Gut Peptide Alterations in Type 2 Diabetes and Obesity: A Narrative Review

PURPOSE OF REVIEW: The gastrointestinal tract acts as an endocrine organ, releasing hormones that regulate glucose homeostasis, appetite, energy expenditure, and gastrointestinal motility. In type 2 diabetes (T2DM) and obesity, this finely tuned hormonal system is disrupted, contributing to metabolic dysfunction. This review summarizes current evidence on fasting and postprandial responses to mixed-meal tests (MMT) and oral glucose tolerance tests (OGTT) of proglucagon-derived peptides (PGDPs), orexigenic and anorexigenic hormones, and less frequently studied gastrointestinal peptides in individuals with T2DM and obesity compared with healthy controls. RECENT FINDINGS: Studies demonstrate that while GLP-1 levels are often preserved, its insulinotropic and glucagonostatic actions are impaired in T2DM and obesity. GIP secretion is maintained or increased but exhibits reduced biological efficacy. Oxyntomodulin and GLP-2 show blunted postprandial responses, whereas glicentin, GRPP, and MPGF remain poorly characterized but appear dysregulated. PYY is reduced in obesity and shows impaired postprandial rises in T2DM, while PP is frequently elevated in T2DM. CCK resistance may diminish satiety signaling, though secretion data are inconsistent. Secretin and amylin exhibit complex, stage-specific alterations, whereas ghrelin and obestatin are typically reduced in both conditions. Gut hormone alterations in T2DM and obesity include both adaptive and pathogenic features, reflecting disruptions across multiple peptide systems. Standardization of peptide measurements and deeper investigation into their mechanistic roles will be essential for advancing precision-based interventions targeting gastrointestinal hormones in metabolic disease.