β-Cell Centric Classification of Diabetes: Implications for Classification, Diagnosis, Prevention, Therapy, Research INSULIN** RESISTANCE Environment* G E N E Epigenetics Inflammation/ Immune Regulation Polygenic Monogenic β-Cell secretion/mass FINAL COMMON DENOMINATOR *Environment=Genetic suceptibility to eg: viruses, endocrine disruptors, food AGEs, Gut Biome **Insulin Resistance= Centrally Induced, Peripheral, Stress Hormones, Gut Biome

Primary Hyperinsulinemia- Genetic propensity( Corkey) INACTIVITY,DIET FFAs INFLAMMATION, OXIDATIVE STRESS INCREASED PAI-1,NFKB,MMPS, ROS,AP-1,Egr-1

Hyperinsulinemia Early in Natural History of DM: ie: May Cause Diabetes by Causing Insulin Resistance in PI3 Kinase Pathway But reduced insulin right after bariatric op- results in Fast improvement in resolution of diabetic state (PI-3 Kinase pathway, before IR improved Pories WJ, MacDonald KG Jr, Morgan EJ, et al. Surgical treatment of obesity and its effect on diabetes: 10-y followup. Am J Clin Nutr 1992;55(2 Suppl):582S-5S. Jimenez A, Perea V, Corcelles R, Moize V, Lacy A, Vidal J. Metabolic effects of bariatric surgery in insulin-sensitive morbidly obese subjects. Obes Surg 2013;23:494-500.

Potential Causes of Insulin Resistance and Their Interplay Central IR Loss of dopamine surge in SCN increased appetite Increased sympathetic tone Hyperinsulinemia Biome IR Peripheral IR Inflammation IR

Natural History of ALL DM Age 0-15 15-40+ 15-50+ 25-70+ Macrovascular Complications Disability IR Phenotype MI CVA Amp IGT ALL DM DEATH Blindness Amputation CRF ETOH BP Smoking Eye Nerve Kidney Disability Microvascular Complications Risk of Dev. Complications 5

Genes, Inflam Envir Hyperinsulinemia FINAL COMMON DENOMINATOR

ARE THE SAME AS THOSE THAT DAMAGE THE Beta-Cell * * * *