Changes in the secretion and efficacy of incretin hormones in type 2 diabetes

The incretin hormones glucose-dependent insulinotropic peptide (GIP) and glucagon-like peptide-1 (GLP-1) are secreted by specialized intestinal cells after oral intake of nutrients and, in a glucose-dependent manner, stimulate insulin secretion. In healthy individuals, they contribute about 63-74% to the incretin effect, with GIP playing a larger role than GLP-1. Despite no overall change in hormone secretion, the incretin effect is diminished, and GIP is largely ineffective in type 2 diabetes, whereas the effects of GLP-1 remain relatively unchanged. While the reasons for this difference remain to be clarified, alterations in GIP receptor expression or general beta-cell functional defects may provide a potential explanation. The ineffectiveness of GIP contrasts with the prominent effects on glycated hemoglobin (HbA(1c)) and body weight of GIP/GLP-1 co-agonists like tirzepatide in type 2 diabetes treatment, as compared to selective GLP-1 receptor agonists. The growing understanding of the secretion and biological efficacy of incretin hormones will help optimize the effectiveness of incretin-based therapeutics for treating type 2 diabetes and obesity.