Mechanisms Underlying Glycemic Reduction Following Roux-en-Y Gastric Bypass Surgery: Foregut Versus Hindgut Contributions

Abstract

Background: Roux-en-Y gastric bypass (RYBG) cures type 2 diabetes in over 80% of cases, although the mechanisms remain incompletely understood. A primary role for exaggerated secretion of glucagon-like peptide-1 (GLP-1) from the hindgut has been established, however the question remains whether omission of an as-yet uncharacterized diabetogenic foregut factor may also contribute. The “foregut hypothesis” derives from a study by Rubino et al. in which glycemic responses to hindgut feeding in duodenal-jejunal bypassed rats (analogous to RYGB anatomy), foregut feeding in gastrojejunal anastomosed rats, and foregut+hindgut feeding in sham-operated pair-fed controls showed that foregut stimulation independently raised blood glucose while bypassing the foregut lowered glucose. We performed a human study analogous to the Rubino study to further evaluate this hypothesis. Methods: Four post-RYGB patients with indwelling gastrostomy-tubes (g-tubes) were fed a standardized 75 g liquid meal on three separate days under differing fasting feeding conditions: 1) isolated oral feeding to the hindgut, 2) isolated g-tube feeding to the foregut, and 3) concomitant oral+g-tube feeding (co-stimulation of foregut and hindgut). Results: Compared to g-tube feeding, oral feeing led to significantly higher glucose (217 vs. 150 mg/dL, p=0.042) and insulin peaks (304 vs. 120 μIU/mL, p=0.021) and lower glucose nadirs (43 vs. 72 mg/dL, p=0.019), while compared to isolated oral or g-tube feeding, concomitant oral+g-tube feeding led to higher glucose (255 mg/dL) and insulin peaks (452 μIU/mL), and higher glucose nadirs (78 mg/dL). Conclusion: Hindgut stimulation and foregut omission may independently contribute to glucose lowering after RYGB.