Sony S. Thazhath, 1,2 Chinmay S. Marathe, 1,2 Tongzhi Wu, 1,2 Jessica Chang, 1,2 Joan Khoo, 1,2 Paul Kuo, 1,2,3 Helen L. Checklin, 1,2 Michelle J. Bound, 1,2 Rachael S. Rigda, 1,2 Benjamin Crouch, 4 Karen L. Jones, 1,2 Michael Horowitz, 1,2 and Christopher K. Rayner 1,2,3 The Glucagon-Like Peptide 1 Receptor Agonist Exenatide Inhibits Small Intestinal Motility, Flow, Transit, and Absorption of Glucose in Healthy Subjects and Patients With Type 2 Diabetes: A Randomized Controlled Trial Diabetes 2016;65:269–275 | DOI: 10.2337/db15-0893 The short-acting glucagon-like peptide 1 receptor ago- nist exenatide reduces postprandial glycemia, partly by slowing gastric emptying, although its impact on small intestinal function is unknown. In this study, 10 healthy subjects and 10 patients with type 2 diabetes received intravenous exenatide (7.5 mg) or saline (230 to 240 min) in a double-blind randomized crossover design. Glucose (45 g), together with 5 g 3-O-methylglucose (3-OMG) and 20 MBq 99m Tc-sulfur colloid (total volume 200 mL), was given intraduodenally (t =0–60 min; 3 kcal/min). Duodenal motility and flow were measured using a com- bined manometry-impedance catheter and small intes- tinal transit using scintigraphy. In both groups, duodenal pressure waves and antegrade flow events were fewer, and transit was slower with exenatide, as were the areas under the curves for serum 3-OMG and blood glucose concentrations. Insulin concentrations were initially lower with exenatide than with saline and subsequently higher. Nausea was greater in both groups with exenatide, but suppression of small intestinal motility and flow was ob- served even in subjects with little or no nausea. The in- hibition of small intestinal motor function represents a novel mechanism by which exenatide can attenuate postprandial glycemia. Therapies specifically targeting postprandial glycemia are important in the management of type 2 diabetes, especially in patients with relatively good overall glycemic control (HbA 1c #7.5%; 58 mmol/mol) (1). The rate of gastric emp- tying is an established determinant of postprandial blood glucose (2), a principle illustrated by “short-acting” glucagon- like peptide 1 (GLP-1) receptor agonists, such as exenatide, where the capacity to slow gastric emptying predominates over the insulinotropic effect in the postprandial setting (3). Small intestinal glucose absorption, predominantly via sodium–glucose cotransporter 1 and GLUT2 transporters, is limited to ;0.5 g/min per 30 cm (2). Interventions that increase the exposure of luminal glucose to the mucosal surface can therefore augment glucose absorption. We pre- viously reported that the anticholinergic agent hyoscine delays the absorption of intraduodenally infused glucose in humans by decreasing small intestinal flow (4), indicating 1 Discipline of Medicine, The University of Adelaide, Royal Adelaide Hospital, Adelaide, Australia 2 Centre of Research Excellence in Translating Nutritional Science to Good Health, The University of Adelaide, Adelaide, Australia 3 Department of Gastroenterology and Hepatology, Royal Adelaide Hospital, Ade- laide, Australia 4 Department of Nuclear Medicine, PET & Bone Densitometry, Royal Adelaide Hospital, Adelaide, Australia Corresponding author: Christopher K. Rayner, chris.rayner@adelaide.edu.au. Received 30 June 2015 and accepted 7 October 2015. Clinical trial reg. no. ACTRN12608000428369, www.anzctr.org.au. This article contains Supplementary Data online at http://diabetes .diabetesjournals.org/lookup/suppl/doi:10.2337/db15-0893/-/DC1. J.K. is currently affiliated with the Department of Endocrinology, Changi General Hospital, Singapore. © 2016 by the American Diabetes Association. Readers may use this article as long as the work is properly cited, the use is educational and not for profit, and the work is not altered. Diabetes Volume 65, January 2016 269 PHARMACOLOGY AND THERAPEUTICS