Effect of duodenal-jejunal exclusion in a non-obese animal model of type 2 diabetes: a new perspective for an old disease

Abstract

Background: The Roux-en-Y gastric bypass and the biliopancreatic diversion effectively induce weight loss and long-term control of type 2 diabetes in morbidly obese individuals. It is unknown whether the control of diabetes is a secondary outcome from the treatment of obesity or a direct result of the duodenal-jejunal exclusion that both operations include. The aim of this study was to investigate whether duodenal-jejunal exclusion can control diabetes independently on resolution of obesity-related abnormalities.

Methods: A gastrojejunal bypass (GJB) with preservation of an intact gastric volume was performed in 10- to 12-week-old Goto-Kakizaki rats, a spontaneous nonobese model of type 2 diabetes. Fasting glycemia, oral glucose tolerance, insulin sensitivity, basal plasma insulin, and glucose-dependent-insulinotropic peptide as well as plasma levels of cholesterol, triglycerides, and free fatty acids were measured. The GJB was challenged against a sham operation, marked food restriction, and medical therapy with rosiglitazone in matched groups of animals. Rats were observed for 36 weeks after surgery.

Results: Mean plasma glucose 3 weeks after GJB was 96.3 +/- 10.1 mg/dL (preoperative values were 159 +/- 47 mg/dL; P = 0.01). GJB strikingly improved glucose tolerance, inducing a greater than 40% reduction of the area under blood glucose concentration curve (P < 0.001). These effects were not seen in the sham-operated animals despite similar operative time, same postoperative food intake rates, and no significant difference in weight gain profile. GJB resulted also in better glycemic control than greater weight loss from food restriction and than rosiglitazone therapy.

Conclusions: Results of our study support the hypothesis that the bypass of duodenum and jejunum can directly control type 2 diabetes and not secondarily to weight loss or treatment of obesity. These findings suggest a potential role of the proximal gut in the pathogenesis the disease and put forward the possibility of alternative therapeutic approaches for the management of type 2 diabetes.

FIGURE 1. Roux-en-Y gastric bypass (A) includes creation of a small gastric pouch while the jejunum is divided 30–50 cm distal to the ligament of Treitz. The distal limb of the jejunum is then anastomosed to the small gastric pouch and a jejuno–jejunostomy is performed 50 to 150 cm distal from the gastrojejunostomy. The biliopancreatic diversion (B) includes resection of the distal stomach and diversion of the biliopancreatic juices to the terminal ileum, 50 to 100 cm proximally to the ileo-cecal valve. The 2 operations thus have in common the exclusion of duodenum and proximal jejunum from the transit of food.

FIGURE 2. Gastrojejunal bypass. The duodenum was separated from the stomach, and bowel continuity was interrupted at the level of the distal jejunum, (8 cm from the ligament of Treitz). The distal of the 2 limbs was directly connected to the stomach (gastrojejunal anastomosis) and the proximal limb carrying the biliopancreatic juices was reconnected downward to the alimentary limb at a distance of 12 cm from the gastrojejunal anastomosis (Roux-en-Y reconstruction)

FIGURE 3. A, Mean fasting glycemia remained constantly lower in GJB rats compared with sham-operated animals. B, AUC indicates the area under the curve for fasting glycemia over the 36-week period of postoperative observation respectively in GJB rats (AUC1) and sham rats (AUC2); P = 0.02. (ANOVA)

FIGURE 4. Glucose tolerance. A, OGTT performed in GJB rats 1 week after surgery showed a striking improvement of glucose tolerance, *42% reduction of AUC; P < 0.001. B, GJB resulted in markedly better glucose tolerance compared to both sham operation and marked food restriction, *GJB vs food restriction: 34% smaller AUC in GJB rats; P < 0.001. C, Glucose tolerance expressed as AUC under the glucose concentration curve during the 36 week follow-up period. †P = 0.03; ††P = 0.02; ‡P = 0.001.

FIGURE 5. A, Both the GJB and the sham-operated group showed less weight gain compared with nonoperated controls (P < 0.05); comparing the GJB group and the sham-operated animals, the difference in weight gain profile was not statistically significant. B, In contrast, food restriction induced significantly greater weight loss than GJB (*P < 0.05).

FIGURE 6. Rosiglitazone and GJB similarly improved glucose tolerance with respect to controls; however, GJB rats had better insulin sensitivity as demonstrated by lower 60-minute glucose levels (41 ± 14 vs. 61±9; P = 0.03) and lower area under blood glucose concentration curve (AUC) at ITT (*GJB vs Rosiglitazone: P < 0.05; **Rosigl. vs controls: P < 0.001; *** GJB vs controls: P < 0.0001).