Treatment of Type 2 Diabetes: Pathophysiology Conclude: do so without Hypoglycemia or Visceral Fat Weight Gain 1

Natural History of Type 2 Diabetes- Insulin Resistance Age 0-15 15-40+ 15-50+ 25-70+ Envir.+ Other Disease Genes Macrovascular Complications Obesity Poor Diet Inactivity IR phenotype Atherosclerosis obesity hypertension HDL, TG Endothelial dysfunction PCO Disability Insulin Resistance MI CVA Amp IGT Type II DM DEATH  Beta Cell Secretion d.ec 1st phase Inc 2nd phase Blindness Amputation CRF Eye Nerve Kidney Risk of Dev. Complications ETOH BP Smoking Disability Microvascular Complications 2

Greater the Insulin Level, > CV Risk

Peripheral Insulin Resistance- Induced Hyperinsulinemia has Adverse Downstream Effects Metabolic pathway (PI3K) Mitogenic pathway (MAPK) Proliferation, ENDOTHELIAL DYSFUCTION, INFLAMMATION Hyperglycemia Glucose transport Glykogen synthese

Multiple Causes of Insulin Resistance-More Ubiquitous and Multiple Therapies Available Central IR Weight Reduction DM MEDS- SGLT-2 inh. GLP-1 RAs Appetite suppressants Bromocriptine-QR Hyperinsulinemia Biome IR OBESITY- Peripheral IR Inflam- mation IR Anti- Inflam. Incretins Pro- Biotics, Pre-Biotics’ Antibiotics Pioglitazone Metformin

Implications for Therapy Understand and Treat Central Mechanisms IR Understand and Treat Peripheral IR- fat, liver, muscle Understand and Treat Inflammation Understand and Treat Biome