Portal milieu and the interplay of multiple anti-diabetic effects after gastric bypass surgery

AIMS: Diabetes is a worldwide health problem. Roux-en-Y-Gastric-Bypass (RYGB) leads to rapid resolution of Type-2-Diabetes (T2D). Decreased hepatic insulin resistance is key but underlying mechanisms are poorly understood. We hypothesized that changes in intestinal function and subsequent changes in portal venous milieu drive some of these postoperative benefits. We therefore aimed to evaluate postoperative changes in portal milieu. METHODS: Two rat strains, healthy (Sprague Dawley; SD) and obese diabetic (Zucker Diabetic Fatty; ZDF) rats, underwent RYGB or control surgery. After 4 weeks, portal and systemic blood was sampled before and during an intestinal glucose bolus to investigate changes in intestinal glucose absorption (Gabsorp) and utilization (Gutil), and intestinal secretion of incretins and GLP-2. Hepatic activity of DPP4, which degrades incretins, was also measured. RESULTS: RYGB decreased Gabsorp in both rat strains. Gutil increased in SD rats and decreased in ZDF rats. In both strains, there was increased expression of intestinal hexokinase and gluconeogenesis enzymes. Systemic incretin and GLP-2 levels also increased after RYGB. This occurred without an increase in secretion. Hepatic DPP4 activity and expression were unchanged. CONCLUSIONS: RYGB perturbs multiple intestinal pathways, leading to decreased intestinal glucose absorption and increased incretin levels in both healthy and diabetic animals. In diabetic rats, intestinal glucose balance shifts towards glucose release. The portal vein as the gut-liver axis may integrate these intestinal changes to contribute to rapid changes in hepatic glucose and hormone handling. This fresh insight into the surgical physiology of RYGB raises the hope of less invasive alternatives.