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Diabetes Complications and Control Trial (DCCT) • Tight control of blood glucose levels significantly decreased risk of diabetic complications. • Finding strongly implicates hyperglycemia or other metabolic abnormalities as the overriding pathogenic abnormality. Most commonly cited metabolic defects include: • Polyol or sorbitol pathway. • Abnormal lipid metabolism (increased de novo diacylglycerol synthesis). • Advanced glycation end product formation. • Increased oxidative stress. • Inflammation (leukocyte adhesion)* These metabolic defects may: • Directly damage specific critical cellular components in a complications-prone tissue. example: peripheral nerve axons or Schwann cells • Indirectly damage functional or structural elements. example: extracellular matrix or microvasculature Sorbitol Hypotheses (example, microvascular complication and diabetic peripheral neuropathy) hyperglycemia glutathione reductase NO synthase arginine GS-SG myo-inositolnitric GSH oxide + citrulline taurine NADPH glucose NADP Aldose reductase glycolysis dihydroxyacetone phosphate SORBITOL Sorbitol dehydrogenase NAD+ Fructose NADH Pyruvate Diacylglycerol (DAG) TCA cycle Increased PKC activity Aldose Reductase Inhibitors • Effective for treatment of retinopathy and neuropathy in diabetic rats and dogs. • Limited usefulness in human trials due to toxicity associated with delivery of drug through blood-retinal barrier. Advanced Glycation End Products • Form non-enzymatically from sugar derived intermediates. • Glucose has slowest rate of AGE formation compared to other sugars such as glucose-6phosphate or glyceraldehyde. • AGE formation is much more rapid inside the cell that outside (ie extracellular matrix). Non-enzymatic formation of advanced glycation end products (AGES). protein sugar Amadori product General mechanisms by which AGE formation cause pathological changes. • AGE can directly alter protein function in target tissue. • AGE can alter signal transduction pathways by altering matrix-matrix and matrix-cell interactions. • AGE can alter the levels of soluble signals, such as cytokines, hormones or free radicals, through interactions with AGE-specific receptors. AGE inhibitor: • Aminoguanidine • Reacts with dicarbonyl intermediates (one step distal to Amidori product formation) • Improves pathologies of the retina, kidney, nerve and artery in diabetic animal models. Oxidative Stress and Free Radicals • Free radicals are highly reactive molecules with unpaired electrons. • Excessive free radicals or inadequate antioxidant defense mechanisms lead to damage of cellular structures and enzymes. Common Players • • • • Superoxide anion Hydrogen peroxide Hydroxyl radical Nitric oxide superoxide + NO peroxynitrite peroxynitrite hydroxyl radical Production of free radicals and lipid peroxidation by hyperglycemia. • Direct autooxidation of glucose. • Increased glucose metabolism (mitochondrial respiration). • Activation of glycation pathways. • Reduction of antioxidant mechanisms. • Interaction of NO with superoxide to generate peroxynitrite and hydroxyl radicals. • Induction and activation of lipoxygenase pathways. Good Day!