580 Ezetimibe Modulates Endogenous LXR Ligands to Regulate Intestinal LDLR Receptors via IDOL

Abstract

Glucose absorption in the small intestine is mediated by sodium dependent glucose cotransporter 1 (SGLT-1) and glucose transporter-2 (GLUT2), and is potentially linked to sweet taste receptor (STR) signaling and incretin hormone secretion. Both glucose absorption and expression of SGLT-1 are increased in obese rats, but human data is lacking. This study aimed to examine intestinal glucose absorption inmorbidly obese humans, and its relationship to glycemia, incretin responses, SGLT-1, GLUT2, and STR expression. Methods: 17 nondiabetic, morbidly obese subjects (5M:12F; 45 ± 3yrs, BMI: 48 ± 4kg/m2) and 11 lean controls (10M:1F; 44 ± 6yrs, BMI: 25 ± 1kg/m2) underwent endoscopic duodenal biopsies prior to intraduodenal glucose infusion (30g glucose over 30 min, with 3g 3-O-methylglucose (3-OMG) to estimate glucose absorption). Blood glucose and plasma concentrations of 3OMG, glucose-dependent insulinotropic polypeptide (GIP), glucagon-like peptide-1 (GLP1), insulin, and glucagon were measured over 240 min. Absolute expression of SGLT-1, GLUT2 and STR (T1R2) transcripts was quantified by PCR. Results: Both the rate of glucose absorption, as assessed by the rise in plasma 3-OMG concentrations (P<0.001) and blood glucose concentrations (P<0.0001) were substantially greater in obese than lean subjects (Fig AB Fig C), but not GLUT2 or T1R2, was higher in the obese than lean subjects, and was related to peaked plasma 3OMG (r=0.61, P=0.01). CONCLUSIONS: Glucose absorption in the proximal intestine is (i) accelerated in morbid obesity, (ii) associated with an incretin profile that potentially promotes both hyperinsulinemia and hyperglycemia, and (iii) associated with increased expression of SGLT-1. These novel findings suggest that accelerated glucose absorption in the proximal gutmay be the X-factor accounting for the foregut theory of obesity and diabetes.