Diabetes Mellitus

Definition

• Robbins & Kumar Basic Pathology, p. 743

Epidemiology

• Over 37 million Americans (11% of the population) have diabetes; ~25% are undiagnosed.
• Approximately 1.4 million new cases are diagnosed yearly in the US.
• Type 2 DM accounts for the vast majority (~90-95%) of cases; Type 1 accounts for 5-10%.
• Rising rates of obesity and sedentary lifestyles have dramatically increased T2D globally.

Diagnosis

• Fasting glucose 100-125 mg/dL ("impaired fasting glucose")
• 2-hr OGTT glucose 140-199 mg/dL
• HbA1c 5.7-6.4%

• Robbins & Kumar Basic Pathology, p. 743-744

Classification

Type 1 Diabetes (T1D)

• Autoimmune destruction of pancreatic β-cells → absolute insulin deficiency
• 5-10% of cases; most common in those <20 years
• Previously called "insulin-dependent" or "juvenile-onset" diabetes
• Characterized by circulating islet autoantibodies
• Prone to diabetic ketoacidosis (DKA) without insulin

Type 2 Diabetes (T2D)

• Insulin resistance in peripheral tissues + relative insulin deficiency from impaired β-cell secretion
• ~90-95% of cases; typically in adults >40 years, but rising in youth
• Strongly associated with obesity (80% of patients)
• No islet autoantibodies; prone to nonketotic hyperosmolar coma

Comparison Table (from Robbins)

Other Types

• Monogenic (MODY): Single-gene mutations affecting β-cell development/function; diagnosed before age 25
• Gestational diabetes: Occurs in ~5% of pregnancies due to pregnancy-induced insulin resistance; resolves post-delivery but raises 10-year T2D risk
• Secondary diabetes: Due to pancreatitis, cystic fibrosis, pancreatic adenocarcinoma, Cushing syndrome, acromegaly

Normal Insulin Physiology (Background)

1. Hepatic glucose production (gluconeogenesis + glycogenolysis)
2. Peripheral glucose uptake (mainly skeletal muscle)
3. The insulin/glucagon axis

• Promotes glucose uptake into muscle and fat
• Stimulates glycogen synthesis, lipogenesis, protein synthesis
• Inhibits gluconeogenesis, lipolysis, and protein degradation
• The primary stimulus for insulin release is glucose; gut-derived incretin hormones (GLP-1, GIP) amplify this response

Pathogenesis

Type 1 DM

1. Genetic susceptibility: Strong linkage to HLA region (MHC class I and II genes); also CTLA4 and PTPN22 polymorphisms
2. Environmental triggers: Viral infections (e.g., enteroviruses) or other environmental factors may precipitate autoimmunity in susceptible individuals
3. Autoimmune insulitis: CD4+ and CD8+ T lymphocytes infiltrate islets; CD8+ cells directly kill β-cells; autoantibodies against islet antigens (anti-GAD, anti-IA-2, anti-insulin) appear years before clinical disease
4. Progressive β-cell loss: Eventually >90% of β-cells are destroyed → overt diabetes

Type 2 DM

• Obesity-associated factors are central: excess non-esterified fatty acids (NEFAs), pro-inflammatory cytokines (TNF-α, IL-6), decreased adiponectin
• Adipokines and inflammatory mediators from visceral fat impair insulin receptor signaling (specifically IRS-1 and IRS-2 phosphorylation)
• Ectopic fat deposition in liver and muscle worsens resistance

• Glucotoxicity (chronic hyperglycemia) and lipotoxicity (excess NEFAs) damage β-cells
• Progressive reduction in β-cell mass and function
• Amyloid deposition (from islet amyloid polypeptide/IAPP) in islets occurs late in disease

Clinical Features

Classic Triad (the "3 Polys")

• Weight loss (especially T1D) - catabolism of fat and muscle
• Blurred vision (osmotic swelling of lens)
• Recurrent infections (impaired leukocyte function)
• Fatigue

Acute Complications

Diabetic Ketoacidosis (DKA) - primarily T1D

• Absolute insulin deficiency → unrestrained lipolysis and gluconeogenesis
• Free fatty acids → hepatic ketone body production (acetoacetate, β-hydroxybutyrate)
• Anion gap metabolic acidosis + hyperglycemia + ketonuria/ketonemia
• Triggers: infection, missed insulin doses

Hyperosmolar Hyperglycemic State (HHS) - primarily T2D

• Extreme hyperglycemia (>600 mg/dL) + severe dehydration without significant ketosis
• Residual insulin prevents ketogenesis but insufficient to prevent hyperglycemia
• High mortality; requires aggressive fluid resuscitation

Hypoglycemia

• Most common acute complication of insulin and sulfonylurea therapy
• Symptoms: sweating, tremor, tachycardia, confusion → seizures, coma

Chronic Complications

1. Advanced Glycation End-Products (AGEs)

• Glucose reacts non-enzymatically with amino groups of proteins → AGEs
• AGEs bind receptor RAGE on endothelium, macrophages, smooth muscle
• Results in: release of TGF-β (excess basement membrane) and VEGF (retinal neovascularization), generation of reactive oxygen species (ROS), increased procoagulant activity, enhanced vascular smooth muscle proliferation

2. Protein Kinase C (PKC) Activation

• Hyperglycemia → de novo synthesis of diacylglycerol (DAG) → PKC activation
• Downstream: VEGF (neovascularization in retinopathy), TGF-β (fibrosis), ECM deposition

3. Polyol Pathway (Sorbitol Accumulation)

• In insulin-independent tissues (nerves, lens, kidneys, vessels): aldose reductase converts excess glucose → sorbitol → fructose
• Consumes NADPH (needed for glutathione regeneration → oxidative stress)
• Osmotic damage in nerves and lens (cataracts)

Macrovascular Disease

• Accelerated atherosclerosis of large and medium arteries
• Consequences: myocardial infarction (2-4x increased risk), ischemic stroke, peripheral arterial disease → gangrene

Microvascular Disease

Increased Susceptibility to Infections

• Impaired neutrophil chemotaxis and phagocytosis
• Skin/soft tissue infections, UTIs, pneumonia, mucormycosis
• Robbins & Kumar Basic Pathology, p. 749-754

Management Overview

Type 1 DM - Insulin is mandatory

• Basal-bolus regimen: long-acting insulin (glargine, degludec) + rapid-acting insulin (aspart, lispro) with meals
• Continuous subcutaneous insulin infusion (CSII) pumps + continuous glucose monitoring (CGM)
• Automated Insulin Delivery (AID) systems combine pump + CGM + algorithm
• Medical nutrition therapy (MNT): carbohydrate counting, avoiding excessive weight gain
• Exercise: 150 min/week moderate aerobic activity; monitor glucose around exercise

Type 2 DM - Stepwise approach

1. Lifestyle: weight loss (5-10%), reduced caloric intake, physical activity
2. Metformin: first-line pharmacotherapy (reduces hepatic glucose output)
3. Additional agents based on comorbidities:
   • GLP-1 receptor agonists (liraglutide, semaglutide) - weight loss benefit, CV protection
   • SGLT-2 inhibitors (empagliflozin, dapagliflozin) - renal/CV protection
   • DPP-4 inhibitors, sulfonylureas, thiazolidinediones, insulin
4. Glycemic targets: HbA1c <7% for most patients (individualized)
5. Cardiovascular risk factor management: BP, lipids, antiplatelet therapy

Key Monitoring Parameters

• HbA1c every 3 months (reflects average glucose over ~3 months)
• Self-monitoring of blood glucose (SMBG) or CGM
• Annual dilated eye exam, urine albumin-to-creatinine ratio, lipid panel, foot exam, blood pressure
• Harrison's Principles of Internal Medicine 22E, p. [insulin management section]
• Robbins & Kumar Basic Pathology, p. 743-757

Summary