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

Problems for animals in the wild

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 Meier AH, Cincotta AH et al. Diabetes Reviews (4): Modern Insulin Resistant Man “Locked” Into Seasonal Insulin Resistance Syndrome Physiology (Neuroendocrinology; Winter Condition All Year Long)

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

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 , 2002

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

*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, RRR=42% KM Curve – Fast-Acting Bromocryptine Safety Trial Cumulative Percent Composite CVD Endpoint Gaziano M. Diabetes Care 2010, March 23 online

Colsevelam in Prediabetes Handelsman

Zieve FJ et al. Clin Ther. 2007;29:74. Bays H et al. Presented at: AACE 16th Annual Meeting & Clinical Congress; April Abstract 204. Fonseca VA et al. Presented at: AACE 16th Annual Meeting & Clinical Congress; April Abstract 409. Goldberg RB, Truitt K. Presented at: AHA Scientific Sessions; November 2006; Chicago, IL. Poster 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, * * *