHYSIOLOGY

OF DIABETES
MELLITUS

WILMAR JUN O. ELOPRE, RND

DEP’T. OF NUTRITION AND DIETETICS
COLLEGE OF HUMAN ECOLOGY
CENTRAL MINDANAO UNIVERSITY
 The constellation of abnormalities caused
by absolute or relative insulin deficiency is
called Diabetes Mellitus.
Diabetes is …

 Characterized by
abnormalities in
the metabolism of
carbohydrate,
protein and fat.

 Associated with
micro vascular,
macro vascular,
and metabolic
complications.
The adult pancreas is made up of collections of cells
called islets of Langerhans

There are ~ 1-2

million islets

There are four

major cell types
in the islets of
Langerhans
http://static.howstuffworks.com/gif/diabetes-pancreas.gif
Beta cells -
produce insulin

Insulin is
anabolic
increases the
storage of
glucose,
fatty acids and
amino acids

© 2001 Terese Winslow, Lydia Kibiuk

Alpha cells- produce
Glucagon

Glucagon is catabolic:
 mobilizes glucose, fatty
acids and amino acids
from stores into the blood
stream

 increases plasma glucose

by stimulating hepatic
glycogenolysis and
gluconeogenesis

 increases lipolysis in http://besttreatments.bmj.com/btuk/images/diabetes-

adipose tissue pancreas_default.jpg
 delta cells - produce somatostatin, which inhibits
secretion of insulin, glucagon and pancreatic
polypeptide.

 F (or PP) cells - responsible for the production of

pancreatic polypeptide, which slows absorption of
food.
 The amino acid sequence of insulin molecule varies
very little from species to species (cows, pigs etc).
These differences do not affect the biological
activity if insulin from one species is given to another
species.

 but they are definitely antigenic and induce antibody

formation against the injected insulin when given
over a prolonged period of time.

 Human insulin is now used to avoid the problem of

antibody formation.
 Insulin is synthesized in the rough endoplasmic
reticulum of β cells

 Insulin is synthesized as a part of a larger pre-pro-

hormone called preproinsulin

 Release of connecting peptide or C-peptide

 Enzyme
linked
receptor

http://arbl.cvmbs.colostate.
edu/hbooks/pathphys/endocrine/pancreas/insulin_phys.html
Insulin binds to the α sub-unit of receptors
Triggers tyrosine kinase activity
Auto-phosphorylation of β sub-unit

Changes in cytoplasmic proteins / enzymes

Activation / inactivation of enzymes

Actions of insulin
Effects of insulin
Rapid (seconds):
Increased transport of glucose, amino acids, and K+ into
insulin sensitive cells.

Intermediate (minutes):
 Stimulation of protein synthesis
 Inhibition of protein degradation
 Activation of glycogen synthase and increased
glycogenesis
 Inhibition of phosphorylase and gluconeogenic enzymes
(decreased gluconeogenesis)

Delayed actions (hours):

 Increase in mRNAs for lipogenic and other enzymes
(increased lipogenesis)
On carbohydrate metabolism..
Reduces rate of release of glucose from the liver by
 inhibiting glycogenolysis
 stimulating glycogen synthesis
 stimulating glucose uptake
 stimulating glycolysis
 inhibiting gluconeogenesis

Increases rate of uptake of glucose into all insulin sensitive

tissues, notably muscle and adipose tissue.
On lipid metabolism…
 Reduces rate of release of free fatty acids from
adipose tissue.

 Stimulates de novo synthesis of fatty acids and

also conversion of fatty acids to triglycerides in
liver.
On protein metabolism…
 Stimulates transport of free amino acids across
the plasma membrane in liver and muscle.

 Stimulates protein synthesis and reduces release

of amino acids from muscle.
 Actions……
 Insulin favors movement of potassium into
cells. Vigorous treatment with insulin (as in DKA)
will cause potassium to move into cells causing
hypokalemia.

 Promotes general growth and development.

Insulin
Na+

Sodium
Potassium
ATPase

K+
 IGF
 Substances with insulinlike activity include IGF I
and IGF II (insulin like growth factors) also called
somatomedins.

 They are secreted by liver, cartilage and other

tissues in response to growth hormone.

 The IGF receptor is very similar to insulin

receptor.
 Glucose enters cells by facilitated diffusion with the help of
glucose transporters, GLUT 1 to GLUT 7
 GLUT 4 is the glucose transporter in muscle and adipose
tissue which is stimulated by insulin
 Transport of glucose
into the intestine
and kidneys is by
secondary active
transport with
sodium i.e. via
sodium dependent
glucose transporters
 Direct feedback effect
of plasma glucose on
β cells of pancreas

http://biomed.brown.edu/Courses/BI108/BI108_2002_
Groups/pancstems/stemcell/pancreas.gif
 Beta cell ATP gated
K+
channel
Stimuli that increase
GLUT 2
cAMP levels in β
Glucose cells increase insulin
Uptake secretion probably by
increasing
intracellular Ca 2+
Glucokinase ATP K+
• β adrenergic
Depolarization agonists
• Glucagon
• Phosphodiesterase
inhibitors such us
Theophylline
Insulin Ca+
Release +

Voltage gated
Storage granules
Ca++ channel
 Tolbutamide and other sulfonylurea derivatives.
 Biguanides (Metformin or Glyciphage) decrease hepatic
gluconeogenesis
 Thiazolidinediones (Rosiglitazone etc) increase insulin
sensitivity by activating Peroxisome Proliferator-Activated
Receptor (PPARγ) receptors in the cell nucleus
 Sympathetic nerve stimulation to pancreas inhibition of
insulin secretion
 Parasympathetic stimulation to pancreas increase in insulin
secretion
 Orally administered glucose has a greater insulin
stimulating effect than intravenously
administered glucose

 This led to the possibility that certain substances

secreted by the gastrointestinal mucosa
stimulated insulin secretion. Glucagon, glucagon
derivatives, secretin, cholecystokinin and gastric
inhibitory peptide, all have such an action.
= The increase of insulin secretion after oral as
opposed to intravenous administration of
glucose.
The two most important Incretin hormones:

 Glucose-dependent insulino-tropic
polypeptide (GIP), formerly known as gastric
inhibitory polypeptide

 Glucagon-like peptide (GLP-1), an additional

gut factor that stimulates insulin secretion.
Glucagon-like polypeptide 1 (GLP-1)
 GLP-1 is synthesized within L cells located
predominantly in the ileum and colon, and a lesser
number in the duodenum and jejunum.

 GLP-1 stimulates insulin secretion, suppresses glucagon

secretion, slows gastric emptying, reduces food intake,
increases β cell mass, maintains β cell function, improves
insulin sensitivity and enhances glucose disposal.

 The glucose lowering effects of GLP-1 are preserved in

type 2 diabetics.
 However, native GLP-1 is rapidly degraded by
dipeptidyl peptidase- IV(DPP-IV) after parenteral
administration.

 GLP-1 receptor (GLP-1R) agonists and DPP-IV

inhibitors have shown promising results in
clinical trials for the treatment of type 2 diabetes.
Chronic disorder characterized by fasting hyperglycemia
or plasma glucose levels that are above defined limits
during oral glucose tolerance testing (OGTT) or
random blood glucose measurements, as defined by
established criteria.
Pre-diabetes

Glycosylated hemoglobin A1c – 5.7-6.4%

Type 1 Diabetes
Immune mediated, absolute insulin deficiency due to
autoimmune destruction of β cells in the pancreatic islets

Genetic
Susceptibility

Islet Auto Antibodies

attack Beta cells

β cell destruction
Environmental Insulin deficiency++
Factors /
Viral infection Type 1 Diabetes
Type 2 Diabetes
Individuals with insulin resistance or insensitivity of tissues to insulin (later leading to
impaired insulin secretion). Maybe due to deficiency of GLUT 4 in insulin sensitive
tissues, or genetic defects in the insulin receptor or insulin molecule itself.

Excess food
Low Birth weight Obesity Motorization
Beta cell defect
TV
Genetic

Beta cell

Secretory Sedentary lifestyle

defect Insulin
β cell exhaustion
Resistance in
Target cells
Type 2 Diabetes (T2D)
Relative Insulin Deficiency
May need Insulin
Etiology of DM Type II
 High fat diet
 High sugar diet (low in complex carbohydrates)
 High BMI and High W:H ratio
 Lack of exercise
 Lack of sleep
 Hyperglycemia
 Glycosuria
 Polydypsia
 Polyuria
 Polyphagia
 Ketosis, acidosis, coma
 eventually death if left untreated
 Reduced entry of glucose into various peripheral tissues

 Increased liberation of glucose into circulation from liver.

Therefore there is an extracellular glucose excess and in
many cells an intracellular glucose deficiency –
“starvation in the midst of plenty”.

 Various signs and symptoms in diabetes are due to

disturbances in carbohydrate, protein and lipid
metabolism.
 Polyuria, Polydypsia and Polyphagia
Consequences of disturbed carbohydrate
metabolism
 Polyuria, polydypsia and polyphagia

 The renal threshold for glucose is 180 mg% i.e. if the

plasma glucose value is raised above 180 mg%, glucose will
start appearing in urine (glycosuria). Thus, as glucose is lost
in the urine, it takes along with it water (osmotic diuresis)
leading to increased urination (polyuria). Since lot of water
is lost in the urine, it leads to dehydration and increased
thirst (polydypsia). Electrolytes are also lost in the urine.
 The quantity of glucose lost in urine is enormous
and thus to maintain energy balance the patient
takes in large quantities of food.

 Also because of decreased intracellular glucose,

there is reduced glucose utilization by the
ventromedial nucleus of hypothalamus (satiety
center) and is probably the cause for the
hyperphagia.
 Way of looking at average blood sugar control over
a period of 3 months.

Glucose in the blood

Haemoglobin in the blood

Glycated haemoglobin

Controlled diabetes: Not much glucose Uncontrolled diabetes: More glucose

Not much Glycated haemoglobin Much more Glycated haemoglobin
 Hyperglycaemia

 High intracellular glucose levels Aldose reductase

(enzyme) activation Sorbitol formation ↓ Sodium
potassium ATP-ase activity
 Glucose attaches (non-enzymatically) to the protein
amino groups amodari products Advanced
glycosylation end products (AGEs) cause cross
linkage of matrix proteins Damage to blood vessels
 ↑ Sorbitol and fructose in Schwann cells disruption
in their structure and function
 circulatory insufficiency due to atherosclerosis
 neuropathy
 protein depletion causes poor resistance to
infections
 AGEs cause a decrease in leukocyte response to
infection
 Consequences of disturbed lipid
metabolism
 The principal abnormalities are acceleration of lipid catabolism
with increasing formation of ketone bodies and decreased
synthesis of fatty acids and triglycerides.

 Acidosis and ketosis is due to overproduction of ketone bodies

(acetoacetate, acetone and β-hydroxybutyrate).

 Most of the hydrogen ions liberated from acetoacetate and β-

hydroxybutyrate are buffered, but still severe metabolic acidosis
still develops.

 The low pH (metabolic acidosis) stimulates the respiratory center

and produces the rapid, deep, regular kussmaul breathing.
 Coma / death

Fruity
odour

Kussmaul
breathing
Low Insulin

Accelerated lipid
catabolism
Liver

↑ Ketone Bodies

Ketonuria Metabolic Acidosis

The acidosis and dehydration can lead to coma and
even death.
Hormone-sensitive lipase
Triglycerides Free fatty acids (FFA) + glycerol

Insulin inhibits the hormone sensitive lipase in adipose

tissue and in the absence of insulin, the plasma level
of FFA doubles. In liver and other tissues, the FFA
are catabolized to acetyl Co A, and the excess acetyl
Co A is converted to ketone bodies.
 ↑ protein breakdown muscle wasting
 ↓ protein synthesis
 ↑ plasma amino acids and nitrogen loss in urine
leading to negative nitrogen balance and protein
depletion.
 Protein depletion is associated with poor resistance
to infections.
 In diabetics, the cholesterol
level is usually elevated
leading to atherosclerotic
vascular disease

 This is due to a rise in the

plasma concentration of
VLDL and LDL (which
maybe due to increased
production by the liver or
decreased removal from
circulation)
 Micro vascular
complications like
retinopathy, nephropathy
and neuropathy involving
the peripheral nerves and
autonomic nervous system.

 Macro vascular
complications like stroke,
peripheral vascular disease
and myocardial infarction
due to increased
atherosclerosis caused by
increased amounts of LDL.
Complete List of Complications
 Hypoglycemia/Insulin Shock
 Hyperglycemia/Diabetic Ketoacidosis (DKA)
 Diabetic retinopathy and cataract
 Diabetic neuropathy
 Diabetic gastroparesis
 Diabetic nephropathy
 Cardiovascular diseases
 Periodontal disease
 Diabetic skin lesions
 Diabetic foot
Management of Diabetes
 Drug and/or Insulin therapy
 Healthy eating
 Physical activity
 Avoidance of stress factors
Methods of Insulin Therapy
Insulin Pen
Methods of Insulin Therapy
External Insulin Pump
Methods of Insulin Therapy
Implantable Insulin Pump
Medical Nutrition Therapy
 TER determination – depends on the patient
DBW and physical activity
 Carbohydrates – 50-70% of TER, low GI foods
 Fats – 25-30% of TER (1/3 saturated; 2/3
unsaturated)
 Proteins – the rest of the TER; 1.1 g/kgDBW or
0.6-0.8 g/kgDBW for diabetics with nephropathy
On Artificial Sweeteners and
Sugar Alcohols…
Thank you