Pathology Of Diabetes Mellitus

Diabetes Mellitus
• Disorder of metabolism (Carb, Prot & Fat)
• Due to Absolute/relative deficiency of
insulin.
• Characterized by hyperglycemia
• Clinically:
• Polyuria
• Polydypsia,
• Polyphagia.
Introduction
• Diabetes mellitus (sweet urine)
• 3% of world population, 100 million people
• Incidence is increasing alarmingly (40% in the
past decade, more in future. 259 m by 2025.
• Most Common non-communicable disease
• High Morbidity & mortality.
• DM shortens life span by 15 years.
• Leading cause of blindness and Kidney disease.
THE ENDOCRINE PANCREAS

• Approximately 1 million Islets of Langerhans

• Most located in the body and tail
• Contain cells that manufacture and secrete
different hormones:
• beta cells 70% insulin
• alpha cells 20% glucagons
• delta cells 5‑10% somatostatin
• PP cells 1‑2% pancreatic polypeptide
• D1 cells rare vasoactive intestinal
peptide (VIP)
• enterochromaffin cells rare serotonin
Blood Glucose & Hormones
Hormone Action
• Insulin ∀ ↓ Glucose
• Glucortocoids ∀ ↑ Glucose
• Glucagon ∀ ↑ Glucose
• Growth Hormone ∀ ↑ Glucose
• Epinephrine ∀ ↑ Glucose
Normal Pancreatic Islet:
ß cells (Insulin) α cells (Glucagon)
Cellular Glucose Uptake

Insulin Requiring Non-Insulin Requiring

• Striated Muscle • Blood Vessels

• Cardiac Muscle • Nerves
• Fibroblasts • Kidney
• FAT • Eye Lens
Pathology in Diabetes:

• Low glucose inside cell

– Decreased cell metabolism (muscle, liver)
• High glucose outside cell
– Glycosylation damage (Blood Vessels)
– Osmotic damage
Pathogenesis of Type I Diabetes Mellitus

Type I DM results from an absolute deficiency in

insulin secondary to a reduced beta‑cell mass.

Three basic components:

1. Genetic susceptibility (e.g. HLA‑DR3, ‑DR4)
2. Autoimmune reaction to islet beta cells
3. Initiating environmental insult (e.g. virus,
chemical, etc.).
Pathogenesis of Type II Diabetes Mellitus

1. Genetic factors more important than in type I DM

2. Age-related
3. Obesity-related
4. No evidence of an autoimmune mechanism

Evidence points to two biochemical defects

8. relative decrease in insulin
9. insulin resistance.
Pathogenesis of Type II Diabetes Mellitus
THEORIES

1. Relative or absolute insulin deficiency

Age-related loss of beta cell ability to manufacture and secrete
insulin, or to respond to hyperglycemic stimuli.

• Peripheral insulin resistance

Obesity causes insulin resistance of its own

Cellular defects in insulin resistance:

• Decreased numbers of insulin receptors on peripheral cells
• Defects in receptor‑associated tyrosine kinase
• Post‑receptor defects in the cytoplasmic glucose transport unit
proteins.
 Type-I DM
• Less common
• Children < 25 Years
• Insulin- Dependent
• Duration: Weeks
• Acute Metabolic complications
• Autoantibody: Yes
• Family History: No
• Insulin levels: very low
• Islets: Insulitis
• 50% in twins
Type-II DM
• More common
• Adult >25 Years
• Insulin Independent *
• Months to years
• Chronic Vascular complications.
• No
• Yes
• Normal or high *
• Normal / Exhaustion
• 60-80% in twins
Insulitis In Type I DM

Insulinitis
Islets in Type II DM
Loss of ß cells, replaced by Amyloid deposits (hyalinization)
Islets in Type II Diabetes:
Loss of ß cells, replaced by Amyloid deposits (hyalinization)
Complications Of DM:
• Short term Complications: (metabolic)
1. Hypoglycemia
2. Diabetic Ketoacidosis
3. Non Ketotic hyperosmolar diabetic coma
4. Lactic acidosis

• Long term Complications:(Angiopathy)

– Microngiopathy:
Retinopathy, Nephropathy Neurophathy,
Dermatopathy
– Macroangiopathy
Atherosclerosis
Microangiopathy Pathogenesis:
Chronic Hyperglycemia

Glycosylation of basement membrane

proteins  Leaky blood vessels.

Thick and Leaky blood vessels

Narrow lumen

Ischemic Organ Damage...

Diabetic Microangiopathy
Normal

 Glucose
 Glycosylation
 BM damage leak
 ‘AGE’ deposition Diabetic
 Neuropathy
• Sensory  Motor (myelin)

• Peripheral Neuropathy
– Bilateral, symmetric
– Progressive, irreversible
– Paraesthesia, pain, muscle atrophy
• Visceral neuropathy
– Cranial nerve – diplopia, Bell palsy
– GIT- constipation, diarrhea
– CVS – orthostatic hypotension
Neuropathic ulcers

:
Features:
•Painless
•At pressure points
•Good foot pulses
•May not be associated with gangrene
DIABETIC NEPHROPATHY

• Kidney is the most severely damaged

organ in DM
• DM is the most common cause of
end‑stage renal disease
• Nephropathy is more common in type I
DM
• Nephropathy develops in kidneys
transplanted in diabetics
 Diabetic Nephropathy
• Arteriolosclerosis

• Diffuse or nodular diabetic

glomerulosclerosis
(Kimmelstiel Wilson Syndrome)

• Renal papillary necrosis

• Pyelonephritis

• End stage kidney

Nephropathy
• Nodular Glomerulosclerosis.
• Deposition of ‘AGE’ (Advanced
Glycosylation End-products) as
nodules
• Nephrotic syndrome
• End stage renal failure

Nodular Glomerulosclerosis
(Kimmelstiel Wilson Syndrome)
Renal papillary necrosis
DIABETIC RETINOPATHY

• Fourth leading cause of legal blindness

• Leading cause of new cases of blindness in adults

• Other causes of blindness in diabetic patients include:

– Glaucoma
– cataracts
– optic neuropathy

• Approximately 60% of diabetics develop retinopathy

• Vision‑threatening retinopathy is commoner in type I DM
• Duration of diabetes is important in the severity of
disease
Normal Retina
Retinopathy
• Non-proliferative
– Microaneurysms,
– Dot blot hemorrhages
– Hard and soft exudates
– Cotton wool – infarcts
– Macular edema.
• Proliferative.
– Neovascularization
– Large hemorrhages
– Retinal detachment
– Fibrosis
Dot blot – Hemorrhages Cotton wool spots

Pre-retinal Hemorrhage Fibrous plaques

Cataract
Macroangiopathy
Atherosclerosis
DM is a major risk factor for the development of
Atherosclerosis
• Hyperlipidemia
∀ ↓ HDL
• Non-Enzymatic Glycosylation
∀ ↑ Platelet Adhesiveness
∀ ↑ Thromboxane A2
• Endothelial damage  Atherosclerosis
Risk Factors for Atherosclerosis:

Non modifiable Potentially Modifiable

• Age • Hyperlipidemia –
• Male Sex, HDL/LDL ratio.
• Genetic - Hyperchol. • Hypertension.
• Family history • Smoking.
• Diabetes.
Atherosclerosis:
Infections in Diabetes:
Causes:
• Decreased metabolism
• Decreased function of lymphocytes & neutrophils
• Glycosylation of immune mediators. Ab
• Impaired inflammation.
• Ischemia & infarctions

• Diabetes  State of immunosuppression

SKIN LESIONS IN DIABETES MELLITUS

Occurs in 30% of diabetic patients

Lesions:
D) Necrobiosis Lipoidica Diabeticorum
E) Diabetic dermopathy ("skin spots")
F) Granuloma Annulare
G) Injection site lipodystrophy