Reshma Ramracheya
University of Oxford, UK
Title: Unravelling the role of the gut hormone PYY in diabetes remission and pancreatic islet function following Roux-En-Y gastric bypass
Biography
Biography: Reshma Ramracheya
Abstract
Roux-En-Y gastric bypass (RYGB) results in long-lasting remission from type-2 diabetes (T2D) in most cases. Improvements in glucose homeostasis occur within days of surgery, but the mechanisms involved remain unclear. Although pancreatic islets play a fundamental role in glucose homeostasis, the impact of RYGB on islet architecture and secretory properties has not been studied thoroughly. T2D is a bihormonal disease characterised by both insufficient insulin secretion and impairment in glucagon regulation. Whether RYGB can correct both hormonal secretory defects remain unexplored.
Using the Goto-Kakizaki (GK) rat model of T2D, we have explored whether RYGB affects islet structure and glucose-stimulated insulin secretion (GSIS) and glucagon release. RYGB restored ‘distorted’ islets from diabetic rats to spheroidal shape as in healthy animals. Compared to the sham-operated animals, RYGB normalised glucose-dependent glucagon and insulin secretion. Thus, islets from RYGB rats exhibited markedly enhanced insulin secretion at 20mM glucose and complete restoration of glucose-induced suppression of glucagon release.
Culture of isolated islets with serum from RYGB animals resulted in improved insulin and glucagon secretion, in support of a humoral factor which remains conserved in serum. These effects were reversed following immuno-neutralization of the gut hormone peptide tyrosine tyrosine (PYY) but persisted in the presence of a glucagon-like peptide-1 (GLP-1) receptor antagonist. Chronic (60-72h) treatment of islets with synthetic PYY enhanced GSIS in a NPY1-receptor-dependent manner. PYY application also restored GSIS and normalised impaired glucose-induced glucagon release in islets from severely diabetic GK rats and human donors with T2D. These data provide a novel mechanistic insight on the effect of RYGB in diabetes and highlight that the mechanism behind the improvement of islet function is dependent on PYY, and not GLP-1.
These findings imply that a pharmacological agent enhancing PYY release or its action could provide an effective and non-surgical therapy for T2D.