Foregut exclusion disrupts intestinal glucose sensing and alters portal nutrient and hormonal milieu

• Published in: Diabetes (New York, N.Y.) Vol. 64; no. 6; pp. 1941 - 1950
• Main Authors: Pal, Atanu, Rhoads, David B, Tavakkoli, Ali
• Format: Journal Article
• Language: English
• Published: United States American Diabetes Association 01.06.2015
• Subjects: Animals; Diabetes; Glucose; Glucose - metabolism; Glucose Tolerance Test; Hormones; In Vitro Techniques; Intestines - metabolism; Male; Metabolism; Proteins; Rats; Rats, Sprague-Dawley; Real-Time Polymerase Chain Reaction; Sodium-Glucose Transport Proteins - genetics; Sodium-Glucose Transport Proteins - metabolism; Sodium-Glucose Transporter 1 - genetics; Sodium-Glucose Transporter 1 - metabolism
• ISSN: 0012-1797; 1939-327X
• DOI: 10.2337/db14-1578

The antidiabetes effects of Roux-en-Y gastric bypass (RYGB) are well-known, but the underlying mechanisms remain unclear. Isolating the proximal small intestine, and in particular its luminal glucose sensors, from the nutrient stream has been proposed as a critical change, but the pathways involved are unclear. In a rodent model, we tested the effects of isolating and then stimulating a segment of proximal intestine using glucose analogs to examine their impact on glucose absorption (Gabsorp) and hormone secretion after a glucose bolus into the distal jejunum. Analogs selective for sodium-glucose cotransporter (SGLT) family members and the sweet taste receptor were tested, and measurements of the portosystemic gradient were used to determine Gabsorp and hormone secretion, including GLP-1. Proximal intestinal isolation reduced Gabsorp and GLP-1 secretion. Stimulation of the glucose-sensing protein SGLT3 increased Gabsorp and GLP-1 secretion. These effects were abolished by vagotomy. Sweet taste receptor stimulation only increased GLP-1 secretion. This study suggests a novel role for SGLT3 in coordinating intestinal function, as reflected by the concomitant modulation of Gabsorp and GLP-1 secretion, with these effects being mediated by the vagus nerve. Our findings provide potential mechanistic insights into foregut exclusion in RYGB and identify SGLT3 as a possible antidiabetes therapeutic target.