Incretin hormones

• a potential role for intestinal peptides in the regulation of postprandial insulin secretion was based on the observation that insulin responses to an oral glucose load exceeded those measured after intravenous administration of an equivalent amount of glucose - this was termed the 'incretin effect'
• the 'incretin effect' is attributed to the insulinotropic action of gut hormones
  • especially glucagon-dependent insulinotropic peptide (GIP) and glucagon-like peptide-1 (GLP-1) - these hormones are secreted by specialised enteroendocrine cells in response to a meal
  • studies have shown that type 2 diabetes exhibit significant reductions in the levels of meal-stimulated, circulating GLP-1 compared to healthy individuals
  • glucoregulatory effects in patients with type 2 diabetes has been achieved via the exogenous administration of GLP-1 - however the short plasma half-life (< 2 minutes) limits the potential of subcutaneous GLP-1 - GLP-1 is rapidly degradaded by the ubiquitous aminopeptidase enzyme, dipeptidyl peptidase-IV
  • GIP stimulates glucose-dependent insulin secretion and is responsible for a higher proportion of the incretin effect than GLP-1 (2)
    • was found to be a potent incretin in animals and human subjects
    • was found to be almost ineffective as an insulinotropic agent in subjects with type 2 diabetes (3)
  • differs from GLP-1 in its effect on glucagon secretion: results in increased glucagon output in the normoglycemic and hypoglycemic state, and is glucagonostatic in the hyperglycemic state
    
    
• incretin hormones promote insulin secretion and inhibit glucagon secretion when blood glucose is high; when blood glucose is low then insulin secretion is inhibited and glucagon secretion is promoted

Reference:

1. Perley M, Kipnis DM. Plasma insulin responses to oral and intravenous glucose: studies in normal and diabetic subjects. J Clin Invest 1967;46: 1954-62
2. Mishra R et al. Adverse Events Related to Tirzepatide, Journal of the Endocrine Society 2023; 7(4), https://doi.org/10.1210/jendso/bvad016
3. Nauck MA, Quast DR, Wefers J, Pfeiffer AFH. The evolving story of incretins (GIP and GLP-1) in metabolic and cardiovascular disease: A pathophysiological update. Diabetes Obes Metab. 2021; 23(Suppl. 3): 5-29. https://doi.org/10.1111/dom.14496