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

Jonathan D. Douros, Jingjing Niu, Sophia Sdao, Trillian Gregg, Matthew J. Merrins, Jonathan Campbell, Jenny Tong, David D'Alessio

Bariatric procedures like vertical sleeve gastrectomy (VSG) alleviate diabetic hyperglycemia in 40-50% of patients. To further study the changes of key glucoregulatory factors after VSG over time, Douros et al. assessed glycemic regulation, incretin secretion, insulin sensitivity, and islet function over 90 days in mice with VSG and sham-operated controls pair-fed to match caloric intake. They found that an acute postoperative enhancement of intrinsic islet function persists over time. This surgical effect is superior to that seen with caloric restriction or weight loss alone. Critically, the early enhancements to incretin secretion and islet function diminish over time as insulin sensitivity increases, indicating modulation of these factors after surgery.

Objective: Bariatric 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.

Methods: Incretin 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.

Results: Glucose 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.

Conclusions: These 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.