The Effect of Standard Versus Longer Intestinal Bypass on GLP-1 Regulation and Glucose Metabolism in Patients With Type 2 Diabetes Undergoing Roux-en-Y Gastric Bypass: The Long-Limb Study https://doi.org/10.2337/dc20-0762 OBJECTIVE Roux-en-Y gastric bypass (RYGB) characteristically enhances postprandial levels of glucagon-like peptide 1 (GLP-1), a mechanism that contributes to its profound glucose-lowering effects. This enhancement is thought to be triggered by bypass of food to the distal small intestine with higher densities of neuroendocrine L-cells. We hypothesized that if this is the predominant mechanism behind the enhanced secretion of GLP-1, a longer intestinal bypass would potentiate the postprandial peak in GLP-1, translating into higher insulin secretion and, thus, additional improve- ments in glucose tolerance. To investigate this, we conducted a mechanistic study comparing two variants of RYGB that differ in the length of intestinal bypass. RESEARCH DESIGN AND METHODS A total of 53 patients with type 2 diabetes (T2D) and obesity were randomized to either standard limb RYGB (50-cm biliopancreatic limb) or long limb RYGB (150-cm biliopancreatic limb). They underwent measurements of GLP-1 and insulin secretion following a mixed meal and insulin sensitivity using euglycemic hyperinsulinemic clamps at baseline and 2 weeks and at 20% weight loss after surgery. RESULTS Both groups exhibited enhancement in postprandial GLP-1 secretion and improve- ments in glycemia compared with baseline. There were no significant differences in postprandial peak concentrations of GLP-1, time to peak, insulin secretion, and insulin sensitivity. CONCLUSIONS The findings of this study demonstrate that lengthening of the intestinal bypass in RYGB does not affect GLP-1 secretion. Thus, the characteristic enhancement of GLP- 1 response after RYGB might not depend on delivery of nutrients to more distal intestinal segments. 1 Department of Metabolism, Digestion and Re- production, Imperial College London, London, U.K. 2 Department of Surgery and Cancer, Imperial College London, London, U.K. 3 Department of Surgery, King’s College London, London, U.K. 4 StatsConsultancy Ltd., London, U.K. 5 Faculty of Health and Medical Sciences, Univer- sity of Surrey, Guildford, U.K. Corresponding author: Francesco Rubino, fran- cesco.rubino@kcl.ac.uk Received 10 April 2020 and accepted 14 August 2020 Clinical trial reg. no. ISRCTN 15283219, www .isrctn.org This article contains supplementary material online at https://doi.org/10.2337/ figshare .12814262. A.D.M. and A.K. equally contributed as first authors. S.R.B., T.T., A.R.A., and F.R. equally contributed as senior authors. © 2020 by the American Diabetes Associatio. 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. More infor- mation is available at https://www.diabetesjournals .org/content/license. See accompanying article, p. XXX. Alexander Dimitri Miras, 1 Anna Kamocka, 1 Bel´ en P´ erez-Pevida, 1 Sanjay Purkayastha, 2 Krishna Moorthy, 2 Ameet Patel, 3 Harvinder Chahal, 1 Gary Frost, 1 Paul Bassett, 4 Lidia Castagnetto-Gissey, 3 Lucy Coppin, 5 Nicola Jackson, 5 Anne Margot Umpleby, 5 Stephen Robert Bloom, 1 Tricia Tan, 1 Ahmed Rashid Ahmed, 1 and Francesco Rubino 3 Diabetes Care 1 CLIN CARE/EDUCATION/NUTRITION/PSYCHOSOCIAL Diabetes Care Publish Ahead of Print, published online November 6, 2020