DIABETES

MELLITUS
 OBJECTIVES
By the end of the session students should be able to:
• Describe diabetes mellitus, classification and
diagnostic criteria.
• Highlight pathogenesis and pathophysiology of
diabetes mellitus.
• Cite main diabetes mellitus complications and major
pathways involved.
• Describe the management approach in diabetes mellitus
 OUTLINE
• Definition of diabetes mellitus
• Epidemiology of DM
• Normal Physiology
• Classification
• Type 1 DM
• Gestational DM
• Type 2 DM
• Complications of DM
• References
 What is diabetes mellitus
Diabetes mellitus is a metabolic disorder
characterized by hyperglycemia
 it is caused by a defect in insulin secretion,
insulin action or both.
Insulin directly affects the metabolism of
 carbohydrate, protein, fat, and indirectly
affects water and electrolyte homeostasis.
 INTRODUCTION
Diabetes mellitus (DM) is defined as a
heterogeneous metabolic disorder characterized by
common feature of chronic hyperglycemia with
disturbance of carbohydrate, fat and protein
metabolism (WHO)

It’s a result of a defect in Insulin secretion, insulin

action or both
 INSULIN PHYSIOLOGY AND
GLUCOSE HOMEOSTASIS
Insulin is a small protein with mwt of 5808 in
human
It contains 51 amino acids arranged in two chains A
& B linked by disulphide bridges (c – peptide)

Insulin is released from pancreatic β islet Cells in

response to elevated serum glucose
 INSULIN SECRETION

Release of Insulin: Insulin release stimuli include:

A low basal rate serum glucose or mannose
Higher rate in response amino acids(leucine arginine)
to various stimuli
Hormones (glucagon, thyroxine,
corticosol and vagal activity
 INSULIN METABOLISM
 The liver and the kidney are the two main organs that
remove insulin from the circulation

The liver normally clears the blood of approx.60% of

the insulin and 35-40% by the kidney
The t1/2 life of circulating insulin is 3-5 minutes

Exogenous subcutaneous Insulin injections, reverses

this ratio, as kidney clears 60% exog. Insulin and the
liver removing the rest
 Cont..

• The most important stimulus that triggers

insulin release and synthesis is glucose.
• A rise in blood glucose levels results in
glucose uptake into body cells.
• Facilitated by an insulin dependent, glucose
transporting protein.
 GLUCOSE TRANSPORTATION
• A rise in blood glucose levels results in glucose uptake into body
cells which is Facilitated by an insulin dependent, glucose
transporting protein
 FUNCTIONS OF INSULIN
• Insulin is a major anabolic hormone. It plays a major
role in:
i) Transmembrane transport of glucose and amino
acids
ii) Glycogen formation in the liver and skeletal
muscles
iii) Glucose conversion to triglycerides
iv) Protein synthesis
v) Mitogenic functions (DNA synthesis – cell growth
and differentiation)
 INSULIN ACTIONS
LIVER ADIPOSE TISSUE SKEL. MUSCLE
Carbohydrates Carbohydrates Carbohydrates
1.↑Glycogen synthesis 1.↑Glucose uptake 1.↑Glucose uptake

2.↓Glycogenolysis 2. Inhibit flow of 2.↑Glycogen synth

3.↓Gluconeogenesis gluconeogenic precursor to [Link] flow gluconeo -
liver (Glycerol) genic precursor to liver
4.↑hepatic Glucose uptake
(Lactate pyruvate)

Fat Fat Fat

1.↑Lipogenesis 1.↓Lipolysis 1. ↓Lipolysis
2.↓Ketogenesis 2.↑Triglyceride formation

Protein Protein Protein

1.↓Protein breakdown --------- 1.↑Protein synthesis

2.↑Protein synthesis --------- 2.↓Protein breakdown

11
Kumar, & Clark. Clinical medicine . Emedicina Forum, 6Th edition
 CLASSIFICATION OF
DIABETES MELLITUS
• Type 1/ insulin dependent diabetes mellitus (DM –I)

• Type 2/ non insulin dependent diabetes mellitus (DM

–II)

• Type 3/ gestational diabetes

• Other specific types of diabetes mellitus

 I. TYPE 1 DIABETES MELLITUS (10%)

Also called Insulin-dependent, or juvenile-onset diabetes

• Type IA DM: Immune-mediated destruction of

pancreatic β cells hence absolute insulin defficiency
• Type IB DM: Idiopathic cause
 II. TYPE 2 DIABETES MELLITUS (80%)

• Also called non-insulin-dependent, or maturity-onset

diabetes)
• Due to a progressive loss of β cell insulin secretion
accompanied by a background of insulin resistance
 III. GESTATIONAL
DIABETES MELLITUS
• refers to hyperglycaemia occurring for the first time during
pregnancy

• Repeated pregnancy may increase the likelihood of

developing irreversible diabetes,
• particularly in obese women; 80% of women with
gestational diabetes ultimately develop permanent
diabetes.
• Resembles type 2 diabetes
 IV. OTHER SPECIFIC
TYPES OF DIABETES (10%)

a) Monogenic diabetes syndromes eg. Neonatal

diabetes and maturity onset diabetes of the young

b) Disease of the exocrine pancreas eg cystic

fibrosis and drug/chemical induced diabetes eg
glucocorticoid use
 PATHOGENESIS OF
DIABETES MELLITUS
• Depending upon etiology of DM, hyperglycemia may
result from the following: 

 Reduced or no insulin secretion

 Decreased glucose use by the body
 Increased glucose production.
DM TYPE 1
 DM - I SUBTYPES
• Subtype 1A (immune-mediated) DM
 characterized by autoimmune destruction of β -
cells which usually leads to insulin deficiency.
 
• Subtype 1B (idiopathic) DM
 characterized by insulin deficiency with tendency to
develop ketosis but these patients are negative for
autoimmune markers.
 DM – I CONT..
• The basic phenomenon in type 1 DM is destruction of β -
cell mass, usually leading to absolute insulin deficiency.

• Currently, pathogenesis of type 1A DM is explained on

the basis of 3 mutually-interlinked mechanisms:
 genetic susceptibility,
 autoimmune factors,
 certain environmental factors
 PATHOGENESIS OF DM -I
[Link] susceptibility

Type 1A DM
involves inheritance of multiple genes that cause susceptibility to
the disorder


About half the cases with type 1A DM have the susceptibility gene
located in the Human Leukocyte Antigen (HLA) region of
chromosome 6 (MHC class II region), particularly HLA DR3 and
DQ locus which plays a role in autoimmune disease

Concordance in identical twins 50%

 
 PATHOGENESIS CONT…
2. AUTOIMMUNE
(i)Presence of islet cell antibodies against GAD (glutamic acid
decarboxylase) and insulin
 (ii) Occurrence of lymphocytic infiltrate in and around the
pancreatic islets termed insulitis. It chiefly consists of CD8+ T
lymphocytes with variable number of CD4+ T lymphocytes and
macrophages.
(iii) Selective destruction of B-cells while other islet cell types
(glucagon-producing alpha cells, somatostatin-producing delta
cells, or polypeptide-forming PP cells) remain unaffected. This
is mediated by T-cell mediated cytotoxicity or by apoptosis
 
 PATHOGENESIS CONT…
3. ENVIRONMENTAL
i)Viral infections preceding onset of disease e.g. mumps,
measles, coxsackie B virus, CMV &infectious
mononucleosis
 ii) Experimental induction of type 1A DM with certain
chemicals has been possible e.g. alloxan, streptozotocin
and pentamidine
iii) Geographic and seasonal variations in its incidence
suggest some common environmental factors
iv) Early exposure to bovine milk proteins and occurrence
of autoimmune process in type 1ADM is being studied
 DIAGNOSIS OF DM-I
• The classic manifestations of the disease
(hyperglycemia and ketosis) occur late in its course,
after >90% of the beta cells have been destroyed
• Blood sugar tests remains fundamental basis for Dx
• Fasting blood sugar ≥ 11.1 mmol/l
• Random blood sugar ≥ 7.0 mmol/l (whole blood ≥ 6.1
mmol/l)
• Urine testing for glucose and ketones
• Other tests: C-Peptide, Insulin Autoantibodies (IAA), Glutamic
Acid Decarboxylase Autoantibodies (GADA or Anti-GAD)
 MANAGEMENT OF TYPE 1
DIABETES
Easier said than done
• The goal is:
 To balance the caloric intake with the glucose
lowering processes (insulin and exercise), and
allowing the patient to live as normal a life as
possible
 With the availability of the Self Monitoring of
Blood Glucose and HbA1C tests adequacy of the
insulin regimen can be assessed.
 MANAGEMENT cont..
• Types of Exogenous insulin according to duration of action
• Rapid-acting:
 Lispro : onset 15’, peak 60-90’ and last from 2-4 hours)
• Short-acting:
 onset is 30-60’, peak in 2-3h and last for 4-6 hours.
• Intermediate-acting:
 NPH or Lente: onset 3-4h, peak 4-12 hours and lst 16-20
hours.
• Long-acting:
 Ultralente, Lantus: onset 6-8h, peak 12-16 h and lasts 20-30h.
 COMPLICATIONS OF INSULIN THERAPY

Hypoglycemia
Allergic reactions
Somogyi effect: (posthypoglycemia hyperglycemia)
Paradoxical tendency of the body to react to
hypoglycemia by producing hyperglycemia
When blood glucose levels drop too low during the
late evening, counterregulatory hormones such as
adrenaline, costeroids, gluconeogenesis and
resultant hyperglycemia in the early morning.
 Dawn phenomenon (DP)
• Morning hyperglycemia is due to decrease level of
endogenous insulin secreted at night
• DP also contribute to morning hyperglycemia to
increased concertation of insulin-antagonist hormone
• Occurs commonly than Somogyi phenomenon
• Both together with Somogyi phenomenon can be
prevented by optimal diabetes control with proper
insulin therapy
GESTATIONAL DIABETES
 GESTATIONAL DIABETES
It is a form of glucose intolerance that is diagnosed during
pregnancy.
Diabetes is a common complication of pregnancy.

The prevalence of diabetes is about 15% in the pregnant

women.

It is also more common among obese women and women

with a family history of diabetes.
The placenta can secrete a variety of hormones which
antagonize the effects of insulin. E.g Estrogen,
progesterone, HPL, HCG.
 GESTATIONAL DIABETES
Decreased insulin sensitivity is the key mechanism of GDM.
There are no placental hormones after delivery of placenta, so
the insulin sensitivity and the blood glucose levels should be
restored to the normal.
During pregnancy, gestational diabetes requires treatment to
normalize maternal blood glucose levels to avoid complications
in the infant.
After pregnancy, 5% to 10% of women with gestational
diabetes are found to have type 2 diabetes.
Women who have had gestational diabetes have a 20% to 50%
chance of developing diabetes in the next 5-10 years.
 SCREENING
• Pregnant women are screened between 24 and 28 weeks
gestation.

• 50-g glucose challenge followed by 1-hour glucose level

• A value above 140 mg/dL is a positive screen

• Positive screen is confirmed with a 3-hour oral glucose

tolerance test (100g glucose is used)
DM TYPE 2
 TYPE 2 DIABETES
 It was previously called non-insulin-dependent
diabetes mellitus (NIDDM) or adult-onset diabetes.

 Type 2 diabetes may account for about 90% to 95%

of all diagnosed cases of diabetes.

 It usually begins as insulin resistance followed by

defective insulin secretion by beta cells.
 Type 2 diabetes is associated with
 older age
 Obesity
 family history of diabetes
 history of gestational diabetes
 impaired glucose metabolism
 physical inactivity
 race/ethnicity
 Type 2 diabetes is increasingly being diagnosed in
children and adolescents.
 PATHOGENESIS: TYPE 2 DM
It is a complex multifactorial disease.
Environmental factors:
 sedentary life style and dietary habits (obesity)
Genetic factors:
 Concordance rate of 35% to 60% in monozygotic twins
 Recent large-scale genome wide association studies -
>more than a dozen susceptibility loci 
called “diabetogenic” genes.
The two metabolic defects that characterize type 2 DM are
 Insulin resistance: A decreased ability of peripheral tissues
to respond to insulin.
 Beta cell dysfunction -- inadequate insulin secretion in the
42
face of insulin resistance and hyperglycemia
 INSULIN RESISTANCE FOR GLUCOSE
After a carbohydrate-rich meal, the gut absorbs glucose
This blood glucose, insulin secretion by pancreatic
beta cells.
Insulin glucose uptake by skeletal muscle and adipose
tissue
1) At the same time, insulin hepatic glucose production
by: inhibiting glycogenolysis and gluconeogenesis,
2) Enhancing glycogen synthesis,
3) blocking the effects of glucagon on the liver and
4) antagonizing glucagon release from the pancreas
.
• All of these effects of insulin are impaired in IR.
• Initially, compromised insulin action is subclinical.

• As the condition progresses, fasting glucose rises or impaired

glucose tolerance develops.

• Eventually, the patient develops frank hyperglycemia and overt

T2DM.

• IR increases hepatic glucose output and reduces glucose uptake

by peripheral tissues, primarily muscles and adipose tissue.
• By itself, insulin resistance rarely causes T2DM:
increased insulin secretion (hyperinsulinism) by beta
cells compensates for these defects and prevents blood
glucose levels from rising.

• Only when the pancreas can no longer keep up with

this high demand do blood glucose levels start to
increase.

• In many obese and prediabetic patients, subclinical

beta cell dysfunction exists before overt diabetes
 BETA CELL DYSFUNCTION

• At first, an impairment in the first phase of insulin

secretion following glucose stimulation precedes
glucose intolerance in T2DM.
• Later in the second phase of the disease, release of
newly synthesized insulin is faulty. This effect can be
reversed, at least in some patients, by restoring good
control of glycemia.
• This partially reversible reduction in insulin secretion
results from a paradoxical inhibitory effect of glucose
upon insulin release that may be seen at high blood
glucose levels (“glucose toxicity”)
• Impaired first-phase insulin secretion can serve as a
marker of risk for T2DM in family members of
subjects with T2DM, and may be seen in patients with
prior gestational diabetes
• Over a long time, insulin secretion in T2DM gradually
declines, together with beta cell mass
 Fig1: Pathogenesis of type 2 diabetes mellitus.
Fig 2: Mechanisms of beta cell dysfunction and insulin resistance. Free fatty acids
directly cause beta cell dysfunction and induce insulin resistance in target tissues and also
induce the secretion of pro-inflammatory cytokines that cause more beta cell dysfunction
and insulin resistance
48
 1. Glucotoxicity (Chronic
Insulin resistance is as strong a
hyperglycemia)
risk factor for cardiovascular 2. Lipotoxicity(High
disease. circulating free fatty
Genetic susceptibility,
obesity, Western lifestyle acids )
3. Over secretion of insulin
to compensate for insulin
resistance.
Insulin resistance
IR  b-cells dysfunction

Hyperglycemia
Dyslipidemia
Hypertension
Damage to blood
Type 2 diabetes
More than 80% of patients progressing to
vessels type 2 diabetes are insulin resistant.
Clotting abnormalities
Inflammation Overall, 75% of patients with type 2
diabetes die from cardiovascular disease.

Rhodes CJ & White MF. Eur J Clin Invest 2002; 32 (Suppl. 3):3–13.
 DIAGNOSIS OF DM II
Plasma glucose values (are 15% higher Interpretation/Diagnosis
than whole blood glucose value)

1. FASTING (FOR > 8 HOURS) VALUE

Below 100 mg/dl (< 5.6 mmol/L) Normal fasting value

100-125 mg/dl (5.6-6.9 mmol/L) Impaired fasting glucose (IFG)

126 mg/dl (7.0 mmol/L) or more Diabetes mellitus
2. TWO-HOUR AFTER 75 GM ORAL GLUCOSE LOAD
(oral glucose tolerance test)

< 140 mg/dl (< 7.8 mmol/L) Normal post-prandial GTT

140-199 mg/dl (7.8-11.1 mmol/L) Impaired post-prandial glucose tolerance
(IGT)

200 mg/dl (11.1 mmol/L) or more Diabetes mellitus

3. RANDOM VALUE
200 mg/dl (11.1 mmol/L) or more Diabetes mellitus
in a symptomatic patient
50
 INVESTIGATIONS
 Urine analysis (glucose, ketones or
microalbuminuria)
 CBC
 U/E/C
 LFT’s
 Serum Cholesterol
 X-RAY, Doppler U/S, Arteriogram
 Fundoscopy
 INVESTIGATIONS
Glycosylated hemoglobin (HbA1C)
Measurement of glucose level in diabetics suffers
from variation due to dietary intake of the previous
day
Long-term objective assessment of degree of
glycemic control is better monitored by measurement
of glycosylated hemoglobin (HbA1C)
This is because the non-enzymatic glycosylation of
hemoglobin takes place over 90-120 days, lifespan of
red blood cells. HbA1C assay, therefore, gives an
estimate of diabetic control and compliance for 3-4
months.
 MANAGEMENT
Is best provided by a multidisciplinary team of health
professionals with expertise in diabetes, working in
collaboration with the patient and family.
Management Includes:
1. Dietary and exercise modifications
2. Medications
3. Appropriate self monitoring of blood glucose
4. Regular monitoring for Complications
5. Laboratory assessment
 NUTRITIONAL THERAPY
American Diabetes Association (ADA)
Guidelines indicate that within the context of an
overall healthy eating plan, a person with diabetes
can eat the same foods as a person who does not have
diabetes.
Overall goal:
Assist people in making changes in nutrition and
exercise habits that will lead to improved metabolic
control.

54
Type 1 DM: Meal plan based on the individual’s
usual food intake and is balanced with insulin and
exercise patterns.
Type 2 DM: Emphasis placed on achieving glucose,
lipid, and blood pressure goals. Calorie reduction.
56
 EXERCISE
Essential part of diabetes management
Increases insulin sensitivity
Lowers blood glucose levels
Decreases insulin resistance
 Exercise should start slowly for patients with limited activity.
 Patients with CV diseases should be evaluated before starting
any exercise
 Best done after meals. Several small carbohydrate snacks can
be taken every 30 minutes during exercise to prevent
hypoglycemia
 Exercise plans should be individualized
 Monitor blood glucose levels before, during, and after exercise
57
 MANAGEMENT
Type 1 DM: All patient need insulin
 To balance the caloric intake with the glucose
lowering processes (insulin and exercise), and
allowing the patient to live as normal a life as
possible.
 The insulin regimen has to mimic the physiological
secretion of insulin.

Type 2DM : Patients need caloric restriction

 Pharmacological therapy include insulin and Oral
Glucose Lowering Agents (OGLA’s)
58
 Insulin


Exogenous insulin:
Required for type 1 diabetes
Prescribed for the patient with type 2 diabetes who cannot
control blood glucose by other means

Types of insulin according to duration of action
Rapid-acting: Lispro : onset 15’, peak 60-90’ and last from
2-4 hours)
Short-acting: Regular: onset is 30-60’, peak in 2-3h and last
for 4-6 hours
Intermediate-acting: NPH or Lente: onset 3-4h, peak 4-12
hours and lst 16-20 hours
Long-acting: Ultralente, Lantus: onset 6-8h, peak 12-16 h and
59

lasts 20-30h
 
Administration of insulin
Subcutaneous administration

Process: pinch skin, inject needle at 90-degree angle
Do not inject into muscle; do not massage after injecting
Rotate injection sites
Minimize painful injections

Problems with insulin therapy
Hypoglycemia
Allergic reactions
Lipodystrophy
60
Somogyi effect
 Treatment
Type 1 diabetes is fatal if not
treated with external insulin

Insulin:
-fast acting and slow acting

Methods:
-subcutaneous injection
-insulin pump
ORAL GLUCOSE LOWERING AGENTS (OGLA’s)
 MONITORING BLOOD GLUCOSE
Self-monitoring of blood glucose
Enables patient to make self-management decisions
regarding diet, exercise, and medication
Important for detecting episodic hyperglycemia and
hypoglycemia
Patient training is crucial
Glycosylated hemoglobin (HbA1C)

63
 COMPLICATIONS OF DM
ACUTE CHRONIC/ LATE
• Diabetic Keto • Macro vascular
Acidosis (DKA) • Peripheral vascular d’se
• Hyperosmolar • CVS d’se( M.I)&CVA
Hyperglycemic Non ( Stroke)
Ketotic State • Micro vascular
(HHS)
• Nephropathy
• Hypoglycemia
• Neuropathy
• Lactic acidosis
• Retinopathy
• Others: GIT, GUT, LL disorders
 ACUTE COMPLICATIONS
Diabetic Keto Acidosis (DKA)

• Almost exclusive complication of DM-1 rarely in DM-II

• The diagnosis is consistent when: hyperglycemia (RBG

>250 mg/dL(13.9mmol/L)), HCO3- (<15 mEq/L), and
pH (<7.3), with ketonemia and moderate ketonuria.
• Commonly triggered by failure to timely injection of
Insulin, Infections, trauma, surgery, Intoxication
Inflammation, Infarction and drugs (steroids)
PATHOGENESIS OF DKA
 PATHOGENESIS OF DKA
• Insulin deficiency plus excess glucagon decreases
peripheral glucose utilization while increasing
gluconeogenesis

• worsened hyperglycemia (13-33 mmol/l)

• osmotic diuresis and dehydration due to ketoacidosis

Diabetic coma (Untreated)

 PATHOGENESIS OF DKA…
• 2nd major effect is activation of ketogenic machinery
(Ketogenesis)

• Insulin deficiency stimulates lipoprotein lipase which

breaks down adipose stores and increase free fatty
acid levels

• FFA reach the liver and are esterified to fatty acyl

coenzyme A then oxidized in liver mitochondria to
form ketone bodies (acetoacetic acid and beta
hydroxybutyric acid, acetone)
 PATHOGENESIS OF DKA…
• The rate of ketones formation may exceed the rate of
tissue utilization leading to ketonemia and ketonuria

• If urine secretion of ketones is compromised, there will

be metabolic acidosis

• Ketones Induces Nausea and Vomiting

• The above leads to further loss of fluids and electrolytes

 CLINICAL PRESENTATION OF DKA

• History of polyuria, polydipsia, nausea, vomiting,

and marked fatigue, with eventual stupor that can
progress to coma.
• Abdominal pain and tenderness may be present
without abdominal disease.

• Increased rate and depth of breathing (i.e.,

Kussmaul’s breathing) with a characteristic fruity
smell

• Hypotension and increased heart rate in

compensating for the decrease in blood volume.
 S/S AND TREATMENT OF DKA
• Treatment goals :
• Replace fluids and electrolytes
• Administer insulin
• Correct metabolic acidosis
• Treat underlying cause
HYPEROSMOLAR HYPERGLYCEMIC NON KETOTIC STATE
(HHNKS)

• Affects DM II and is caused by severe dehydration

resulting from sustained hyperglycemic diuresis

• Common in older diabetic patients disabled by

stroke or infection and unable to take enough
water
 HHNKS cont.
• More severe than DKA due to the absence of
ketoacidosis thus no N/V or kussmauls breathing
thus delay in seeking medical attention till severe
dehydration and impaired mental signs occur

• Blood sugar ranges from 33 to 67mmol/l

• In treatment give lower doses of insulin as compared

to DKA
 CONTRASTING FEATURES OF DKA AND HHS
Lab Findings DKA HHS
Plasma glucose(mg/dl) 250-600 >600

Plasma acetone + Less+

[Link](mEq/l) Usually low Low or High, Normal

S.K(mEq/L) Normal,high or low Normal or high

[Link](mEq/l) Normal or high Normal or high

[Link] Normal or High Normal or high

[Link](mEq/L usually<15 Usually>20

Blood pH <7.30 >7.30

[Link](mOsm/l) <320 >330

[Link](mmol/L) 2-3 1-2

[Link](mg/dl) less greater
Plasma insulin Low to 0 some
 HYPOGLYCEMIA
• Caused by too much insulin, missed meal, too much
exercise, Oral hypoglycemic (phase of dose finding)

• Most common acute complication affecting Both

DM I and II
• Has neurogenic and hyper-adrenagic signs and
symptoms

• In treatment, if alert, give oral glucose if not, IV 50%

glucose 20-50mls, if o/s then IM glucagon
 LACTIC ACIDOSIS
• Rare complication in patients taking biguanides e.g.
metformin
• Present with metabolic acidosis without significant
hyperglycemia or ketosis

• Treatment is rehydration and bicarbonate( only in

severe cases)
 CHRONIC COMPLICATIONS
Macro vascular
• Caused by damage of large and medium sized arteries
due to atherosclerosis
• The main pathology is on fibrous plaque formed ,the
proliferation of sub-endothelial smooth muscle of
arteries

• Commonly affects Brain (stroke), heart(MI) and

peripheries (gangrene of the toes and feet)
 Micro vascular

Caused by damage to small vessels due poor ability

of its cells to down-regulate glucose entry
These effects are profound in
 Retina (retinopathy)
 Kidneys (nephropathy)
 Peripheral nerves(neuropathy)
 Micro vascular
Mechanisms proposed to explain the development of
late complications of DM:
 Formation of Advanced Glycosylation End
Products
 Activation of Protein Kinase C
 Oxidative stress and Disturbance in Polyol
Pathways
 Hexosamine Pathways and Generation of Fructose
-6-Phosphate
 FORMATION OF ADVANCED GLYCOSYLATION END PRODUCTS
(AGEs)

Result from non-enzymatic reactions between

intracellular glucose derived dicarbonyl precursors
(glyoxal, methylglyoxal, and 3-deoxyglucosone) with
the amino groups of both intracellular and extracellular
proteins.
Rate of AGEs formation is accelerated in presence of
hyperglycemia
AGEs bind to specific receptor (RAGE) on
inflammatory cells (macrophages and T cells),
endothelium, and vascular smooth muscles
 AGEs cont..
AGE-RAGE signaling within vascular
compartment leads to:-
Release of cytokines and growth factors (TGFbeta causes
deposition of excess basement memb material and VEGF
affects retinopathy)
Generation of reactive O2 species
Increased procoagulant activity
Enhanced proliferation of vascular smooth muscle cells
and synthesis of ECM
 ACTIVATION OF PROTEIN KINASE C

Intracellular hyperglycemia stimulates synthesis of

diacyl glycerol (DAG) from glycolytic
intermediates causing excess PKC activation

PKC causes production of VEGF and TGF beta and

plasminogen activator inhibitor-1(PAI-1) by
vascular endothelium
 DISTURBANCE IN POLYOL PATHWAYS

Due to Nicotinamide dinucleotide phosphate hydrogen

(NADPH) deficiency
Excess intracellular glucose is metabolized to a polyol
called sorbitol and then to fructose in a reaction that
needs NADPH as a co factor
Sorbitol accumulation in lens leads to cataract
NADPH is also needed in glutathione reductase to
regenerate glutathione(GSH) an anti oxidant GSH
Reduced GSH causes cell susceptibility to ROS
HEXOSAMINE PATHWAYS AND GENERATION OF
FRUCTOSE -6-PHOSPHATE
Hyperglycemia through hexosamine pathway
increases intracellular levels of fructose-6-phosphate a
substrate for glycosylation of proteins leading to
excess production of proteoglycans

The glycosylation changes are accompanied by

abnormal expression of TGFbeta or PAI-1 which
worsen end organ damage
 DIABETIC NEPHROPATHY

Initially there is constriction of efferent arterioles and

dilatation of afferent arterioles leading to glomerular
capillary HTN and hyper filtration which gradual
changes to hypo filtration over time.
Concurrently, there are changes within glomerulus
itself
 DIABETIC NEPHROPATHY
Glomerular lesions
Renal vascular lesions (arteriosclerosis)
Pyelonephritis
The most important glomerular lesions are:-
 Capillary basement membrane thickening
 Diffuse mesangial sclerosis
 Nodular glomeruloscelrosis
 DIABETIC RETINOPATHY
Main types are:-
 proliferative( neovascularization)
 non proliferative(no neovascularization)
VEGF is secreted by the ischemic retina and leads to
increased vascular permeability resulting in retinal
edema
And angiogenesis of new blood vessels
Sorbitol accumulation in lens leads to cataract
 Diabetic Retinopathy

Cataract (acquired opacification of lens)

Glaucoma ( increased intraocular pressure)
Optic nerve damage
Retinal vasculopathy
 Others

GIT- gastro paresis, diarrhea, constipation

GUT- erectile dysfunction, female sexual
dysfunction
Lower extremities – diabetic foot, hammer toe,
claw toe, Charcot foot
 References

Harsh Mohan. Textbook of Pathology. Jtendar P Vij, 6th edition,

2010 .
Kumar, & Clark. Clinical medicine . Emedicina Forum, 6Th edition.
Fauci at all. Harrison's principles of internal medicine . Mc Graw-
Hill , 17th edition, 2008, Part 15.
Gray RP & Yudkin JS. Cardiovascular disease in diabetes mellitus. In
Textbook of Diabetes 2nd Edition, 1997. Blackwell Sciences
The Netter collection of medical illustrations, 2nd edition.
Davidson’s principles and practise of clinical medicine, 20th edition.