Diabetes Mellitus - Robbins, Cotran & Kumar Pathologic Basis of Disease

Definition

• Diabetes is the leading cause of end-stage renal disease, adult-onset blindness, and nontraumatic lower limb amputations in the United States.

Epidemiology

• 30 million Americans (~11% of the population) have diabetes; ~1.9 million have Type 1, the rest have Type 2.

• ~96 million US adults have "prediabetes" (impaired glucose tolerance not meeting T2D criteria).
• ~422 million people affected worldwide (WHO estimate).
• Native Americans, African Americans, and Hispanics are 1.5-2x more likely to develop diabetes than non-Hispanic Europeans.
• T2D rates in adolescents have increased dramatically in recent years ("diabetes epidemic").

Diagnosis (ADA/WHO Criteria)

1. Fasting plasma glucose ≥ 126 mg/dL
2. Random plasma glucose ≥ 200 mg/dL with symptoms of hyperglycemia (polyuria, polydipsia, unexplained weight loss)
3. 2-hour plasma glucose ≥ 200 mg/dL during an oral glucose tolerance test (OGTT; 75 g glucose)
4. HbA1c ≥ 6.5%

• Normal fasting blood glucose = 70-120 mg/dL
• Prediabetes / Impaired Glucose Tolerance: HbA1c 5.7-6.4%, or fasting glucose 100-125 mg/dL

Classification

Type 1 Diabetes (T1D)

• Autoimmune destruction of β cells → absolute insulin deficiency

Type 2 Diabetes (T2D)

• Peripheral insulin resistance + relative β-cell failure

Monogenic Forms (formerly MODY and others)

• Single-gene defects in β-cell function or insulin receptor signaling

Secondary / Other Specific Types

• Pancreatitis, pancreatectomy/trauma, pancreatic cancer, cystic fibrosis, hemochromatosis, fibrocalculous pancreatopathy

• Acromegaly, Cushing syndrome, hyperthyroidism, pheochromocytoma, glucagonoma

• Cytomegalovirus, Coxsackie B virus, congenital rubella

• Glucocorticoids, thyroid hormone, interferon-α, protease inhibitors, β-adrenergic agonists, thiazides, nicotinic acid, phenytoin, Vacor

• Down syndrome, Klinefelter syndrome, Turner syndrome, Prader-Willi syndrome

Gestational Diabetes Mellitus (GDM)

Islet Cell Histology (Normal)

Comparative Features: Type 1 vs Type 2 Diabetes

Type 1 Diabetes - Pathogenesis

Genetic Susceptibility

• MHC class II (HLA-DR3, HLA-DR4, or both) accounts for ~50% of genetic susceptibility.
  • HLA-DR3 or DR4: 3-5x increased risk
  • HLA-DR3/DR4 heterozygotes: 10x increased risk
• Protective: HLA-DR2, HLA-DQ6
• Also: polymorphisms in CTLA4 (T-cell regulation), PTPN22 (T-cell signaling), insulin gene VNTRs (thymic insulin expression)

Environmental Triggers

• Viral infections (Coxsackie B, CMV, congenital rubella) may trigger autoimmunity via molecular mimicry or direct β-cell injury.

Immunological Mechanisms

• CD4+ T-helper cells and CD8+ cytotoxic T cells infiltrate the islets ("insulitis")
• Autoantibodies (anti-GAD65, anti-IA2, anti-ZnT8) appear years before clinical onset
• Progressive β-cell destruction → absolute insulin deficiency

Type 2 Diabetes - Pathogenesis

1. Insulin Resistance

• Reduced uptake of glucose in muscle; reduced glycogen synthesis
• Failure of insulin to suppress hepatic gluconeogenesis
• Increased free fatty acid (FFA) release from adipocytes

• Obesity (especially central/visceral adiposity) - most important risk factor
• Physical inactivity
• Adipokines: TNF-α and IL-6 promote insulin resistance; adiponectin (protective) is reduced in obesity
• Excess FFAs lead to lipid accumulation in liver and muscle (lipotoxicity)
• Metabolic-associated steatotic liver disease (MASLD) is common in T2D/metabolic syndrome

2. β-Cell Dysfunction

• Lipotoxicity: excess FFAs impair β-cell function and attenuate insulin release
• Glucotoxicity: chronic hyperglycemia itself impairs β-cell function
• Abnormal incretin effect: reduced GIP and GLP-1 secretion → reduced insulin release
• Amyloid (IAPP) deposition in islets - present in >90% of long-standing T2D islets
• Genetic polymorphisms in insulin-secretion genes (TCF7L2, etc.)

The Incretin System

• GIP and GLP-1 are secreted by intestinal cells after oral food intake.
• They increase insulin secretion, suppress glucagon, delay gastric emptying, and promote satiety.
• DPP-4 degrades GLP-1/GIP → DPP-4 inhibitors slow this degradation.
• GLP-1 receptor agonists and tirzepatide (dual GIP/GLP-1 agonist) are now key treatments for T2D; also approved for obesity.

Insulin Action (Normal Physiology)

• Muscle: glucose → glycogen or ATP; amino acid uptake → protein synthesis
• Adipose: glucose → triglyceride synthesis (lipogenesis); inhibits lipolysis
• Liver: suppresses gluconeogenesis; promotes glycogen synthesis and lipogenesis

Monogenic Forms of Diabetes

MODY (Maturity-Onset Diabetes of the Young)

• Germline loss-of-function mutations; autosomal dominant, onset usually <25 years
• Glucokinase (GCK) mutations: altered "set point" for insulin secretion → hyperglycemia but usually no microvascular complications
• Other MODY forms (HNF-1α, HNF-4α, etc.) → frank diabetes with complications
• Insulin gene mutations also identified as a cause

Defects in Insulin Receptor Signaling

• Rare insulin receptor mutations → severe insulin resistance syndromes

Acute Metabolic Complications

Diabetic Ketoacidosis (DKA) - Primarily T1D

• Absolute insulin deficiency → lipolysis (FFAs) → hepatic ketogenesis
• Glucagon excess promotes gluconeogenesis
• Hyperglycemia → osmotic diuresis → glycosuria, ketonuria, polyuria
• Volume depletion → polydipsia
• Negative energy balance → polyphagia
• Kussmaul breathing, nausea, vomiting → coma if untreated

Hyperosmolar Nonketotic Coma - More common in T2D

• Extreme hyperglycemia (600-1200 mg/dL) without ketoacidosis (residual insulin prevents ketogenesis)
• Severe dehydration; no nausea/vomiting to prompt early medical attention

Hypoglycemia

• Common with insulin or sulfonylurea therapy
• Causes: missed meals, excess exercise, overdose
• Symptoms: dizziness, confusion, sweating, palpitations, tachycardia → loss of consciousness
• "Hypoglycemia unawareness" in long-standing disease
• Treat immediately with oral or IV glucose

Chronic Complications of Diabetes

Glycemic Monitoring

• HbA1c = gold standard for long-term glycemic control (reflects ~120-day average)
• Target: HbA1c <7% in most patients
• Time-in-range (from continuous glucose monitors) is an emerging, potentially superior metric

Pathogenesis of Chronic Complications (4 Mechanisms)

1. Advanced Glycation End-Products (AGEs)
   • Non-enzymatic glycosylation of proteins and lipids
   • AGEs cross-link collagen in vessel walls → reduced compliance, thickening
   • AGE receptors (RAGE) on macrophages/endothelium → cytokine release, ROS → vascular injury
   • HbA1c is itself a product of this mechanism
2. Activation of Protein Kinase C (PKC)
   • Intracellular hyperglycemia → diacylglycerol (DAG) → PKC activation
   • PKC alters VEGF, TGF-β, NF-κB → vascular permeability, neovascularization, extracellular matrix synthesis, and inflammation
3. Polyol Pathway (Intracellular Glucose Metabolism)
   • Aldose reductase converts excess glucose → sorbitol → fructose
   • Intracellular sorbitol accumulation → osmotic stress, ROS
   • Important in cells that do not require insulin for glucose uptake (lens, peripheral nerves, kidney)
4. Hexosamine Pathway
   • Excess glucose → glucosamine-6-phosphate → alters O-GlcNAc modification of proteins → epigenetic changes, impaired signaling

Morphology of Chronic Diabetic Lesions

Diabetic Macrovascular Disease (Atherosclerosis)

• Accelerated atherosclerosis of aorta and large/medium muscular arteries
• 2-4x increased risk of coronary artery disease vs. nondiabetics; 4x higher risk of dying from cardiovascular complications
• Myocardial infarction equally common in diabetic females as in diabetic males (unlike non-diabetic women who are relatively protected in reproductive years)
• Hypertension in ~75% of T2D patients; dyslipidemia (↑TG, ↑LDL, ↓HDL) common

Hyaline Arteriolosclerosis

• Thickening and hyalinization of afferent (and sometimes efferent) arteriolar walls in the kidney
• Similar changes in other tissues; contributes to nephrosclerosis

Diabetic Nephropathy

• Glomerular lesions (most characteristic):
  • Glomerular basement membrane (GBM) thickening - earliest change
  • Diffuse mesangial sclerosis: diffuse increase in mesangial matrix and cells; correlates with proteinuria and progression to renal failure
  • Nodular glomerulosclerosis (Kimmelstiel-Wilson lesion): ovoid/spherical deposits of matrix in the mesangium periphery - pathognomonic of diabetic nephropathy; associated with microaneurysm formation
• Vascular lesions: hyaline arteriolosclerosis (efferent arteriole involvement is characteristic of diabetes)
• Tubular lesions: "Armanni-Ebstein lesion" - glycogen accumulation in tubular epithelial cells (now rarely seen with good glycemic control)
• Increased susceptibility to infection: pyelonephritis and papillary necrosis more common in diabetics

Diabetic Ocular Complications

• Cataract: glucose → sorbitol accumulation in lens → opacification
• Glaucoma: increased intraocular pressure → optic nerve damage
• Diabetic Retinopathy (most profound):
  • Background (preproliferative) retinopathy: microaneurysms, dot/blot hemorrhages, hard exudates, cotton-wool spots, macular edema
  • Proliferative retinopathy: neovascularization (VEGF-driven), vitreous hemorrhage, retinal detachment, blindness

Diabetic Neuropathy

• Affects up to 50% of diabetics overall; up to 80% of those with disease >15 years
• Peripheral symmetrical polyneuropathy most common (distal sensorimotor)
• Autonomic neuropathy: gastroparesis, bladder dysfunction, sexual dysfunction, orthostatic hypotension
• Mechanism: polyol pathway (sorbitol accumulation) + microvascular ischemia of nerves

Clinical Manifestations of Chronic Diabetes (Summary)

Pancreatic Morphology in Diabetes

• Reduction in number and size of islets (β-cell depletion)
• Insulitis: lymphocytic infiltration (predominantly T cells) of islets
• Islet fibrosis in long-standing disease

• Subtle reduction in β-cell mass
• Amyloid (islet amyloid polypeptide / IAPP) deposition in >90% of islets - characteristic finding
• No insulitis