The molecular mechanisms of incretin resistance in Type 2 Diabetes Mellitus (T2DM)

Incretin hormones, specifically glucagon-like peptide-1 (GLP-1) and glucose-dependent insulinotropic polypeptide (GIP), serve as crucial mediators of postprandial glucose homeostasis by primarily enhancing glucose-stimulated insulin secretion. Research indicates that the incretin effect accounts for approximately 50% of insulin secretion in individuals without diabetes, which is significantly reduced to 30% or less in those with Type 2 Diabetes Mellitus (T2DM). The mechanisms underlying this incretin resistance have emerged as critical causes of postprandial hyperglycemia. Incretin-based therapies, including GLP-1 receptor agonists (GLP-1RAs) and DPP-4 inhibitors, have demonstrated efficacy in managing T2DM; however, intrinsic resistance mechanisms may limit their effectiveness. Understanding the processes by which T2DM affects incretin action, from hormone secretion to the modulation of signal transduction, is essential for optimizing current therapies and developing new interventions to enhance β-cell responsiveness and improve glycemic control. The concept of incretin resistance has a well-established history in literature, dating back to at least the early 1990 s. It is used to describe a reduced insulinotropic responsiveness to incretin hormones in individuals diagnosed with T2DM. This review examines how hyperglycemia, chronic inflammation, and genetic susceptibility collectively inhibit incretin signaling through distinct yet interconnected molecular pathways. This impairment exacerbates postprandial hyperglycemia and accelerates β-cell dysfunction. We propose novel hypotheses regarding selective β-arrestin signaling, enhancers, epigenetic regulation, interactions between gut microbiota and incretins, inflammation-induced endoplasmic reticulum (ER) stress, and genotype-specific therapeutic responses. The hypotheses presented in this review serve as a framework for future research and therapeutic development to combat the phenomenon of incretin resistance and improve the clinical management of T2DM.