1. Evolving Treatment Strategies: The Complexity of Energy Homeostasis Artificial sweetners lead to weight gain?

2. Energy Balance and Body Weight: What is Metabolism? Body Weight Energy In (Caloric Intake) Energy Out (Metabolism)

3. Energy Homeostasis: The Quick Fix?

4. The Diet Strategy Failure Rate of Diet Alone 90-98% Weight Baseline Counter-Regulation New Set Point ↓ 5-10%

5. Weight Management Counter-Regulation and the Failure of the “Diet” – HCG Diet

6. Weight Loss Counter-Regulation and the Failure of the “Diet ” – Ideal Protein 295 Ideal Protein Diet ↓ 28% 211 308 Fatigue, Depression, Fibromyalgia, Sleep Disorder, “Must be something hormonal”

7. Energy Balance and Body Weight: What is Metabolism? Body Weight Energy In (Caloric Intake) Energy Out (Metabolism)

9. Low Metabolism How Do I Fix It? – “Get Your Ducks in a Row” Sleep Problems – Sleep Apnea Vitamin D Deficiency Thyroid Vitamin B12 Low Testosterone (male) Medications (centrally acting)

10. Energy Homeostasis: The Miracle Pill?

11. Energy Homeostasis: The Search for the Magic Pill? Substrates Glucose Aminoacids Free Fatty Acids Lipids Hormones Insulin Leptin Ghrelin PYY CCK Adiponectin Mechanical Gastric Distension Neural Vagal Afferents Psychological Pleasure Reward Visual Olfactory Taste Hypothalmus Dopamine, Cannabanoids Norepinephrine, NPY Serotonin, POMC, GABA etc… Sibutramine(Meridia)Sibutramine(Meridia) Topiramate(Topomax)Topiramate(Topomax) PhenterminePhentermine RimonobantRimonobant Qsymia (phentermine + topiramate) Qsymia Contrave (bupropion + naltrexone) Contrave Energy Balance Center Belviq Lorcaserin (5HT2C) Belviq Weight Loss Pills Empatic (bupropion + zonisamide) Empatic Tesofensine () ( NS2330 )Tesofensine 4-8% Total body weight loss Not sustainable 20-30% Non-response rate The Miracle Pill Making Progress?? Belviq N=8,000 52-104 weeks Weight Loss: 3-3.7% over placebo 47% loss >5% Dosing: 10mg BID Belviq N=8,000 52-104 weeks Weight Loss: 3-3.7% over placebo 47% loss >5% Dosing: 10mg BID Qsymia N=3,700 52-104 weeks Weight Loss: 6.7-8.9% over placebo 70% loss >5% Dosing: 3.75/23mg, 7.5/46mg, 11.25/69mg, 15/92mg Qsymia N=3,700 52-104 weeks Weight Loss: 6.7-8.9% over placebo 70% loss >5% Dosing: 3.75/23mg, 7.5/46mg, 11.25/69mg, 15/92mg

12. The Ominous Octet – Treatment Strategies Islet  -cell Impaired Insulin Secretion NeurotransmitterDysfunction Decreased Glucose Uptake Islet  -cellIncreased Glucagon Secretion IncreasedLipolysis Increased Glucose Reabsorption IncreasedHGP Decreased Incretin Effect Surgery?

13. ADA Clinical Practice Recommendations 2011: Changing Treatment Paradigms

14. Energy Homeostasis: A Role for Surgery? Lap Band Restriction of caloric intake Gastric Bypass (Roux-En-Y) Restriction of caloric intake Malabsorption of nutrients X

15. Gastric Bypass: Five Operations CONFIDENTIAL

16. Gastric Bypass: Five Operations 1.Isolation of gastric cardia CONFIDENTIAL

17. Gastric Bypass: Five Operations 2.Exclusion of distal stomach CONFIDENTIAL

18. Gastric Bypass: Five Operations 3.Exclusion of duodenum and proximal jejunum CONFIDENTIAL

19. Gastric Bypass: Five Operations 4.Exposure of distal jejunum to undigested nutrients CONFIDENTIAL

20. Gastric Bypass: Five Operations 5.Partial vagotomy CONFIDENTIAL

21. Energy Homeostasis: A Role for Surgery? Sleeve Gastrectomy Stomach becomes a “sleeve” Alters signaling mechanisms Independent glycemic effect

22. Metabolic Surgery: The STAMPEDE Trial Type 2 DM, A1c > 7.0%, BMI 27 - 43 N = 150, single center, one surgeon Intensive Medical Therapy No Surgery Sleeve Gastrectomy Gastric Bypass Primary Outcome: Proportion with A1c < 6.0% at 12 months

23. Metabolic Surgery: The STAMPEDE Trial

26. THE END