Incretin effect (revision 15)

The incretin effect is the observation that oral intake of glucose evokes a substantially larger insulin secretory response than intravenous infusion of glucose at an identical glycaemic excursion. This difference was first documented in the early 20th century but was not explained until the 1960s, when two peptide hormones secreted by the small intestine — Glucagon-like peptide-1 (GLP-1) and Glucose-dependent insulinotropic polypeptide (GIP) — were shown to potentiate insulin secretion in response to nutrients.^[1]

In healthy adults, the incretin effect accounts for approximately 50–70% of the total insulin secretion that follows oral glucose intake. The remaining 30–50% comes from direct stimulation of beta cells by the rising blood glucose itself, termed the glucose-stimulated response. This dual-mechanism design — nutrient-sensing via hormones, plus direct glucose sensing — confers tight glycaemic control in the postprandial state while minimizing the risk of hypoglycaemia when glucose is low.^[2]

In type 2 diabetes, the incretin effect is markedly reduced, accounting for only 10–30% of the insulin secretory response. This defect is a primary lesion in the pathophysiology of the disease and is the mechanistic rationale for GLP-1-directed and dual-agonist therapeutics, which restore or amplify this pathway.^[3]

The observation that oral glucose intake provokes a larger insulin response than intravenous glucose at matched glycaemic levels was documented in the 1920s, but the mechanism was unknown for over 40 years. Early hypotheses included a direct effect of the intestinal mucosa on the pancreas (Loewi's "enteroinsular axis") and nervous reflexes, but these remained speculative until the insulin-secreting peptide hormones of the gut were isolated and characterized.^[1]

Glucagon, isolated in 1923, was the first gut hormone to be recognised, but its insulinotropic effect is glucose-independent and was therefore insufficient to explain the oral-glucose phenomenon. The isolation and characterization of GLP-1 (in the early 1980s) and the demonstration of its glucose-dependent insulinotropic properties resolved the question. GIP, previously known only as a gastric-inhibitory peptide, was subsequently recognised to be the second arm of the incretin axis.^[4]