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 (p<0.0001), 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.