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4th INTERNATIONAL CONSENSUS SUMMIT FOR SLEEVE GASTRECTOMY II: Mechanisms of Action FIGURE 1. Blood glucose response to a standardized meal test with saline infusion (black squares) or exendin-(9-39) (open diamonds) in subjects with remission of T2DM antedating SG. 4. 5. for the outcome of T2DM following SG, the GLP-1 response to meal intake would differ among our three study groups. We expected larger GLP-1 responses in those in remission as compared to those in the other two study groups. In contrast to our expectation, the GLP-1 response to meal intake was almost superimposable in the three groups irrespective of the glucose tolerance status. Thus, our data strongly suggest that an enhanced GLP-1 response to meal intake is not sufficient to maintain normal glucose tolerance in the long-term after SG. Understanding the role of endogenous GLP-1 in metabolic physiology has been greatly enhanced by the availability of a potent GLP-1 receptor antagonist, exendin-(9–39). Exendin-(9-39) blockade of GLP-1 action in healthy volunteers results in a significant enlargement of postprandial glucose excursions.8 Thus, it could be envisioned that the infusion of exendin-(9-39) may help us elucidate the role of GLP-1 following SG from a causative point of view rather than from mere association. If GLP-1 is critical for the metabolic effects of SG, the blockade of GLP-1 action by means of exendin-(9-39) infusion would result in deterioration of glucose tolerance to the pre-surgical state. We have recently conducted a clinical study demonstrating this is not the case. Our A8 data show that at long term after SG, blocking the action of GLP-1 with exendin-(9-39) results in limited deterioration of the glucose response to a mixed-meal in subjects with remission of T2DM antedating surgery as compared to the same experimental condition but with saline infusion (Figure 1). Of note, we have obtained similar data when evaluating a similar group of subjects who had undergone gastric bypass.9 Furthermore, in accordance with our findings, it has recently been shown in two different rodent models that the amelioration of glucose tolerance following SG is preserved even in the absence of GLP1 receptor.10 In summary, our data and that from others strongly suggest that the critical role of GLP-1 as mediator of improved glucose tolerance following SG needs re-evaluation. 6. 7. 8. 9. REFERENCES 1. 2. 3. Bariatric Times • May 2013 • Supplement A Jiménez A, Casamitjana R, Flores L, et al. Long-term effects of sleeve gastrectomy and Roux-en-Y gastric bypass surgery on type 2 diabetes mellitus in morbidly obese subjects. Ann Surg. 2012;256:1023–1029. Schauer PR, Kashyap SR, Wolski K, et al. Bariatric surgery versus intensive medical therapy in obese patients with diabetes. N Engl J Med. 2012;366:1567–1576. Dirksen C, Jorgensen NB, Bojsen- 10. Moller KN, et al. Mechanisms of improved glycaemic control after Roux-en-Y gastric bypass. Diabetologia. 2012; 55:1890–1901. Peterli R, Wölnerhanssen B, Peters T, et al. Improvement in glucose metabolism after bariatric surgery: comparison of laparoscopic Roux-enY gastric bypass and laparoscopic sleeve gastrectomy. Ann Surg. 2009;250:234–241. Romero F, Nicolau J, Flores L, et al. Comparable early changes in gastrointestinal hormones after sleeve gastrectomy and Roux-En-Y gastric bypass surgery for morbidly obese type 2 diabetic subjects. Surg Endosc. 2012;26:2231–2239. Valderas JP, Irribarra V, Rubio L, et al. Effects of sleeve gastrectomy and medical treatment for obesity on glucagon-like peptide 1 levels and glucose homeostasis in non-diabetic subjects. Obes Surg. 2011;21:902–909. Buse J., Caprio S, Cefalu W, et al. How do we define cure of diabetes? Diabetes Care. 2009;32:2133–2135. Deane AM, Nguyen NQ, Stevens JE, et al. Endogenous glucagon-like peptide-1 slows gastric emptying in healthy subjects, attenuating postprandial glycemia. J Clin Endocrinol Metab. 2010;95:215–221. Jiménez A, Casamitjana R, ViaplanaMasclans J, Lacy A, Vidal J. GLP-1 action and glucose tolerance in subjects with remission of type 2 diabetes mellitus after gastric bypass surgery. Diabetes Care. 2013 Jan 28. [Epub ahead of print] Wilson-Pérez HE, Chambers AP, Ryan KK, et al. Vertical sleeve gastrectomy is effective in two genetic mouse models of glucagonlike peptide-1 receptor deficiency. Diabetes. 2013 Feb 22. [Epub ahead of print].