Pathogenesis of Complications in Diabetes Mellitus

Introduction

"The long-term effects of diabetes, rather than acute metabolic complications, are responsible for most of the morbidity and mortality of this disease."

• Robbins Pathologic Basis of Disease

Overview of Complications

• Macrovascular disease: Accelerated atherosclerosis → myocardial infarction, stroke, lower limb ischemia/gangrene
• Microvascular disease: Retinopathy, nephropathy, neuropathy

PATHOGENESIS - Four Core Mechanisms

1. Formation of Advanced Glycation End Products (AGEs)

• AGEs form via nonenzymatic reactions between glucose-derived metabolites (glyoxal, methylglyoxal, 3-deoxyglucosone) and the amino groups of intracellular/extracellular proteins
• Rate of AGE formation is accelerated by hyperglycemia
• AGEs bind to a specific receptor called RAGE (Receptor for AGE), expressed on inflammatory cells (macrophages, T cells), endothelium, and vascular smooth muscle

• Release of TGF-β → excess basement membrane deposition
• Release of VEGF → neovascularization (diabetic retinopathy)
• Generation of reactive oxygen species (ROS) in endothelial cells
• Increased procoagulant activity on endothelial cells and macrophages
• Enhanced proliferation of vascular smooth muscle cells and extracellular matrix synthesis

• Cross-linked proteins trap other plasma proteins (e.g., LDL gets trapped in large-vessel walls → accelerates atherosclerosis; albumin gets trapped in capillary walls → basement membrane thickening of microangiopathy)

2. Activation of Protein Kinase C (PKC)

• Intracellular hyperglycemia stimulates de novo synthesis of diacylglycerol (DAG) from glycolytic intermediates
• DAG activates protein kinase C (PKC) - an important intracellular signal transduction pathway

• Production of VEGF (pro-angiogenic) - neovascularization in retinopathy
• Production of TGF-β (pro-fibrogenic) - increased extracellular matrix and basement membrane deposition (microangiopathy)
• Production of PAI-1 (plasminogen activator inhibitor-1) - procoagulant effect on vascular endothelium

Note: Effects of AGEs and activated PKC overlap - both contribute to diabetic microangiopathy.

3. Oxidative Stress and Disturbances in Polyol Pathways

• In tissues that do not require insulin for glucose transport (nerves, lens, kidneys, blood vessels), persistent hyperglycemia causes excess intracellular glucose
• This glucose is metabolized by aldose reductase to sorbitol (a polyol) and then to fructose
• This reaction consumes NADPH as a cofactor
• NADPH is also required by glutathione reductase to regenerate reduced glutathione (GSH) - a key antioxidant
• Progressive depletion of NADPH compromises GSH regeneration → increased oxidative stress
• Sorbitol accumulation in the lens contributes to cataract formation

4. Hexosamine Pathway Overload

• Hyperglycemia induces flux of glycolytic intermediates through the hexosamine pathway (generating fructose-6-phosphate)
• This results in cell damage, enhanced oxidative stress, and ultimately contributes to insulin resistance and vascular complications

MORPHOLOGY OF CHRONIC COMPLICATIONS

A. Diabetic Macrovascular Disease

• Accelerated atherosclerosis affecting aorta, large/medium arteries
• Results in: myocardial infarction (2-4x greater risk), stroke, lower extremity ischemia, gangrene
• Patients with diabetes have a 2-4x greater incidence of coronary artery disease and 4-fold higher risk of dying from cardiovascular complications
• Myocardial infarction is almost as common in females with diabetes as in males (unlike the general population)
• Contributing factors: hypertension (present in ~75% of T2D), dyslipidemia (high TG, high LDL, low HDL)

B. Diabetic Microangiopathy

• Diffuse thickening of basement membranes is the most consistent morphologic feature
• Seen in capillaries of: skin, skeletal muscle, retina, renal glomeruli, renal medulla
• Also in nonvascular structures: renal tubules, Bowman capsule, peripheral nerves
• Despite thickening, capillaries are leakier than normal to plasma proteins
• Underlies retinopathy, nephropathy, and neuropathy

C. Diabetic Nephropathy

• Capillary basement membrane thickening - best appreciated by electron microscopy; begins ~2 years after onset of T1D; ~30% increase by 5 years
• Diffuse mesangial sclerosis - diffuse increase in mesangial matrix; PAS-positive deposits; progressive obliteration of glomeruli
• Nodular glomerulosclerosis (Kimmelstiel-Wilson lesion) - oval/spherical deposits of laminated matrix material in the periphery of the glomerulus; pathognomonic for diabetic nephropathy; associated with heavy proteinuria

• Arteriolosclerosis - affects both afferent AND efferent arterioles (efferent arteriolar hyalinosis is virtually diagnostic of diabetes)

• More common and severe in diabetics
• Includes papillary necrosis (necrotizing papillitis) - much more prevalent in diabetics

D. Diabetic Ocular Complications

• Background/preproliferative retinopathy: microaneurysms, hard exudates, dot-blot hemorrhages, macular edema
• Proliferative retinopathy: neovascularization attributable to hypoxia-induced VEGF expression; can lead to vitreous hemorrhage and retinal detachment
• Leading cause of adult blindness in the United States
• 60-80% of patients develop some form of retinopathy

• Cataracts - hyperglycemia → sorbitol accumulation in lens → acquired lens opacification
• Glaucoma - increased intraocular pressure → optic nerve damage

E. Diabetic Neuropathy

• Prevalence: up to 50% of diabetic patients overall; up to 80% of those with disease >15 years
• Can affect: central nervous system, peripheral sensorimotor nerves, autonomic nervous system

• Distal symmetric polyneuropathy (most common) - "glove-and-stocking" pattern; begins in lower extremities, later involves upper extremities; both motor and sensory function affected
• Autonomic neuropathy - bowel and bladder dysfunction, erectile dysfunction, orthostatic hypotension
• Mononeuropathy - sudden foot-drop, wrist-drop, isolated cranial nerve palsies

F. Infections

• Increased susceptibility to skin infections, tuberculosis, pneumonia, and pyelonephritis
• Cause ~5% of diabetes-related deaths
• In patients with diabetic neuropathy, a trivial toe infection may initiate a cascade: gangrene → bacteremia → pneumonia → death

Summary Table

Key Concepts (Robbins)

• Long-term complications of diabetes involve four potential mechanisms from sustained hyperglycemia: AGE formation, PKC activation, polyol pathway disturbances, and hexosamine pathway overload
• Long-term complications include macroangiopathy (atherosclerosis, ischemic heart disease, lower extremity ischemia) and microangiopathy (retinopathy, nephropathy, neuropathy)
• HbA1c should be maintained below 7% to reduce risk of chronic complications
• Kimmelstiel-Wilson nodules = pathognomonic for diabetic nephropathy
• Efferent arteriolar hyalinosis = virtually diagnostic of diabetes
• Renal failure is #2 cause of death in diabetes (after MI)