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 glucose argininenitric oxide + citrulline NO synthase NAD + NADH SORBITOL NADPH NADP Aldose reductase Fructose Sorbitol dehydrogenase glycolysis dihydroxyacetone phosphate Diacylglycerol (DAG) Increased PKC activity GS-SGGSH glutathione reductase myo-inositoltaurine Pyruvate TCA cycle

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-6- phosphate or glyceraldehyde. AGE formation is much more rapid inside the cell that outside (ie extracellular matrix).

Amadori product Non-enzymatic formation of advanced glycation end products (AGES). protein sugar

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!