PHYSIOLOGICAL

BASIS OF

DIABETES
MELLITUS
ARNAB RAY
SUGATA MAHAPATRA

3rd Semester
MBBS,
IIMSAR &

GOALS

DEFINITION
TYPES
SECRETION, REGULATION & PHYSIOLOGICAL ACTIONS OF INSULIN
PHYSIOLOGICAL COMPLICATIONS OF DIABETES MELLITUS
MODE OF COMPLICATIONS
PATHOPHYSIOLOGY OF THE DISEASE

Definition & Types Of Diabetes Mellitus

Diabetes mellitus is derived from the Greek worddiabetesmeaning siphon - to pass through
and the Latin wordmellitusmeaning honeyed or sweet.

Diabetes is a group of metabolic diseases characterized by hyperglycaemia resulting from

defects in insulin secretion, insulin action, or both.

Classification

Features

Etiology

I. Type 1 Diabetes

Beta cell destruction, usually leading to absolute insulin deficiency

A.
B.

Immune mediated
Idiopathic

II. Type 2 Diabetes

Range from predominantly insulin resistance with relative insulin deficiency

to a predominantly secretory defect with insulin resistance

A.
B.

Genetic
Environmental

III. Other specific types

A. Genetic defects of beta-cell function

MODY3

Chromosome 12, HNF-1a

MODY2

Chromosome 7, glucokinase

MODY1

Chromosome 20, HNF-4a

MODY4

Chromosome 13, insulin promoter factor-1

MODY5

Chromosome 17, HNF-1b

MODY6

Chromosome 2, NeuroD1

Others

B. Genetic defects in insulin action

1. Type A insulin resistance 2. Leprechaunism 3. Rabson-Mendenhall syndrome 4. Lipoatrophic diabetes 5. Others

C. Diseases of the exocrine pancreas

1. Pancreatitis 2. Trauma/pancreatectomy 3. Neoplasia 4. Cystic fibrosis 5. Hemochromatosis 6. Fibrocalculous

pancreatopathy 7. Others

D. Endocrinopathies

1. Acromegaly 2. Cushings syndrome 3. Glucagonoma 4. Pheochromocytoma 5. Hyperthyroidism 6.

Somatostatinoma 7. Aldosteronoma

E. Drug or chemical induced

1. Vacor 2. Pentamidine 3. Nicotinic acid 4. Glucocorticoids 5. Thyroid hormone 6. Diazoxide 7. -adrenergic

agonists 8. Thiazides 9. Dilantin

F. Infections

1. Congenital rubella 2. Cytomegalovirus 3. Others

SECRETION OF INSULIN
Ca+
+
Ca++
ATPas depolarizat chann
ion
e
el
K
K++

AT
P

K
+
Vesicle with
Insulin
Hormone

glucose

GLU
T-2

glucos
e
Glycolysi
s
pyruva
te
TCA
Mitochondri
a

-cell of
Pancreas
EXOCYTOSI
S
AT
P

Secretion
of the
Insulin
Hormone

REGULATION OF INSULIN SECRETION

The normal concentration of insulin measured by RIA in the peripheral venous plasma of fasting normal humans is 070microU/mL.The amount of insulin secreted in basal state is about 1U/h, with a five fold to ten fold increase following ingestion of
food.

STIMULATING FACTORS
1)Increased blood levels of glucose, mannose,amino acids(esp leucine &
arginine),free fatty acids, beta-ketoacids
2)Gut hormones(incretins) e.g.gastrin, secretin, cholecystokinin, GLP,GIP
3)Glucagon, growth hormone & glucocorticoids
4)Parasympathetic stimulation & acetyl choline
5)Beta adrenergic stimulation
6)Drugs like theophylline, sulfonylureas
INHIBITORY FACTORS
1)Decreased blood glucose level
2)Administration of 2-deoxyglucose, mannoheptulose & drugs like
phenytoin, alloxan, microtubule inhibitors,insulin
3)Gut hormones e.g.somatostatin
4)Alpha adrenergic stimulation

Effects of
insulin on
various
tissues

Adipose tissue

Muscle

Liver

General

Increased
glucose entry
Increased fatty
acid synthesis
Activation of
lipoprotein lipase
Inhibition of
Hormone sensitive
lipase
Increased K+
uptake

Increased
glucose entry
Increased
glycogen
synthesis
Increased
protein synthesis
Increased
ketone uptake
Increased k+
uptake

Decreased
gluconeogenesis
Increased
glycogen
synthesis &
glycolysis
Increased
protein synthesis
Increased lipid
synthesis

Increased cell
growth

Actions
of insulin
based on
time

Rapid action

Intermediate action

Delayed action

Increased
transport of
glucose,amino
acids & k+ into
insulin-sensitive
cells

Stimulation of
protein synthesis
Activation of
glycolytic
enzymes &
glycogen
synthase
Inhibition of
gluconeogenic
enzymes

Increase in
mRNAs for
lipogenic & other
enzymes

Complications Of Diabetes

MECHANISMS OF COMPLICATIONS
4 theories,which are not mutually exclusive,on how hyperglycaemia might lead to chronic
complications of DM include the following pathways:
Increased intracellular glucose formation of Amadori products advanced glycosylation
end products(AGEs),which bind to a cell surface receptor, via the non-enzymatic
glycosylation of intra & extracellular proteins cross linking of proteins, accelerated
atherosclerosis, glomerular dysfunction, endothelial dysfunction & altered extracellular
matrix composition
Hyperglycemia increases glucose metabolism via sorbitol pathway related to enzyme
aldol reductase
Hyperglycemia increases DAG formationactivation of PKCaltered transcription of
genes for fibronectin,type iv collagen,contractile proteins etc
Hyperglycemiaflux through hexosamine pathwayfructose-6- phosphateOlinked glycosylation & proteoglycan productionaltered function of proteins(by
glycosylation) such as endothelial NOS

TYPE 1 DIABETES MELLITUS

It is the result of interactions
of
genetic, environmental &
immunologic factors leading to
destruction of pancreatic cells
& insulin deficiency
It can develop at any age but
develops most commonly before
20 yrs of age , so also known as
juvenile diabetes
A genetic susceptibility, coupled
with viral or toxic agents that
damage the islet cells, culminates in
an autoimmune reaction with islet
destruction that underlies type 1
diabetes

GENETIC CONSIDERATIONS
At least 20 different chromosomal regions have been linked to type 1 diabetes
(T1D) susceptibility in humans.
The largest contribution from a single locus (IDDM1) comes from several genes located in
the MHC complex on chromosome 6p21, accounting for at least 40% of the familial
aggregation of this disease.
ENVIRONMENTAL FACTORS
Numerous environmental events have been proposed to trigger the autoimmune process in genetically
susceptible
individuals but none have been conclusively linked to diabetes. Putative environmental triggers include viruses,
bovine milk proteins & nitrosurea compounds

PATHOPHYSIOLOGY

T1DM is an autoimmune disease

The fundamental immune abnormality is a failure of self tolerance in T-cells specific for islet
antigens. So the autoreactive T cells are poised to respond to self antigens & these cells traffic to
the pancreatic islets(process known as insulitis) on getting activated in the peripancreatic lymph
nodes
After the cells are destroyed, it is thought that the inflammatory process abates & the islets
become atrophic.
Islets are nearly absent by the onset of overt diabetes and there is an absolute lack of circulating
insulin. Lack of insulin results in catabolism of adipose tissue and muscle, leading to metabolic
acidosis

TYPE 2 DIABETES MELLITUS

It is the most common type of diabetes & is usually associated with insulin resistance & abnormality
in insulin secretion accompanied by abnormal fat metabolism with intact cell morphology & insulin
content in it

It usually develops after the age of 40 years, so also known as adult-onset diabetes. However,in
recent years, there is a steady increase of T2DM in a number of younger individuals of less than 20
years

Obesity is an important risk factor for the development of T2DM

GENETIC CONSIDERATIONS

T2DM has a strong genetic component.Concurdance of T2DM in identical twins is between 70-90%

The disease is polygenic & multifactorial(nutrition,obesity,physical activity etc modulate the

phenotype)

Most prominent gene is a variant of transcription factor-7-like 2 gene that has been associated with
T2DM in several populations & with IGT in one population at high risk for DM

Genetic polymorphisms associated with T2DM have also been found in genes encoding PPAR-,inward
rectifying K+ channel,Zn2+ transporter,IRS & calpain 10.

PATHOPHYSIOLO
GY

Unlike patients with T1DM, those with T2DM have detectable

levels of circulating insulin.
On the basis of OGTT, the essential elements of T2DM can be
divided into 4 distinct groups; those with normal glucose
tolerance, chemical diabetes, diabetes with minimal fasting
hyperglycaemia(fasting<140mg/dl), and diabetes mellitus
with overt fasting hyperglycaemia(>140mg/dl).
The major clinical complications of T2DM are the result of
persistent hyperglycaemia which leads to numerous
physiological consequences. As the glucose level rises in the
blood, the blood becomes more viscous which makes
circulation of the blood in the small capillaries difficult. The
reduced circulation results in neuropathy(resulting in
numbness in the extremities and tingling in fingers and
toes), poor wound healing, and erectile dysfunction. In
addition to these major clinical complications, the body
reacts by increasing the level of glucose excretion by the
kidneys leading to frequent urination which is called
polyuria.As the glucose is excreted there is concomitant loss
of water to maintain the normal osmolarity of the urine. The
water loss leads to excessive thirst called polydipsia.

PATHOPHYSIOLOGIC
AL BASIS
OF
COMPLICATIONS IN
DIABETES
MELLITUS

Pathophysiology of diabetic
ketoacidosis

DKA results from relative or absolute insulin deficiency combined with counter regulatory hormone excess
(glucagon, catecholamine, cortisol, and growth hormone). Both insulin deficiency and glucagon excess, in
particular, are necessary for DKA to develop

The decreased ratio of insulin to glucagon promotes gluconeogenesis, glycogenolysis, and ketone body
formation in the liver, as well as increases in substrate delivery from fat and muscle (free fatty acids, amino
acids) to the liver

Ketosis results from a marked increase in FFA release from adipocytes, with a resulting shift toward ketone
body synthesis in the liver. Reduced insulin levels, in combination with elevations in catecholamines and
growth hormone, increase lipolysis and the release of free fatty acids. Normally, these FFAs are converted to
TGs or VLDL in the liver. However, in DKA, hyperglucagonemia alters hepatic metabolism to favor ketone
body formation.

At physiologic pH, ketone bodies exist as ketoacids, which are neutralized by bicarbonate. As bicarbonate
stores are depleted, metabolic acidosis ensues. Increased lactic acid production also contributes to the acidosis.

Pathophysiology of hyperglycaemic and

hyperosmolar state

Hyperosmolar hyperglycaemic state is a life-threatening emergency manifested by marked

elevation of blood glucose, hyperosmolarity, and little or no ketosis.
Hyperosmolar hyperglycemic state is a relatively common, life-threatening endocrine
emergency that is reported in all age groups,1 but it most frequently affects older
patients with type 2 diabetes.
The hallmark of hyperosmolar hyperglycemic state is profound dehydration,
marked hyperglycemia, and often some degree of neurologic impairment with
mild or no ketosis.

The initiating event in hyperosmolar hyperglycaemic state is glucosuric diuresis. Glucosuria impairs
the concentrating capacity of the kidney, further exacerbating water loss. Under normal conditions,
the kidneys act as a safety valve to eliminate glucose above a certain threshold and prevent further
accumulation. However, decreased intravascular volume or underlying renal disease decreases the
glomerular filtration rate, causing the glucose level to increase. The loss of more water than sodium
leads to hyperosmolarity.10 Insulin is present, but it is not adequate to reduce blood glucose levels,
particularly in the presence of significant insulin resistance

PATHOPHYSIOLOGY OF CHRONIC COMPLICATIONS OF

DIABETES MELLIITUS

DIABETIC RETINOPATHY

Retinopathy
Diabetic retinopathy is a general term for all disorders of the
retina caused by diabetes. There are two major types of
retinopathy: nonproliferative and proliferative.

Nonproliferative retinopathy
In nonproliferative retinopathy, the most common form of
retinopathy, capillaries in the back of the eye balloon and
form pouches. Nonproliferative retinopathy can move through
three stages (mild, moderate, and severe), as more and more
blood vessels become blocked.

Macular edema
Although retinopathy does not usually cause vision loss at this
stage, thecapillarywalls may lose their ability to control the
passage of substances between the blood and the retina. Fluid
can leak into the part of the eye where focusing occurs, the
macula. When the macula swells with fluid, a condition called
maculaedema, vision blurs and can be lost entirely.

Proliferative retinopathy
In some people, retinopathy progresses after several years to
a more serious form calledproliferative retinopathy. In this
form, the blood vessels are so damaged they close off. In
response, new blood vessels start growing in the retina. These
new vessels are weak and can leak blood, blocking vision,
which is a condition called vitreous haemorrhage. The new
blood vessels can also cause scar tissue to grow. After the scar
tissue shrinks, it can distort the retina or pull it out of place, a

GLAUCOMA
Glaucoma occurs when there is a gradual increase in the normal
fluid pressure inside the eyes. The increased pressure can damage
the optic nerve, causing vision loss.
Neovascular glaucoma that tends to be associated with diabetes
occurs when new, abnormal blood vessels grow on the iris, the
colored part of the eye. These blood vessels block the normal flow
of fluid out of the eye, raising the eye pressure.

CATARACT
The enzyme aldose reductase catalyzes the reduction of
glucose to sorbitol through the polyol pathway, a process
linked to the development of diabetic cataract.
Intracellular accumulation of sorbitol leads to osmotic changes
resulting in hydropic lens fibres that degenerate and form sugar
cataracts. In the lens, sorbitol is produced faster than it is
converted to fructose by the enzyme sorbitol dehydrogenase. In
addition, the polar character of sorbitol prevents its intracellular
removal through diffusion. The increased accumulation of sorbitol
creates a hyperosmotic effect that results in an infusion of fluid to
countervail the osmotic gradient. Intracellular accumulation of
polyols leads to a collapse and liquefaction of lens fibers, which
ultimately results in the formation of lens opacities.

CARDIOVASCULAR COMPLICATIONS IN DIABETES

Coronary heart disease (CHD) is currently the leading cause of death worldwide and together with
diabetes, poses a serious health threat, particularly in the Indian Asian population
There are a number of differences in the lipid profile of diabetic and non-diabetic patients
which contribute to the increase of atherosclerosis.
Atherogenic risk factors i.e hyperglycemia, hypertension, dyslipidemia and
central obesity cluster together with insulin resistance in the metabolic
syndrome( Syndrome X) which is associated with accelerated atherosclerosis and
CVD.
At any lipoprotein level, diabetic patients have more significant CHD than nondiabetic persons.
In diabetics, there is increased concentrations of LDL and lipoprotein a. In
addition, the oxidation of lipoproteins, in particular LDL,seems to be enhanced in
diabetics.
Glycation of apoB is increased in diabetic individuals and contribute to the development of
atherosclerosis. Glycation causes impaired recognition of LDL by its receptor on
hepatocytes, thereby increasing its half-life. The glycated LDL is then taken up preferentially
by macrophages via a separate receptor and degraded.
Immunohistochemical analysis of coronary arteries in patients with type 2 diabetes showed
high levels of Advanced Glycosylation End products (AGE) within atherosclerotic
plaque.

DIABETIC NEPHROPATHY
Diabetic nephropathy is a clinical syndrome characterized by the occurrence of persistent
microalbuminuria in concomitance with insulin- or noninsulin-dependent diabetes.
Hyperglycemia induces renal damage directly or through hemodynamic modifications. It
induces activation of protein kinase C, increased production of advanced glycosylation end
products, and diacylglycerol synthesis. In addition, it is responsible for hemodynamic
alterations such as glomerular hyperfiltration, shear stress, and microalbuminuria. These
alterations contribute to an abnormal stimulation of resident renal cells that produce more
TGF-1. This growth factor upregulates GLUT-1, which induces an increased intracellular
glucose transport and d-glucose uptake. TGF-1 causes augmented extracellular matrix
protein deposition (collagen types I, IV, V, and VI; fibronectin, and laminin) at the
glomerular level, thus inducing mesangial expansion and glomerular basement membrane
thickening. However, low enzymatic degradation of extracellular matrix contributes to an
excessive accumulation.
An abnormal ECM production contributes to glomerular sclerosis and tubulointerstitial
damage leading to diabetic nephropathy.

DIABETIC NEUROPATHY
Diabetic neuropathy occurs in ~50% of individuals with long-standing
type 1 and type 2 DM.
It may manifest as: polyneuropathy, mononeuropathy, and autonomic
neuropathy.

In the development of neuropathy, the hyperglycemic state leads to an increase in action of the enzymes
aldose reductase and sorbitol dehydrogenase. This results in the conversion of intracellular glucose to
sorbitol and fructose.
The accumulation of these sugar products results in a decrease in the synthesis of nerve cell myoinositol,
required for normal neuron conduction. Additionally, the chemical conversion of glucose results in a
depletion of nicotinamide adenine dinucleotide phosphate stores, which are necessary for the detoxification
of reactive oxygen species and for the synthesis of the vasodilator nitric oxide. There is a resultant
increase in oxidative stress on the nerve cell and an increase in vasoconstriction leading to ischemia,
which will promote nerve cell injury and death. Hyperglycemia and oxidative stress also contribute to the
abnormal glycation of nerve cell proteins and the inappropriate activation of protein kinase C, resulting in
further nerve dysfunction and ischemia.

CLINICAL MANIFESTATIONS
FOOT
DISEASE

OF DIABETIC NEUROPATHY: DIABETIC

The development of lower extremity ulcers is a well known potential complication for patients with
diabetes.
Once an ulcer has developed, there is an increased risk of wound progression that may ultimately lead to
amputation; diabetic ulceration has been shown to precede amputation in up to 85% of cases
Diabetic foot ulcers result from the simultaneous action of multiple contributing causes.The major
underlying causes are noted to be peripheral neuropathy and ischemia from peripheral vascular disease.
Damage to the innervations of the intrinsic foot muscles leads to an imbalance between flexion and
extension of the affected foot. This produces anatomic foot deformities that create abnormal bony
prominences and pressure points, which gradually cause skin breakdown and ulceration.
Autonomic neuropathy leads to a diminution in sweat and oil gland functionality. As a result, the foot loses
its natural ability to moisturize the overlying skin and becomes dry and increasingly susceptible to tears
and the subsequent development of infection.
The loss of sensation as a part of peripheral neuropathy exacerbates the development of ulcerations. As
trauma occurs at the affected site, patients are often unable to detect the insult to their lower extremities.
As a result, many wounds go unnoticed and progressively worsen as the affected area is continuously
subjected to repetitive pressure and shear forces from ambulation and weight bearing.

REFERENCES
Harrisons Principles of Internal Medicine, 19th edition
WHO Diabetes Programme_
http://www.who.int/diabetes/en/
American Diabetic Association_
http://www.diabetes.org
National Center for Biotechnology
Information_http://www.ncbi.nlm.nih.gov/
Davidsons Principles and Practice of Medicine, 22nd
Edition
Ganongs Review of Medical Physiology, 24th Edition

THANK YOU