Liberty Medical

Microvascular and Macrovascular

Pathogenesis  Formation of Advanced Glycation End Products (AGEs) Glucose byproducts react with IC and EC proteins AGEs bind RAGE receptor (Inflammatory cells, endothelium, vascular smooth muscle) ○ Increase inflammation, ROS, procoagulant activity AGEs also cross link collagen ○ Decreases elasticity of vessels ○ Helps trap LDL and Proteins (albumin)  Activation of PKC IC hyperglycemia stimulates PKC and DAG ○ Pro-inflammatory, pro-fibrinolytic ○ Increases endothelin 1 and decreases NO ○ Increase VEGF (neovascularization in diabetic retinopathy)

Pathogenesis (cont.)  Intracellular Hyperglycemia Nerves, Lenses, Kidneys and BV uptake glucose without help of insulin Excess Glucose  Sorbitol  Fructose ○ Uses Aldolase Reductase ○ Uses NADPH Reduces NADPH needed to regenerate glutathione (an antioxidant) May be major underlying cause of Diabetic Neuropathy

Macrovascular  Endothelial Dysfunction  HTN  CVA, Hemorrhage  Accelerated Atherosclerosis All arteries incl. large renal arteries  CAD/CHF/MI Coronary atherosclerosis Most common cause of death  Gangrene of the Lower Extremities

Diabetic Nephropathy  Leading Cause of End-Stage Renal Disease  20 years: 75% of type I and 20% of type II  Starts as Microalbuminuria and progresses to macroalbuminuria Marker for increase CV morbidity

Diabetic Retinopathy  60-80%  Result of Neovascularization  Also: Increased risk of glaucoma and cataract formation

Diabetic Neuropathy  Variety of clinical syndromes  Most Common: Distal Symmetric Polyneuropathy Decreased motor and sensory function particularly of distal lower extremities Eventually involve upper extremities  Autonomic Neuropathy Bowel, bladder and sexual dysfunction  Diabetic Mononeuropathy Ex. Wrist or foot drop; isolated CN palsy

Infections  Immunosupressed State TB Pneumonia Pyelonephritis Many reasons (decreased neutrophil function, impaired cytokine production, vascular compromise) 5% of deaths

Resources  Robbins