Evaluating the mechanisms of improved glucose homeostasis after bariatric surgery in Ossabaw miniature swine

Abstract

Background: Roux-en-Y gastric bypass (RYGB) is the most common bariatric operation; however, the mechanism underlying the profound weight-independent effects on glucose homeostasis remains unclear. Large animal models of naturally occurring insulin resistance (IR), which have been lacking, would provide opportunities to elucidate such mechanisms. Ossabaw miniature swine naturally exhibit many features that may be useful in evaluating the anti diabetic effects of bariatric surgery.

Methods: Glucose homeostasis was studied in 53 Ossabaw swine. Thirty-two received an obesogenic diet and were randomized to RYGB, gastrojejunostomy (GJ), gastrojejunostomy with duodenal exclusion (GJD), or Sham operations. Intravenous glucose tolerance tests and standardized meal tolerance tests were performed prior to, 1, 2, and 8 weeks after surgery and at a single time-point for regular diet control pigs.

Results: High-calorie-fed Ossabaws weighed more and had greater IR than regular diet controls, though only 70% developed IR. All operations caused weight-loss-independent improvement in IR, though only in pigs with high baseline IR. Only RYGB induced weight loss and decreased IR in the majority of pigs, as well as increasing AUCinsulin/AUCglucose.

Conclusions: Similar to humans, Ossabaw swine exhibit both obesity-dependent and obesity-independent IR. RYGB promoted weight loss, IR improvement, and increased AUCinsulin/AUCglucose, compared to the smaller changes following GJ and GJD, suggesting a combination of upper and lower gut mechanisms in improving glucose homeostasis.

Figure 1

Preoperative body weight and HOMA-IR in high-calorie and regular diet Ossabaws. Scatter plot of preoperative weight and HOMA-IR in pigs exposed to the high-fat, high-calorie diet for >180 days and those maintained on a normal diet. The dashed regression line shows overall mild positive correlation between weight and HOMA-IR (R ² = 0.08, P = 0.05). Insulin resistance in this model was defined as HOMA-IR > 2 standard deviations above the regular diet group mean (>2.61).

Figure 2

(a) Change in body weight and HOMA-IR by operation. Scatterplot shows percent change in weight and HOMA-IR 8 weeks postoperatively. ∗Sham pig values are at 2 weeks, as 8-week data was unavailable. (b) Change in body weight and HOMA-IR among high HOMA-IR pigs only. Percent change in weight and HOMA-IR 8 weeks postoperatively in pigs with above median baseline HOMA-IRs. ∗Sham pig values are at 2 weeks, as 8-week data was unavailable.

Figure 3

(a) IVGTT AUC_insulin/AUC_glucose. Pre- and postoperative IVGTT AUC_insulin/AUC_glucose for RYGB, GJ, GJD, and Sham procedures. (b) MTT AUC_insulin/AUC_glucose. Pre- and postoperative MTT AUC_insulin/AUC_glucose for RYGB, GJ, GJD, and Sham procedures. “∗indicates” statistical significance (P < 0.05).