PYY-Dependent Restoration of Impaired Insulin and Glucagon Secretion in Type 2 Diabetes following Roux-En-Y Gastric Bypass Surgery.

Reshma D Ramracheya,Anne Clark,Duan Chen,Chun-Mei Zhao,Laura J Mcculloch,Magnus Kringstad Olsen,Xing Cai,Helene Johannessen,Patrik Rorsman,David Wiggins

doi:10.1016/j.celrep.2016.03.091

Abstract

SummaryRoux-en-Y gastric bypass (RYGB) is a weight-reduction procedure resulting in rapid resolution of type 2 diabetes (T2D). The role of pancreatic islet function in this restoration of normoglycemia has not been fully elucidated. Using the diabetic Goto-Kakizaki (GK) rat model, we demonstrate that RYGB restores normal glucose regulation of glucagon and insulin secretion and normalizes islet morphology. Culture of isolated islets with serum from RYGB animals mimicked these effects, implicating a humoral factor. These latter effects were reversed following neutralization of the gut hormone peptide tyrosine tyrosine (PYY) but persisted in the presence of a glucagon-like peptide-1 (GLP-1) receptor antagonist. The effects of RYGB on secretion were replicated by chronic exposure of diabetic rat islets to PYY in vitro. These findings indicate that the mechanism underlying T2D remission may be mediated by PYY and suggest that drugs promoting PYY release or action may restore pancreatic islet function in T2D.

Highlights

Roux-en-Y gastric bypass (RYGB) is the most common form of weight loss surgery
Human type 2 diabetes (T2D) is characterized by dysfunction of both glucosestimulated insulin secretion (GSIS) from pancreatic b cells and inappropriate regulation of glucagon production from a cells (Unger and Cherrington, 2012)
RYGB Restores Impaired Islet Secretory Properties and Improves Metabolic Parameters Both insulin and glucagon secretion was assessed in islets isolated from spontaneously diabetic Goto-Kakizaki (GK) rats post-RYGB surgery

Summary

Introduction

Roux-en-Y gastric bypass (RYGB) is the most common form of weight loss surgery. Developed originally as a weightreduction therapy, RYGB can lead to full and durable remission of type 2 diabetes (T2D) in up to 90% of cases (Buchwald et al, 2004). The remission occurs within days of surgery and before any significant weight loss. The mechanisms behind this improvement remain unknown. Human T2D is characterized by dysfunction of both glucosestimulated insulin secretion (GSIS) from pancreatic b cells and inappropriate regulation of glucagon production from a cells (Unger and Cherrington, 2012). The importance of glucagon in diabetes is confirmed by the finding that mice lacking glucagon receptors remain normoglycemic even after complete destruction of b cells (Lee et al, 2012)

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