1. Diabetes Mellitus 101 for Medical Professionals An Aggressive Pathophysiologic Approach to Cardiometabolic Therapy for Type 2 Diabetes: Stan Schwartz MD,FACP Clinical Associate Professor of Medicine, U of Pa. Cardiometabolic Institute Penn-Presbyterian Hospital, UPHS Part 6

2. Problems for animals in the wild

3. ADAPTIVE Insulin Resistance MAL-ADAPTIVE Insulin Resistance Insulin resistance begets insulin resistance: hyperinsulinemia in hypothalamus reduces nutrient sensing via increased NE/5HT, overcoming normal spring rise in dopa/decreasing dopa in spring Cincotta AH. et al. Taylor and Francis, Eds Hansen, B Shafrir, E London. 2002. 271-312. Meier AH, Cincotta AH et al. Diabetes Reviews. 1996. 4(4):464-86. Modern Insulin Resistant Man “Locked” Into Seasonal Insulin Resistance Syndrome Physiology (Neuroendocrinology; Winter Condition All Year Long)

4. The Biologic Clock Integrator of Signals Uses DOPAMINE SCN Afferent signals to SCN that maintain low dopa set include 1. persistent hyperglycemia, 2. high fat/ high sugar diet, 3. no exercise 4. altered sleep/ wake cycle, 5. stress High Dopa Set AM-Summer Low IR Low Sympathetic tone Hyperglycemia, high fat/sugar diets, altered sleep/wake cycles, no exercise, stress Low Dopa Set PM-Winter High IR High Sympathetic tone Persistent Summer Winter patients with genetically susceptible b-cell Diabetes Mellitus Maladaptive

5. Bromocryptine QR: Proposed mechanism of action Morning administration (within 2 hours of waking) of AGENT Corrects Restoration of morning peak in dopaminergic activity (via D2 receptor-mediated activity) Decreased postprandial glucose levels Reduction in insulin resistance Day-long reduction in plasma glucose, TGs and FFAs  Sympathetic tone  HPA axis tone  Hepatic gluconeogenesis  FFA and TG  Insulin resistance  Inflammation/hypercoagulation Low dopaminergic tone in hypothalamus in early morning in diabetes  Sympathetic tone  HPA axis tone  Hepatic gluconeogenesis  FFA and TG  Insulin resistance  Inflammation/hypercoagulation Impaired glucose metabolism, hyperglycemia and insulin resistance Adverse cardiovascular pathology 5 Fonseca. Use of Dopamine agonists in Type-2-Diabetes. Oxford American Pocket Cards. OUP, 2010 Cincotta. Hypothalamic role in Insulin Resistance and insulin Resistance Syndrome. Frontiers in Animal Diabetes Research Series. Taylor and Francis, Eds Hansen, B Shafrir, E London, pp 271-312, 2002

6. Bromocriptine-QR (Cycloset) Holt RIG, et al. Diabetes, Obesity and Metabolism 12: 1048–57, 2010 Dosing: Start with 0.8 mg (one tablet) within two hours of awakening in the AM. Increase weekly as tolerated to target dose of 1.6 to 4.8 mg upon awakening

7. *MI, Stroke, hospitalization unstable angina, hospitalization CHF, or coronary revasc. KM Curve: the separation in favor of Cycloset begins 3 months and persists through the end of the study HR 0.58; 95% CI, 0.35-0.96 RRR=42% KM Curve – Fast-Acting Bromocryptine Safety Trial Cumulative Percent Composite CVD Endpoint Gaziano M. Diabetes Care 2010, March 23 online

8. Colsevelam in Prediabetes Handelsman

9. Zieve FJ et al. Clin Ther. 2007;29:74. Bays H et al. Presented at: AACE 16th Annual Meeting & Clinical Congress; April 2007. Abstract 204. Fonseca VA et al. Presented at: AACE 16th Annual Meeting & Clinical Congress; April 2007. Abstract 409. Goldberg RB, Truitt K. Presented at: AHA Scientific Sessions; November 2006; Chicago, IL. Poster 1581. Effects of Colesevelam on A1C Levels in Add-On Therapy Trials: ≥0.50% Reductions Mean Change in A1C (%) GLOWS Week 12 Metformin Week 26 Sulfonylurea Week 26 Insulin Week 16 * P≤0.007 n=>1,000 -0.50 * -0.54 * -0.50 * -0.60 -0.50 -0.40 -0.30 -0.20 -0.10