Customization of biliopancreatic limb length to modulate and sustain antidiabetic effect of gastric bypass surgery

A. Pal, D. B. Rhoads, A. Tavakkoli

Although Roux-en-Y Gastric Bypass (RYGB) remains the most effective treatment for obesity and Type 2 Diabetes (T2D), many patients fail to achieve remission, or relapse. Increasing intestinal limb lengths of RYGB may improve outcomes, but the mechanistic basis for this remains unclear. We hypothesize Bilio-Pancreatic (BP) limb length modulates the anti-diabetic effect of RYGB. Rats underwent RYGB with a 20-cm (RYGB-20cm) or 40-cm (RYGB-40cm) BP limb, and were compared to control animals. After two and four weeks, portal and systemic blood was sampled during intestinal glucose infusion. Portosystemic gradient was used to calculate intestinal glucose utilization (Gutil), absorption (Gabsorp), and hormone secretion. Intestinal morphology and gene expression were assessed. At 2 weeks, Gabsorp progressively decreased with increasing BP limb length; this pattern persisted at 4 weeks. Gutil increased ≈70% in both RYGB-20cm and -40cm groups at 2 weeks. At 4 weeks, Gutil progressively increased with limb length. Furthermore, Roux limb weight, and expression of hexokinase and preproglucagon exhibited a similar progressive increase. At 4 weeks, GLP-1 and GLP-2 levels were higher after RYGB-40cm, with associated increased secretion. BP limb length modulates multiple anti-diabetic mechanisms, analogous to the dose-response relationship of a drug. Early postoperatively, a longer BP limb reduces Gabsorp Later, Gutil, Roux limb hypertrophy, hormone secretion and hormone levels are increased with longer BP limb. Sustained high incretin levels may prevent weight regain and T2D relapse. This data provides the basis for customizing BP limb length according to patient characteristics and desired metabolic effect.