Altered GIP/GLP-1 Secretion Ratio is Associated With Impaired β Cell Function in Humans

Abstract Introduction The entero-insular axis, mediated by the incretin hormones glucose-dependent insulinotropic polypeptide (GIP) and glucagon-like peptide-1 (GLP-1), is fundamental to maintaining glucose homeostasis. Dysregulation of these hormones’ biology contributes to the pathogenesis of type 2 diabetes (T2D), but the existence of a dysfunctional secretory pattern of incretins toward deterioration of glucose tolerance is still debated. In this study, we evaluate possible impairments in the overall incretin secretion from normal glucose tolerance to overt diabetes, as well as their association with impaired insulin secretion. Methods Sixty subjects with an unknown history of T2D who were not on antidiabetic treatments were divided into 3 groups according to oral glucose tolerance test-derived glucose tolerance: normal glucose tolerance (NGT) (n = 23), impaired glucose tolerance (IGT) (n = 16), and diabetes mellitus (DM) (n = 21). All subjects underwent deep metabolic evaluation with a mixed meal test (MMT) and euglycemic hyperinsulinemic clamp. During the MMT, we calculated the GIP/GLP-1 secretion ratio (SR) and the GIP/GLP-1 SR areas under the curve. Parameters of β cell function were obtained by mathematical modeling. Results Linear mixed model analysis revealed similar GIP and GLP-1 responses to MMT among the 3 groups, while GIP/GLP-1 SR was reduced in DM subjects compared to NGT and IGT. Further, multiple regression analysis showed a predictive role of GIP/GLP-1 SR on rate sensitivity and standardized insulin secretion at 5 mmol/L. Conclusion Our findings demonstrate that, despite similar GIP and GLP-1 secretion, the GIP/GLP-1 SR declines as glucose tolerance deteriorates, reflecting an imbalance in incretin dynamics rather than absolute hormone secretion. This imbalance may indicate early β cell dysfunction and chronic incretin resistance.