Weight-Independent Changes in Blood Glucose Homeostasis After Gastric Bypass or Vertical Sleeve Gastrectomy in Rats

Abstract

Background & Aims Roux-en-Y gastric bypass (RYGB) and vertical sleeve gastrectomy (VSG) reduce weight and improve glucose metabolism in obese patients, although it is not clear if metabolic changes are independent of weight loss. We investigated alterations in glucose metabolism in rats following RYGB or VSG. Methods Rats underwent RYGB or VSG and were compared to sham-operated rats that were fed ad lib or pair-fed with animals that received RYGB. Intraperitoneal glucose tolerance and insulin sensitivity tests were performed to assess glycemic function, independent of the incretin response. A hyperinsulinemic euglycemic clamp was used to compare tissue-specific changes in insulin sensitivity following each procedure. A mixed-meal tolerance tests was used to assess the effect of each surgery on post-prandial release of GLP-1(7–36) and glucose tolerance, and were also performed in rats given the GLP-1 receptor antagonist exendin9–39. Results Following RYGB or VSG, glucose tolerance and insulin sensitivity improved, in proportion to weight loss. Hepatic insulin sensitivity was significantly better in rats that received RYGB or VSG, compared with rats fed ad lib or pair-fed, whereas glucose clearance was similar in all groups. During the mixed-meal tolerance test, plasma levels of GLP-1(7–36) and insulin were greatly and comparably increased in rats that received RYGB and VSG, compared with those that were pair-fed or fed ad lib. Administration of a GLP-1 receptor antagonist prevented improvements in glucose and insulin responses after a meal among rats that received RYGB or VSG. Conclusion In obese rats, VSG is as effective as RYGB at increasing secretion of GLP-1 and insulin secretion and at improving hepatic sensitivity to insulin; these effects are independent of weight loss.

Surgical control of obesity and diabetes: The role of intestinal vs. gastric mechanisms in the regulation of body weight and glucose homeostasis

“…Our findings thus challenge the conventional ''hindgut'' hypothesis. On the contrary, consistent with previous reports, (8,32,33), SG resulted in a fourfold increase in postprandial GLP-1 ( Figure 3D) in this study, therefore supporting a role of FIGURE 4 Postoperative plasma levels of total GIP, PYY, total ghrelin and glucagon during OGTT. (A,B) SG dramatically increased glucosestimulated GIP and PYY (**P < 0.01) and reduced fasting ghrelin levels (C) (**P < 0.01).…”

“…Bariatric surgery causes durable weight loss, remission or improvement of type 2 diabetes, hypertension, dyslipidemia, sleep apnea, and reduction of cardiovascular disease and death (3)(4)(5)(6). Although weight reduction might in theory explain improvement of insulin resistance and associated conditions, studies in rodents (7)(8)(9) and humans (10,11) showed that the anti-diabetes effect of certain bariatric procedures, particularly gastric bypass surgery, results from mechanisms at least in part independent of weight loss (12)(13)(14).Understanding the mechanisms of action of surgery provides an opportunity to elucidate the pathophysiology of obesity and diabetes and may lead to the development of new treatments of curative intent.…”

Hormonal Signaling in the Gut

“…Indeed, gastric bypass results in dramatically and rapidly enhanced meal-stimulated GLP-1, independent of weight loss and calorie restric- tion, likely from more direct nutrient exposure to intestinal L-cells (45). Furthermore, antagonism of the GLP-1R following Roux-en-Y gastric bypass (RYGB) worsens glucose tolerance and postprandial insulin secretion (46). Additionally, responsiveness to GLP-1R agonism in rodents was able to predict improvements in glycemic control following bariatric surgery, independent of weight loss (47).…”

GLP-1 receptor signaling is not required for reduced body weight after RYGB in rodents

“…A major hypothesis is that changes in gut hormone release are crucial. Drastically increased postprandial circulating levels of GLP-1 and PYY have been demonstrated in clinical studies (18,32,33,36,38,44,47,50) and in rodent models (13,16,37,56) for both Roux-en-Y gastric bypass and vertical sleeve gastrectomy.…”