Although data in humans and pigs support a role for GLP-1 in controlling glucose after RYGBP, experiments with knock out (KO) animal models challenge the role of GLP-1 in the control of body weight and glucose after RYGBP or VSG. Berthoud et al. [89] showed that chronic brain infusion of exendin-9-39 into the lateral cerebral ventricle similarly increased food intake and body weight in both RYGBP and sham-operated rats, suggesting that, while contributing to the physiological control of food intake and body weight, central GLP-1 receptor signaling tone is not the critical mechanism uniquely responsible for the body weight-lowering effects of RYGBP. In a separate experiment, the same authors showed that obese GLP-1R-deficient mice lost the same amount of body weight and fat mass and maintained similarly lower body weight compared with wild-type mice after a RYGBP-like procedure [89]. GLP-1 levels are also enhanced after VSG in humans [90] and rodents [91], and are thought to be a mediator of diabetes remission after this surgery [92]. However, VSG-operated GLP-1 receptor-deficient mice respond similarly to wild-type controls in terms of body weight loss, improved glucose tolerance, food intake reduction, and altered food selection [93]. These data demonstrate that GLP-1 receptor activity is not necessary for the metabolic improvements induced by VSG or RYGBP surgery in these animal models. The relevance of these KO experiments to clinical observations is unclear.

The main effect of the incretins is enhancement of glucose stimulated-insulin secretion. In order to single out the incretin effect from the weight loss effect of the surgery, we have used two approaches. One is to compare the effect of an oral glucose challenge to that of an isoglycemic IV glucose clamp on beta cell function, to quantify the incretin effect. Presumably, the change in beta cell response to oral glucose after RYGBP would engage neural and hormonal gut mechanisms, while the response to IV glucose would only be a function of the change in glycemia related to weight loss. The other approach is to block the effect of the endogenous incretins. Although there is no available GIP receptor inhibitor for human use, the specific GLP-1 receptor inhibitor exendin 9-39 has been used in four cross sectional [94–97] studies and one longitudinal short term [98] study in post-RYGBP patients. Exendin 9-39 administration has little to no effect prior to surgery, but completely blunts the recovery of beta cell glucose sensitivity (BCGS) , or the insulin secretin rate in response to incremental changes in blood glucose during a glucose challenge, observed 1 week and 3 months after RYGBP [98]. The administration of Exendin 9-39 worsens postprandial glucose tolerance, although only minimally [97]. Exendin 9-39 suppresses insulin secretion in response to a meal by 50 % [94, 97] and corrects the profound reactive hypoglycemia in patients with severe neuroglycopenia [94]. So clearly the exaggerated GLP-1 response to ingestion of food or glucose plays a key role in postprandial insulin secretion and glycemic control after RYGBP. To assess beta cell function, we measured BCGS and the disposition index (DI), i.e. the relationship between insulin secretion and insulin sensitivity. Both measures were calculated using data from an oral glucose load and from a matched isoglycemic IV glucose load, collected on separate days, in patients with T2DM and severe obesity, before and at 1 month, then yearly for 3 years after RYGBP surgery. Prior to surgery, BCGS after either an oral or IV isoglycemic glucose challenge, was, as expected, significantly impaired in patients with T2DM compared to lean controls, and to obese controls with normal glucose tolerance (NGT), matched for BMI. After RYGBP, all patients were in diabetes remission (HbA1C < 6.5 %, fasting glucose <126 mg/dl, on no diabetes medications). The BCGS and DI measured using parameters derived from the oral glucose test improved rapidly at 1 month and normalized to the levels of the lean and the obese NGT controls at 1 year. However, BCGS and DI measured after IV glucose administration improved only minimally and remained much impaired compared to that of the lean and obese NGT non-operated controls [99]. This experiment highlights the role of the incretins and other gut-mediated factors in the amelioration of beta cell response to oral nutrients after RYGBP. It also clearly shows a persistent beta cell defect that cannot be rescued with an IV glucose challenge, 3 years after the surgery, even in persons who are in clinical diabetes remission. In humans, there is no evidence to date for a full recovery of beta cell function to IV stimuli in patients in diabetes remission [99].

In order to distinguish between a caloric restriction/weight loss effect and an effect independent of weight loss, we compared individuals studied before and after RYGBP to individuals studied before and after an equivalent 10 % weight loss by caloric restriction with or without AGB. BCGS and DI after IV glucose stimulus improved significantly and similarly after the two modes of weight loss. After the oral glucose challenge, beta cell function improved significantly more after RYGBP than after diet. Results from this experiment underscore the importance of the engagement of the gut and the incretin effect, rather than weight loss, in the metabolic response to nutrient stimulation after RYGBP [100].