Diabetes Mellitus

Definition

Epidemiology

• Affects >30 million people (>11% of the US population)
• ~1.9 million have Type 1; the vast majority (~90-95%) have Type 2
• ~96 million US adults have prediabetes
• WHO estimates 422 million people with diabetes worldwide
• 7th leading cause of death in the USA
• Total yearly cost in the US: ~$327 billion

Diagnosis (ADA/WHO Criteria)

Classification

Type 1 Diabetes (T1D) - ~5-10%

• Most common in patients <20 years, but can occur at any age
• Requires insulin for survival
• Risk of diabetic ketoacidosis (DKA)
• LADA (Latent Autoimmune Diabetes in Adults) is a slowly progressive adult form

Type 2 Diabetes (T2D) - ~90-95%

• Most individuals are overweight/obese
• Prevalence rising sharply in children and adolescents

Other Forms

• Monogenic diabetes: MODY (Maturity-Onset Diabetes of the Young) - genetic defects in β-cell function or insulin action
• Gestational diabetes: glucose intolerance first recognized during pregnancy
• Secondary causes: pancreatitis, Cushing syndrome, acromegaly, drug-induced

Glucose Homeostasis (Normal)

1. Hepatic glucose production (gluconeogenesis + glycogenolysis)
2. Peripheral glucose uptake (mainly skeletal muscle)
3. Insulin/glucagon balance

• Fasting: low insulin, high glucagon → hepatic glucose release prevents hypoglycemia
• Post-meal: insulin rises, glucagon falls → glucose uptake in muscle and fat

Pathogenesis of Type 1 Diabetes

Genetic Susceptibility

• HLA gene cluster contributes ~50% of genetic risk
• 90-95% of European patients carry HLA-DR3 or HLA-DR4 (vs ~40% of normal subjects)
• 40-50% of T1D patients are DR3/DR4 compound heterozygotes (vs 5% of normal subjects)
• DR3 or DR4 + DQ8 haplotype = highest inherited risk
• Other susceptibility genes: CTLA4, PTPN22, STAT3, AIRE mutations

Environmental Factors

• Viral infections may trigger islet autoimmunity through molecular mimicry (viral epitopes cross-react with islet antigens)
• Diet, gut microbiome, and hygiene hypothesis also implicated

Mechanisms of β-Cell Destruction

• CD8⁺ cytotoxic T cells directly kill β-cells
• CD4⁺ Th1 cells activate macrophages that produce cytokines damaging β-cells
• Autoantibodies (anti-insulin, anti-GAD65, anti-IA-2) are markers of T1D but not primary effectors
• Progressive loss of β-cell mass over years before clinical presentation

Pathogenesis of Type 2 Diabetes

1. Insulin Resistance

• Free fatty acids (FFAs): Central adipose tissue is highly lipolytic; excess FFAs accumulate toxic lipid intermediates (DAG, ceramides) that impair insulin receptor signaling and activate inflammatory pathways. In the liver, attenuated insulin signaling unleashes phosphoenolpyruvate carboxykinase, driving excess gluconeogenesis.
• Adipokines: Adipose tissue secretes hormones. Adiponectin (which improves insulin sensitivity) is reduced in obesity, worsening resistance.
• Inflammation: Excess FFAs and glucose activate the inflammasome in macrophages and β-cells → IL-1β secretion → proinflammatory cytokine cascade → insulin resistance at peripheral tissues.

2. β-Cell Failure

• β-cell exhaustion and reduced mass (partly from amyloid deposition - islet amyloid polypeptide/IAPP)
• Glucotoxicity and lipotoxicity accelerate β-cell dysfunction
• Eventually, insulin secretion is inadequate → frank hyperglycemia

Mechanisms of Vascular Complications (Common to T1D & T2D)

1. Advanced Glycation End-products (AGEs)

• Glucose non-enzymatically glycates proteins and lipids → AGEs
• AGEs bind RAGE receptors on endothelial cells, smooth muscle, macrophages → release of cytokines (TGF-β, VEGF), ROS, and procoagulant factors → basement membrane thickening, vascular injury

2. Protein Kinase C (PKC) Activation

• Hyperglycemia → excess diacylglycerol (DAG) synthesis → PKC activation → overproduction of VEGF (retinopathy), TGF-β (glomerulosclerosis), and PAI-1 (thrombosis)

3. Polyol Pathway & Oxidative Stress

• In insulin-independent tissues (nerves, lens, kidney, vessels): excess glucose → aldose reductase converts glucose to sorbitol (polyol pathway)
• This depletes NADPH → impairs glutathione regeneration → ↑ oxidative stress
• Sorbitol accumulation in the lens contributes to cataracts

Long-Term Complications

Macrovascular Disease

• Most common cause of death in long-standing diabetes
• 2-4× higher risk of coronary artery disease
• 4× higher risk of dying from cardiovascular complications
• Risk elevated even at the prediabetes stage
• ~75% of T2D patients have hypertension, which amplifies vascular damage
• Diabetic dyslipidemia: ↑ triglycerides, ↑ LDL, ↓ HDL

Diabetic Nephropathy

• Leading cause of end-stage renal disease in the USA
• 30-40% of all diabetic patients develop clinical nephropathy
• Earliest sign: microalbuminuria (30-300 mg/day urinary albumin)
• Progresses to macroalbuminuria → hypertension → ESRD
• Morphology: glomerular basement membrane thickening, diffuse and nodular glomerulosclerosis (Kimmelstiel-Wilson nodules)

Diabetic Ocular Disease

• 60-80% of patients develop diabetic retinopathy - leading cause of adult blindness in the USA
• Key lesion: neovascularization driven by VEGF
• Also: cataracts (sorbitol), glaucoma

Diabetic Neuropathy

• Most common complication: peripheral neuropathy (symmetric, distal sensorimotor)
• Also: autonomic neuropathy (gastroparesis, orthostatic hypotension, impotence)
• Affects up to 50% overall; up to 80% of those with disease >15 years

Infections

• Impaired neutrophil function and poor tissue perfusion increase susceptibility
• Foot infections → gangrene → leading cause of nontraumatic limb amputation

Acute Metabolic Complications

Morphology Summary

Classic Triad of Symptoms

Key Summary

• T1D: Autoimmune → absolute insulin deficiency → requires exogenous insulin
• T2D: Insulin resistance + relative insulin deficiency → begins with lifestyle/pharmacotherapy, may eventually need insulin
• Complications arise from chronic hyperglycemia damaging blood vessels and nerves via AGEs, PKC activation, and oxidative stress
• Severity of complications correlates directly with both the degree and duration of hyperglycemia - tight glycemic control demonstrably reduces end-organ damage