The mechanism of diabetes control after gastrointestinal bypass surgery reveals a role of the proximal small intestine in the pathophysiology of type 2 diabetes

Abstract

Summary background data: Most patients who undergo Roux-en-Y gastric bypass (RYGB) experience rapid resolution of type 2 diabetes. Prior studies indicate that this results from more than gastric restriction and weight loss, implicating the rearranged intestine as a primary mediator. It is unclear, however, if diabetes improves because of enhanced delivery of nutrients to the distal intestine and increased secretion of hindgut signals that improve glucose homeostasis, or because of altered signals from the excluded segment of proximal intestine. We sought to distinguish between these two mechanisms.

Methods: Goto-Kakizaki (GK) type 2 diabetic rats underwent duodenal-jejunal bypass (DJB), a stomach-preserving RYGB that excludes the proximal intestine, or a gastrojejunostomy (GJ), which creates a shortcut for ingested nutrients without bypassing any intestine. Controls were pair-fed (PF) sham-operated and untreated GK rats. Rats that had undergone GJ were then reoperated to exclude the proximal intestine; and conversely, duodenal passage was restored in rats that had undergone DJB. Oral glucose tolerance (OGTT), food intake, body weight, and intestinal nutrient absorption were measured.

Results: There were no differences in food intake, body weight, or nutrient absorption among surgical groups. DJB-treated rats had markedly better oral glucose tolerance compared with all control groups as shown by lower peak and area-under-the-curve glucose values (P < 0.001 for both). GJ did not affect glucose homeostasis, but exclusion of duodenal nutrient passage in reoperated GJ rats significantly improved glucose tolerance. Conversely, restoration of duodenal passage in DJB rats reestablished impaired glucose tolerance.

Conclusions: This study shows that bypassing a short segment of proximal intestine directly ameliorates type 2 diabetes, independently of effects on food intake, body weight, malabsorption, or nutrient delivery to the hindgut. These findings suggest that a proximal intestinal bypass could be considered for diabetes treatment and that potentially undiscovered factors from the proximal bowel might contribute to the pathophysiology of type 2 diabetes.

Figures

FIGURE 1. Interventions. A, Duodenal-jejunal bypass (DJB). This operation does not impose any restriction to the flow of food through the gastrointestinal tract. The proximal small intestine is excluded from the transit of nutrients, which are rapidly delivered more distally in the small bowel. Food exits the stomach and enters the small bowel at 10 cm from the ligament of Treitz, and digestive continuity is reestablished approximately 25% of the way down the jejunum. B, Gastrojejunostomy (GJ). This operation consists of a simple anastomosis between the distal stomach and the first quarter of the jejunum. The site of the jejunum that is anastomosed to the stomach is chosen at the same distance as in DJB (10 cm from the ligament of Treitz). Hence, the DJB and GJ share the feature of enabling early delivery of nutrients to the same level of small bowel. In contrast to DJB, the GJ does not involve exclusion of duodenal passage, and nutrient stimulation of the duodenum is maintained. C, Ileal bypass (ILB). This operation reduces intestinal fat absorption by preventing nutrients from passing through the distal ileum, where most lipids are absorbed.

FIGURE 2. Reoperations. A, Duodenal jejunal exclusion after GJ. To verify the effects of excluding the intestinal foregut from the passage of food, GJ-treated rats underwent a second operation to divide the duodenum from the stomach, re-creating duodenal and proximal jejunal exclusion, as in DJB. After this operation, nutrients can only pass through the gastrojejunal anastomosis, and the duodenum and proximal jejunum are excluded from antegrade passage of food. B, Restoration of duodenal nutrient passage after DJB. To verify the effect of luminal nutrient stimulation of the proximal intestine, duodenal passage was restored in rats that had initially undergone DJB, by reanastomosing the proximal duodenum to the stomach but leaving the gastrojejunostomy intact. These rats have the same shortcut for nutrients to the hindgut as do DJB rats, but nutrient flow through their proximal small intestine is reestablished.

FIGURE 3. Food intake and body weight gain. Each box in the chart shows the median, quartiles, and extreme values. A, Food intake (g/day per rat) in GK rats. All operated animals ate less food compared with nonoperated controls, but no significant differences were found among surgical groups (DJB, GJ, PF-sham). GK-sham rats were pair-fed to the intake of GK-DJB rats; consequently, both groups had the same food intake throughout the study. B, Operated rats gained less weight than did nonoperated GK controls (*P < 0.05); however, there were no significant differences among DJB, GJ, and sham-PF animals.

FIGURE 4. Glucose time course and AUC after a 3 g/kg oral glucose load (OGTT). Glucose time course (A) and AUC glucose (B) in GK diabetic rats, showing markedly improved glucose tolerance in DJB-treated animals. In contrast with the results of diabetic rats, glucose time course and AUC glucose in nondiabetic Wistar rats show that DJB slightly deteriorated glucose tolerance in normal animals. *P < 0.01, **P < 0.001.

FIGURE 5. Glucose tolerance (AUC) after reoperation that excluded the duodenum from nutrient passage in GJ-treated rats. GJ-treated rats underwent a second operation to create duodenal exclusion, as in DJB. Glucose tolerance improved after duodenal exclusion, as shown by lower AUC glucose after an OGTT (*P = 0.02).

FIGURE 6. Hypothesis regarding the possible contribution of the proximal intestine to the alterations of glucose metabolism in type 2 diabetes. The passage of nutrients through the intestinal foregut may trigger, in addition to the known incretin response, a concomitant counter-regulatory signal (“anti-incretin factor”) aimed to prevent hypoglycemia. This signal may interfere with pathways of the incretin system and/or act downstream to inhibit insulin action. In predisposed individuals, chronic stimulation with particular nutrients may create an imbalance between incretin and “anti-incretin” signals, resulting in insulin resistance and type 2 diabetes.