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 fed ad lib or pair-fed to animals that received RYGB. Intraperitoneal glucose tolerance and insulin sensitivity tests were performed to assess glycemic function independent of incretin response. A hyperinsulinemic euglycemic clamp was used to compare tissue-specific changes in insulin sensitivity following each procedure. A mixed-meal tolerance test was used to assess the effect of each surgery on postprandial release of glucagon-like peptide 1 (GLP-1)(7-36) and glucose tolerance, and was also performed in rats given GLP-1 receptor antagonist exendin(9-39).

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.

Conclusions: In obese rats, VSG is as effective as RYGB for increasing secretion of GLP-1 and insulin and improving hepatic sensitivity to insulin; these effects are independent of weight loss.

Figure 1

A. Cummulative food intake in Sham (n=10), RYGB (n=4), VSG (n=7), and Pair-fed (n=10) rats after 120-days. Average cumulative food intake was significantly higher in Sham operated rats vs. RYGB, VSG, and Pair-fed animals, P<0.05. B. Body weight was also significantly higher in Sham rats compared to the other treatment groups, P<0.05. C. Lean tissue mass was slightly higher in Sham operated rats vs. RYGB rats after 28-days, P<0.05, and slightly higher than in VSG rats after 105-days, P<0.05. D. Fat tissue mass was substantially higher in Sham vs. all other treatment groups at 28-days, P<0.05, and 105-days, P<0.05, after surgery. Bonferroni’s Post-test; ^*P<0.05 vs. Pair-fed, ^$P<0.05 vs. RYGB, ^#P<0.05 vs. VSG.

Figure 2

IP insulin sensitivity (A-B) and glucose tolerance (C-D) are improved in proportion to weight loss after RYGB and VSG surgeries. A. Blood glucose levels before (time 0) and after an IP injection of insulin in Sham (n=10), RYGB (n=4), VSG (n=7), and Pair-fed rats (n=10). RYGB, VSG, and Pair-fed rats were more sensitive to effect of insulin on circulating glucose levels than ad lib fed Sham rats, P<0.05. B. The same data expressed as a percentage of baseline shows that changes in insulin sensitivity were not due to differences in basal circulating glucose. C. Blood glucose levels before (time 0) and after an IP injection of glucose show that RYGB, VSG, and Pair-fed rats also had lower glucose excursions and D. plasma insulin levels relative to sham operated rats in response to peripherally administered glucose. Bonferroni’s Post-test; ^*P<0.05 vs. Pair-fed, ^$P<0.05 vs. RYGB, ^#P<0.05 vs. VSG.

Figure 3

Whole body insulin sensitivity as measured by hyperinsulinemic euglycemic clamp. Average glucose infusion rate in Sham (n=8), RYGB (n=7), VSG (n=6), and Pair-fed (n=7) rats during steady state (final 40-min) clamp conditions. Glucose infusion rates were significantly increased in RYGB and VSG vs. ad lib fed Sham rats, P<0.05. Differences between RYGB, VSG, and Pair-fed rats were non-significant, P>0.05. Bonferroni’s Post-test; ^$P<0.05 vs. RYGB, ^#P<0.05 vs. VSG.

Figure 4

A. Endogenous glucose production during hyperinsulinemic euglycemic was similar at baseline between Sham (n=8), RYGB (n=7), VSG (n=6), and Pair-fed (n=7) rats, P>0.05. However, during steady state conditions glucose production was significantly reduced in RYGB and VSG rats vs. Sham and Pair-fed rats, P<0.05. B. Glucose clearance was similar between treatments at baseline and during the final 40-min of the clamp, P>0.05. Bonferroni’s Post-test; ^*P<0.05 vs. Pair-fed, ^$P<0.05 vs. RYGB, ^#P<0.05 vs. VSG.

Figure 5

Active levels of the incretin hormone GLP-1(7–36) before (time 0) and after an oral gavage of Ensure Plus liquid diet in Sham (n=8), RYGB (n=6), VSG (n=6), and Pair-fed (n=9) rats. Post-prandial plasma levels of GLP-1(7–36) were significantly higher in RYGB and VSG rats relative to Sham and Pair-fed animals (15, 30, 45-min) P<0.05. RYGB rats also had significantly higher GLP-1(7–36) relative to Pair-fed rats after 60-min. Differences between Sham and Pair-fed rats were not significant, P>0.05. Bonferroni’s Post-test; ^*P<0.05 vs. Pair-fed, ^$P<0.05 vs. RYGB, ^#P<0.05 vs. VSG.

Figure 6

Blood glucose (A-B) and plasma insulin (C-D) levels before (time 0) and after an oral gavage of Ensure Plus liquid diet in Sham (n=8), RYGB (n=6), VSG (n=6), and Pair-fed (n=9) rats. A. Blood glucose levels were significantly lower in RYGB and VSG rats relative to ad lib fed Sham animals at 45 and 60-min, P<0.05. B. Differences in oral glucose tolerance were not significant between treatments when the data were expressed as AUC, P>0.05. C. Plasma insulin levels were significantly lower at baseline in RYGB and VSG rats relative to ad lib fed Sham animals, P<0.05. Pair-feeding reduced plasma insulin levels relative to ad lib fed Sham rats at 15, 30 and 60-min, P<0.05 D. Insulin excursions expressed as a percentage of baseline showed that RYGB and VSG produced similar increases in postprandial insulin release that were not seen in Pair-fed animals. Bonferroni’s Post-test; ^*P<0.05 vs. Pair-fed, ^$P<0.05 vs. RYGB, ^#P<0.05 vs. VSG.

Figure 7

Blood glucose (A-B) and plasma insulin (C-D) levels before (time 0) and after an oral gavage of Ensure Plus liquid diet in rats pretreated with the GLP-1(7–36) receptor antagonist Exendin(9–39). Sham (n=8), RYGB (n=6), VSG (n=6), and Pair-fed (n=9) rats. A. AUC glucose was significantly lower in Pair-fed vs. VSG rats, P<0.05. B. Glucose excursions were significantly lower in Pair-fed animals vs. RYGB and VSG rats after 15-min, P<0.05, and Pair-fed vs. ad lib fed Sham operated rats after 60-min, P<0.05. C. Plasma insulin levels were not significantly different between treatments, P>0.05. D. Insulin levels expressed as a percentage of baseline were significantly higher in RYGB vs. Pair-fed and Sham rats at 15-min, P<0.05, but at no other time. ^*P<0.05 vs. Pair-fed, ^$P<0.05 vs. RYGB, ^#P<0.05 vs. VSG.