1. Bromocriptine QR The Biologic Clock

2. 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)

3. 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

4. Bromocriptine 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 4 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

5. Bromocriptine Effect on HbA1c in Combination with other OHAs