1619-P: Insulin Resistance Stimulates Intraislet GLP-1 Secretion from a-Cells in Diet-Induced Obese Mice

It has been recently hypothesized that alpha α-cells are a potential source of intraislet GLP-1, eventually exerting paracrine effects on islet function. However, it is still unknown whether intraislet GLP-1 production and secretion is modulated by insulin resistance and glucose dysmetabolism. In this study, we aim to explore the impact of insulin resistance on intraislet proglucagon-derived peptides in a population of Diet-Induced Obese (DIO) mice. We performed a 75 min pancreatic perfusion on n=8 DIO vs. n=8 C57BL/6 control mice at low (3.5 mM) and medium (7 mM) glucose concentrations + 3.5 mM Vamine and 10 mM arginine stimulation; at the end, we infused insulin receptor antagonist S961 (n=4) or GLP-1 receptor antagonist Exendin 9 (n=4) to investigate possible involvement of insulin and GLP-1 receptor signaling. Total GLP-1 levels were measured using RIA; Insulin and Glucagon levels were measured through commercial ELISA kit (Mercodia). Compared to controls, DIO mice showed a significant secretion of total GLP-1 over time during perfusions (p0.0001), with no differences between 3.5 and 7 mM glucose and with a preserved response to arginine. Further, S961 did not affect total GLP-1 secretion, whereas Exendin 9 led to increased intra-islet total GLP-1 secretion, as in a positive feedback-control mechanism. As expected, DIO mice showed increased insulin secretion at 7 mM glucose and during arginine stimulation, while no differences were observed in the glucagon secretion. S961 and Exendin 9 did not affect insulin nor glucagon secretion in the 2 groups. Our data demonstrate that intraislet GLP-1 secretion is significantly increased in a rodent model of obesity and insulin resistance. In particular, this secretion pattern seems to be regulated by the activity of GLP-1 receptor itself. Further studies will be necessary to clarify the pathophysiologic action of intrapancreatic GLP-1 on insular environment. Disclosure G. Di Giuseppe: None. S.L. Jepsen: None. J. Vergara Ucin: None. B. Hartmann: Board Member; Bainan Biotech. A. Giaccari: None. J.J. Holst: Advisory Panel; Novo Nordisk A/S, Merck Sharp Antag Therapeutics. T. Mezza: None. Funding This study was supported by grants from the Universita Cattolica del Sacro Cuore (Fondi Ateneo Linea D.3.2, Fondi Ateneo Linea D.1, anno 2019, and Fondi Ateneo Linea D.1, anno 2020); the Italian Ministry of Education, University, and Research (MIUR; GR-2018-12365577 and RF-2019û12369293); the European Foundation for the Study of Diabetes award supported by Astra Zeneca and MIUR and MUIR (PRIN 2020SH2ZZA)