Pathology of Diabetes Mellitus

Diagnosis

Classification

Type 1 Diabetes (T1D) — ~5–10% of cases

• Autoimmune destruction of pancreatic β cells → absolute insulin deficiency
• Most common in patients < 20 years; nonobese
• Progressive fall in insulin levels
• Circulating islet autoantibodies (anti-GAD65, anti-IA2, anti-ZnT8)
• Risk of diabetic ketoacidosis (DKA)

Type 2 Diabetes (T2D) — ~90–95% of cases

• Combination of peripheral insulin resistance + inadequate β-cell compensatory response
• ~80% are obese; increasingly seen in adolescents
• Early hyperinsulinemia, then relative insulin deficiency
• No islet autoantibodies
• Risk of nonketotic hyperosmolar coma

Other Types

• Monogenic (MODY): Loss-of-function mutations in glucokinase (GCK/MODY2), HNF1α (MODY3), HNF4α (MODY1), PDX1, HNF1β, NEUROD1, and others
• Gestational diabetes mellitus (GDM)
• Secondary causes: pancreatitis, haemochromatosis, drug-induced, endocrinopathies (Cushing syndrome, acromegaly)

Comparison Table: T1D vs T2D

Pathogenesis of T1D

1. Genetic susceptibility: Strong linkage to MHC class II alleles (HLA-DR3, DR4, DQ variants); polymorphisms in CTLA4 and PTPN22 impair T-cell regulation
2. Environmental triggers: Viral infections (enteroviruses), gut microbiome alterations, and dietary factors may trigger islet autoimmunity in genetically susceptible individuals
3. Insulitis: CD8+ and CD4+ T cells and macrophages infiltrate the islets, directly killing β cells via perforin/granzyme and Fas-FasL pathways
4. Autoantibodies: Anti-islet antibodies (anti-GAD65, anti-IA2, anti-ZnT8) appear years before clinical disease and serve as biomarkers

Pathogenesis of T2D

1. Insulin Resistance

• Obesity (especially visceral adiposity): excess free fatty acids (FFAs) activate serine kinases that phosphorylate IRS-1, impairing downstream PI3K–AKT signalling
• Adipokines: Leptin resistance, reduced adiponectin, elevated TNF-α and IL-6 from adipose tissue promote hepatic gluconeogenesis and impair glucose uptake
• Lipotoxicity: Ectopic fat deposition in muscle and liver
• Metabolic syndrome: Insulin resistance + hypertension + dyslipidaemia + central obesity

2. β-Cell Dysfunction

• Initially, β cells hyperfunction to compensate for insulin resistance
• Eventually, β cells fail due to: lipotoxicity, glucotoxicity (chronic hyperglycemia), impaired incretin effect (reduced GLP-1 and GIP secretion), and islet amyloid polypeptide (IAPP/amylin) deposition
• Islet amyloid deposition is present in >90% of long-standing T2D islets, but whether it causes or results from β-cell burnout is debated

Pathogenesis of Chronic Complications (Glucotoxicity)

1. Advanced Glycation End Products (AGEs)

• Nonenzymatic glycation of proteins generates AGE precursors (glyoxal, methylglyoxal, 3-deoxyglucosone)
• AGEs bind RAGE receptor on endothelium, macrophages, vascular smooth muscle → release of TGF-β, VEGF, ROS, and procoagulant factors
• Cross-link extracellular matrix proteins → trap LDL in vessel walls (accelerating atherosclerosis) and albumin in capillary walls (basement membrane thickening)

2. Protein Kinase C (PKC) Activation

• Intracellular hyperglycemia increases diacylglycerol (DAG) from glycolytic intermediates → activates PKC
• Downstream: increased VEGF (retinopathy), TGF-β (fibrosis), PAI-1 (thrombosis), reduced eNOS (impaired vasodilation)

3. Hexosamine Pathway

• Excess glucose shunted into hexosamine pathway → O-GlcNAc modification of transcription factors → abnormal gene expression, impaired insulin signalling

4. Polyol Pathway

• Aldose reductase converts glucose to sorbitol (consumes NADPH) → oxidative stress, depletion of glutathione → endothelial damage (especially in lens and peripheral nerves)

Morphologic Changes (Organ Pathology)

Pancreas

• T1D: Reduced islet number and size; insulitis (lymphocytic infiltrate); β-cell depletion; α, δ, and PP cells preserved
• T2D: Mild β-cell reduction; islet amyloid (amylin deposits, Congo red positive)

Vascular System

• Macrovascular disease (large and medium arteries): Accelerated atherosclerosis → myocardial infarction, stroke, peripheral arterial disease
• Microvascular disease (capillaries and arterioles): Basement membrane thickening; hyaline arteriolosclerosis (especially afferent and efferent renal arterioles); pericyte loss

Kidneys — Diabetic Nephropathy

1. Glomerular lesions: Diffuse glomerulosclerosis (most common — diffuse increase in mesangial matrix); nodular glomerulosclerosis (Kimmelstiel-Wilson nodules) — ovoid PAS-positive deposits in the mesangium, pathognomonic of diabetic nephropathy
2. Vascular lesions: Hyaline arteriolosclerosis of both afferent and efferent arterioles (efferent arteriole involvement is virtually diagnostic of diabetes)
3. Tubular lesions: Glycogen accumulation in tubular epithelial cells ("Armanni-Ebstein lesion"); thickening of tubular basement membranes

• Progression: microalbuminuria → macroalbuminuria → declining GFR → ESRD

Diabetic nephropathy — nodular glomerulosclerosis. PAS stain shows Kimmelstiel-Wilson nodules (ovoid mesangial deposits). — Robbins & Kumar Basic Pathology

Eyes

• Diabetic retinopathy: Background (preproliferative) retinopathy — microaneurysms, dot-blot haemorrhages, hard exudates, cotton-wool spots; Proliferative retinopathy — neovascularisation driven by VEGF, vitreous haemorrhage, retinal detachment
• Cataracts: Sorbitol accumulation in the lens (polyol pathway) → osmotic injury → lens opacification
• Glaucoma: Increased intraocular pressure → optic nerve damage

Nervous System — Diabetic Neuropathy

• Peripheral symmetric polyneuropathy (most common) — predominantly sensory loss in stocking-glove distribution
• Autonomic neuropathy — gastroparesis, orthostatic hypotension, bladder dysfunction, impotence
• Mechanism: microangiopathy of vasa nervorum + direct axonal damage from sorbitol accumulation and AGEs

Infections

• Increased susceptibility to bacterial and fungal infections (impaired neutrophil function, poor tissue perfusion)
• Particularly: foot infections, urinary tract infections, mucormycosis, malignant otitis externa (Pseudomonas aeruginosa), "emphysematous" infections (gas-forming organisms)

Long-Term Complications Overview

Systemic complications of long-standing diabetes. — Robbins & Kumar Basic Pathology

Acute Complications

Gestational Diabetes Mellitus (GDM)

• Glucose intolerance first detected during pregnancy (typically 2nd–3rd trimester)
• Caused by insulin resistance from placental hormones (human placental lactogen, progesterone, cortisol)
• Risks to fetus: macrosomia, neonatal hypoglycemia, respiratory distress syndrome
• ~50% of women with GDM develop T2D within 5–10 years postpartum