Temporal plasticity of insulin and incretin secretion and insulin sensitivity following sleeve gastrectomy contribute to sustained improvements in glucose control

Abstract

ObjectiveBariatric surgery acutely improves glucose control, an effect that is generally sustained for years in most patients. The acute postoperative glycemic reduction is at least partially mediated by enhanced incretin secretion and islet function, and occurs independent of caloric restriction, whereas the sustained improvement in glucose control is associated with increased insulin sensitivity. However, studies in humans with bariatric surgery suggest that these elevations are not static but undergo coordinated regulation throughout the postoperative time course. The studies described here test the hypothesis that incretin secretion, islet function, and peripheral insulin sensitivity undergo temporal regulation following bariatric surgery as a means to regulate glucose homeostasis.MethodsIncretin secretion, islet function, and insulin sensitivity in mice with vertical sleeve gastrectomy (VSG) were compared to sham-operated controls that were pair-fed for 90d, matching food consumption and body-weight between groups.ResultsGlucose clearance and insulin secretion were enhanced in VSG mice compared to controls during mixed-meal tolerance tests (MMTT) at 12 and 80 days postoperatively, as were prandial GLP-1, GIP, and glucagon levels. Insulin sensitivity was comparable between groups 14d after surgery, but significantly greater in the VSG group at day 75, despite similar body-weight gain between groups. Glucose stimulated insulin secretion was greater in VSG mice compared to controls in vivo (I.P. glucose injection) and ex vivo (islet perifusion) indicating a rapid and sustained enhancement of β-cell function after surgery. Notably, glycemia following a MMTT was progressively higher over time in the control animals but improved in the VSG mice at 80d despite weight regain. However, meal-stimulated incretin secretion decreased in VSG mice from 10 to 80 days postoperative, as did meal-stimulated and I.P. glucose-stimulated insulin secretion. This occurred over the same time period that insulin sensitivity was enhanced in VSG mice, suggesting postoperative islet output is tightly regulated by insulin demand.ConclusionsThese data demonstrate a dynamic, multifactorial physiology for improved glucose control after VSG, whereby rapidly elevated insulin secretion is complimented by later enhancements in insulin sensitivity. Critically, the glucose lowering effect of VSG is demonstrably larger than that of caloric-restriction, suggesting these adaptations are mediated by surgical modification of gastrointestinal anatomy and not weight-loss per se.

A surrogate of Roux-en-Y gastric bypass (the enterogastro anastomosis surgery) regulates multiple beta-cell pathways during resolution of diabetes in ob/ob mice

“…Our results also differed from those of Mokadem et al. in the post-operative time course (6–7 weeks versus 28 days in our study) which is characterized by a progressive increase of glycemia over time and possible reduction of meal-stimulated incretin and insulin secretion following the RYGBP in ob/ob mice [71] . Hao et al., [69] reported that, in ob/ob mice, body weight was reduced by RYGB transiently in the first week, recovered in the second week and increased over the baseline thereafter.…”

“…These differences with our results may be explained, first, by differences in surgical technique since Mokadem et al performed a Roux-en-Y reconstruction of the gastrointestinal tract with two anastomosis (distal transected jejunal limb to the proximal anterior gastric wall and the proximal transected jejunal limb to the afferent Roux limb). Our results also differed from those of Mokadem et al in the post-operative time course (6À7 weeks versus 28 days in our study) which is characterized by a progressive increase of glycemia over time and possible reduction of meal-stimulated incretin and insulin secretion following the RYGBP in ob/ob mice [71]. Hao et al, [69] reported that, in ob/ob mice, body weight was reduced by RYGB transiently in the first week, recovered in the second week and increased over the baseline thereafter.…”

Discovery of a potent GIPR peptide antagonist that is effective in rodent and human systems

“…We further assessed the ability of 7 to block endogenous incretin action on glucose control in the context of an oral glucose tolerance test. We injected mice with either vehicle or 7 (500 nmol/kg and 1500 nmol/kg) 1 h prior to an oral gavage of glucose at a dose demonstrated to stimulate endogenous GIP secretion ( Figure 5 C,D) [ 30 , 31 ]. Pretreatment with the high dose of peptide 7 worsened glucose control in this context, indicating that peptide 7 can antagonize endogenous incretin action in mice in the dose range tested here.…”

Bile acids, gut microbiota and metabolic surgery

“…In most VSG and RYGB studies, GLP-1 and PYY levels are found to be elevated after the surgeries. In studies done in rats and mice, GLP-1 level was elevated after VSG and RYGB ( 18 , 19 ). Numerous studies done in humans show similar findings.…”