1. The Surgical: proximal and distal intestine, partial removal of the stomach, ileal transposition, others Alper Çelik, M.D. Associate Professor of Surgery Yeni Yüzyıl University Medical Faculty & Taksim German Hospital Metabolic Surgery Unit www.metabolicsurgeryistanbul.com

2. 1st Question? Did initial vertebrates have an appendix epiploica?

4. Herbivore Carnivore Gastrointestinal adaptation to fiber-poor diets

5. Who consumes the diet with higher caloric index?

6. The goat has a bigger stomach that than the dog’s stomach. And longer intestines also. the dog is not restricted. The dog is adapted! Is Sleeve gastrectomy a restrictive or adaptive procedure? Reflections o the concept of Restriction and Adaptation.

7. Change in Food Industry Refined food Saccharification Coca-colanisation!!! And their metabolic outcomes.

8. Obesity and Metabolic Syndrome Duodenojejunal Hyperactivity High GIP Ileal Hypoactivity Low PYY, GLP-1 and OXM A Proximal – Distal Imbalance

9. By bringing the ileum proximal We will obtain an Adaptive and Neuroendocrine support How about pathophysiology?

10. TRIUNVIRATO 1.Inadequate insulin release from beta cells, disrupted early phase insulin effect 2.Insulin Resistance (IR) in peripheral tissues 3.Increased endogenous glucose production (hepatic / intestinal glucose output) 4.Adipocytes OCTETO 5. Gastrointestinal tractus (incretin insufficiency / resistance) 6. Alpha cell (hyperglucagonemia) 7. Kidney (glucose reabsorption) 8. CNS (insulin resistance - others) Diabetes 2009:58; 773-95.

11. Steps for Success in Metabolic Surgery 1)Caloric restriction and weight adjustments based on “hormonal thermostat” mechanism. 2)Increased gastric emptying and decreased ghrelin levels 3)Early term food contact with the ileal mucosa, increase in GLP-1 and correction of the first phase insulin release (“jejuno ileal nutrient sensing”) 4)Correction of first + second phase (20-120 min) glucose dependent plasma insulin response due to GIP effect 5)Correction of late phase inadequate glucagon supression 6)Decrease in Hepatic and peripheral insulin resistance 7)Decrease in Hepatic Glucose Output * Breen DM, et al. Nature Med 2012; 18: 950-955.

12. 1) Caloric Restriction Sleeve Gastrectomy causes functional restriction and endocrine adjustments

13. 2) Increased gastric emptying and decreased ghrelin levels It reduces Ghrelin (Now we know it also enhances GLP1 and PYY) Ghrelin Pre-opPost-op

14. What is Ghrelin? Hormone?

15. GHRELIN Growth Hormone Receptor Ligand Ghrelin deficiency may not be innocent! Keep an eye on Journal of Bone & Mineral Research!

16. 3-4-5) Incretin Effect & Glucagon Supression In patients with T2DM insulin release and beta cell functions are altered. Insulin has a biphasic release pattern from pancreas. Early phase occuring within first 30 min Late phase that platoes after 2nd hour The earliest possible sign of beta cell dysfunction is the disrupted early phase insulin release. Kahn SE Int J Clin Pract 2001;123:13-18

17. Early Phase Insulin Release -1 If early phase insulin release is disrupted; 1 – Insulin sensitive tissues fail to adequately perform glucose transport. 2 – Glucagon secretion, FFA release and Hepatic Glycogenolysis can not be prevented. 3 – Circulating glucose load and glycemic variability will increase. Luzi L et al Am J Physiol 1989;257:E241-E246

18. Early Phase Insulin Release -2 The reason for these changes is intrinsic beta cell defect + Defective changes in factors promoting postprandial insulin secretion (Incretin Resistance & Insufficiency). There are two forms of basic physiologically active incretins (Intestinal İnsulinomimetic Polipeptides): GIP and GLP-1.

19. GIP (Glucose-Dependent Insulinotropic Polypeptide ) Is GIP a good hormone or a bad hormone?

20. GIP The answer is “both” (depending on the situation). It is mainly released from the K cells in the duodenum. Especially in pts with IGT its levels increase in parallel to hyperinsulinemia. Oral glucose load exeggerates this increase. RESULT: K cell desensitisation to oral glucose GIP receptor desensitisation Beta cell GIP Resistance Theodorakis MJ, et al Diabetes Care 2004; 27: 1692-98.

21. GIP & Trivial Pattern Liver / Muscle Adipocyte Adipocyte Insulin GIP – trivial effect Fat Fat

22. GIP & Decreased insulin Fat Liver / Muscle Adipocyte Adipocyte Decreased insulin activity GIP – effective

23. GIP & Corrected Insulin Fat Liver / Muscle Adipocyte Adipocyte Corrected insulin activity GIP – inhibition

24. “Vicious Cycle” of GIP Molecule Hyperphagia K-cell hyperplasia GIP Increased Beta-cell hyperplasia Insulin Resistance Hyperinsulinemia Hyperglycemia Glucose Intolerance Beta-cell stimulation Gault, VA et al (2005). Diabetes 54:2436-2446.

25. GLP-1 (Glucagon Like Peptide 1) It is mainly released from L cells in Ileum. It leads to Receptive Partial Antagonism with Glucagon (“dysinhibition”). GLP-1 shows a secretion kinetic based on the oligosaccharides within ileum and is the main factor in adjusting early phase insulin release. GLP-1 secretion is altered in T2DM.

26. p<0.001 - preoperative vs postoperative a p<0.05 - 1-12months vs 25-38 months *** * * Time Based Evaluation (3 years) of Insulin Sensitivity After II-SG in T2DM Patients with BMI<35 Vencio S. Endocrine Reviews 2010;31(3):S1-257 *a*a

27. Surgical Success – Things To Do! Sleeve gastrectomy Correction of disrupted GIP secretion (Duodenal Exclusion) GLP-1 effect (ileal proximalisation) Glucagon Suppression Decrease in hepatic glucose output Without long term malapsorption.

28. BPD + Duodenal Switch Bypassed duodenum and jejunum for a Malabsorptive component Neuroendocrine component by enhancing entero- hormones

29. Is the answer BPD/DS? If we want to end one form of addiction and give our patients a new form of addiction (vitamins, minerals, calcium, iron, and trace elements); than the answer is YES.

30. One possible option: transit bipartition Intentional Neuroendocrine component Easier and safer anastomosis NO excluded segment TOTAL endoscopic access NO Nutritional problems Santoro et al. Obes Surg 2006; 16:1371-79 Obes Surg 2008; 18:1343–1345 Ann Surg. 2012 Jul;256(1):104-10.

31. Bipartition Gastroileoanastomosis 240 to 260 cm from the cecum

32. A very flexible procedure A Smaller gastric remnant “More bariatric procedure” A Bigger remnant “More metabolic procedure” 80 to 130cm Shorter Common segment “More bariatric procedure” Longer common segment “More metabolic procedure” L cells of distal gut are very close anyway

33. Transit Bipartition Pylorus Gastro-ileal Anastomosis

34. And the second option could be: DS-II Sleeve resection/ Gastric fundectomy Duodenal Transection Ileo – Jejunal Interposition

36.  -cell glucose sensitivity * p<0.001 vs corresponding group before surgery * * * Mechanisms of action in insulin sensitivity and beta cell functions after II-SG DePaula AL, Ferranninni E, et al. – J Gastrointest Surg 2011;15(8):1344-1353

37. Evaluation of Insulin Sensitivity and Secretion by Eauglycemic Hyperinsulinemic Clamp + IVGTT in patients with BMI<35 * Glucose dependent C-peptide release *p<0.001 – preoperatif vs postoperatif Vencio S et al.- Diabetes 2010;59:S1

38. 26 Insulin Sensitivity * * * * p<0.001 vs corresponding group before surgery Increase in Insulin Sensitivity According to BMI Values DePaula AL, Ferranninni E, et al. – J Gastrointest Surg 2011;15(8):1344-1353

39. Without long term Nutritional Effects