108-OR: Insulin Resistance Is Associated with Alterations in the Dynamics of Incretin Secretion

GIP and GLP-1 exert a fundamental role in glucose homeostasis, but it is still debated if modifications in GIP and GLP-1 secretion can affect the metabolic state, as well as their contribution to the dynamics of incretin-induced insulin secretion. In this study we aimed to explore the relative effect of GIP and GLP-1 secretion on glucose metabolism and beta-cell function. 41 subjects with no previous diagnosis of T2DM were divided into 3 groups according to OGTT-derived glucose tolerance: NGT (12) IGT (12) DM (17). All subjects underwent a mixed meal test (MMT) with glucose, insulin, c-peptide, GIP and GLP-1 levels assessment. Further, we calculated the GIP/GLP-1 Secretion Ratio (GIP/GLP-1 SR) for each timepoint normalized for basal levels and the AUC of the ratio of GIP and GLP-1 secretion. Further, all subjects underwent a euglycemic hyperinsulinemic clamp (EHC) to assess insulin sensitivity. During MMT we observed higher glucose levels in DM subjects compared to NGT and IGT (p0.01), while insulin and c-peptide secretion showed a non-significant decreasing trend in DM subjects compared to NGT and IGT (p=0.10 and p=0.21). Further, we observed a non-significant decreasing trend in GIP secretion in IGT and DM subjects (p=0.08). No differences in GLP-1 secretion were detected among the 3 groups (p=0.65). Interestingly, IGT and DM groups showed a reduced GIP/GLP-1 SR compared to NGT (p=0.02 for interaction). Further, we found that the AUC of GIP/GLP-1 SR was positively correlated with the EHC-derived M-value (R=0.45, p=0.01). Our data show that, rather than an altered secretion of the incretin hormones per se, insulin resistance leads to an imbalance in the dynamics of incretin secretion overall: the GIP/GLP-1 SR appears to be an early marker of impaired glucose homeostasis. Further studies are needed to investigate whether the altered GIP/GLP-1 secretion is the cause or the effect of altered beta-cell incretin sensitivity and the potential metabolic effects of unbalanced incretin secretion. Disclosure G. Di Giuseppe: None. L. Soldovieri: None. G. Ciccarelli: None. M. Brunetti: None. F. Cinti: None. S. Moffa: None. J.J. Holst: Advisory Panel; Novo Nordisk A/S, Merck Sharp Antag Therapeutics. A. Giaccari: None. 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)