Bypassing the duodenum does not improve insulin resistance associated with diet-induced obesity in rodents

Abstract

Roux-en-y gastric bypass (RYGB) surgery rapidly improves glucose tolerance and reverses insulin resistance in obese patients. It has been hypothesized that this effect is mediated by the diversion of nutrients from the proximal small intestine. We utilized duodenal-jejunal bypass (DJB) as a modification of gastric bypass to determine the effect of nutrient diversion from the foregut without gastric restriction on insulin resistance in obese rats. The effects of DJB or Sham surgery on glucose homeostasis were determined in both high-fat-fed Long-Evans and Wistar rats. Body weight and food intake were measured weekly postoperatively, and body composition was monitored before and after surgery. Glucose tolerance was tested before and as early as 1 month postoperation; additionally, in Wistar rats, insulin sensitivity was determined by a hyperinsulinemic-euglycemic clamp (HIEC). DJB did not affect body weight, body composition, glucose tolerance, or insulin concentrations over the period of the study. The average glucose infusion rate (GIR) during the HIEC was 6.2 ± 1.16 mg/kg/min for Sham rats compared to 7.2 ± 1.71 mg/kg/min for DJB rats (P = 0.62), and neither endogenous glucose production (EGP; P = 0.81) nor glucose utilization (glucose disappearance (R(d)), P = 0.59) differed between DJB and Sham rats. DJB does not affect insulin resistance induced by a high-fat diet in Long-Evans and Wistar rats. These data suggest that duodenal bypass alone is an insufficient mechanism to alter insulin sensitivity independent of weight loss in obese, nondiabetic rodents.

Figure 1

The effect of duodenal–jejunal bypass (DJB) or Sham surgery in Long-Evans rats fed a high-fat diet (DJB-HFLE, inverted closed triangles and Sham-HFLE, closed circles) or chow diet (Sham-CLE, open circles). (a) Body weight and (b) daily food intake were followed for 4 weeks postoperatively. (c) Percent body fat was measured pre- and 4 weeks postoperatively by EchoMRI. Statistically different compared to Sham-CLE for the given time point (*) or compared to preoperative values within the same group (#) when P < 0.05. Statistical data are presented as mean ± s.e.

Figure 2

Blood glucose concentrations (a) during a 2-g D-glucose OGTT test or (b) during a 0.5 U/kg subcutaneous insulin tolerance test (ITT) performed at 4 weeks postoperatively in high-fat-fed duodenal-–jejunal bypass (DJB-HFLE, inverted closed triangles), high-fat-fed Sham (Sham- HFLE, closed circles), and chow-fed Sham Long-Evans rats (Sham-CLE, open circles). Glucose concentrations from the ITT are displayed as the percentage of the fasting glucose concentrations. Statistically different compared to Sham-CLE for given time point (*) when P < 0.05. Statistical data are presented as mean ± s.e.

Figure 3

The effect of duodenal–jejunal bypass (DJB, closed circles) or Sham surgery (open circles) in high-fat-fed Wistar rats on (a) body weight, and (b) food intake. (c) The percent body fat was measured by EchoMRI preoperatively, and at 4 and 9 weeks postoperatively. (d) Fecal fat absorption was quantified with the use of a nondigestible fat marker, sucrose polybehenate, added to a 33% kcal from fat diet fed to all groups for 3 days. Statistically different between the two groups for the given time point (*) or compared to preoperative values within the same group (#) when P < 0.05. Statistical data are presented as mean ± s.e.

Figure 4

(a) Blood glucose and (b) plasma insulin concentrations during a 2-g D-glucose OGTT at 7 weeks postoperatively in duodenal–jejunal bypass (DJB, closed circles) or Sham (open circles) high-fat-fed Wistar rats. Data are presented as mean ± s.e.

Figure 5

The average plasma basal (60–90 min) and clamp period (150–180 min) (a) glucose and (b) insulin concentrations during a hyperinsulinemic–euglycemic clamp study performed ~11 weeks after duodenal–jejunal bypass (DJB) or Sham surgery in high-fat-fed Wistar rats. Statistical data are presented as mean ± s.e.

Figure 6

(a) The average rate of glucose appearance (Ra) in the basal period, (b) glucose infusion rate (GIR) during the clamp period, (c) rate of endogenous glucose production (EGP) during the clamp period, and (d) rate of glucose disappearance (Rd) during the clamp period from a hyperinsulinemic–euglycemic clamp study performed ~11 weeks after duodenal–jejunal bypass (DJB) or Sham surgery in high-fat-fed Wistar rats. Statistical data are presented as mean ± s.e.