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 (p<0.01), 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.