Incretin effect (revision 48)

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]

GLP-1 and GIP together account for the incretin effect through glucose-dependent potentiation of insulin secretion. Neither hormone stimulates insulin secretion at low glucose concentrations, a feature that minimizes hypoglycaemia risk compared to insulin secretagogues like sulfonylureas, which do so.^[2]

GLP-1 is secreted by L cells of the distal small intestine and colon, in response to glucose, fat and amino acids. Its plasma half-life is approximately 2 minutes due to rapid inactivation by Dipeptidyl peptidase-4. GIP is secreted earlier, by K cells of the duodenum and proximal jejunum, and has a half-life of approximately 7 minutes. The two hormones act through distinct receptors on beta cells; both couple to adenylyl cyclase and raise intracellular cAMP, but through non-identical signalling cascades, and each contributes approximately equally to the total incretin effect in health.^[3]

The incretin effect is usually quantified as a percentage:

\text{Incretin effect} = (I_\text{oral} - I_\text{iv}) / I_\text{oral} \times 100\%

where I_\text{oral} is the integrated insulin secretion over 2–3 hours following oral glucose, and I_\text{iv} is that following intravenous glucose at matched glucose kinetics.^[3]

Measurement requires both an oral glucose-tolerance test and a euglycaemic-hyperglycaemic clamp on separate days. Because the clamp is labour-intensive and requires careful blood sampling, the incretin effect is not routinely measured in clinical practice; it is a research tool for mechanistic investigations and for assessing drug effects.

In type 2 diabetes, the incretin effect is reduced to approximately 10–30% of the normal value. This is a primary pathophysiological lesion rather than a secondary consequence of hyperglycaemia, as it is present early in the course of the disease, in first-degree relatives of affected individuals, and in people with impaired glucose tolerance.^[5]

The defect is asymmetric: GIP-mediated insulin secretion is lost disproportionately, whereas GLP-1 responsiveness is better preserved, though also impaired. This asymmetry is clinically important: it explains why GLP-1-directed drugs work as monotherapy in type 2 diabetes whereas GIP-directed drugs do not, and why the later addition of GIP agonism to GLP-1 monotherapy produces further benefit.^[3]

• Glucagon-like peptide-1
• Glucose-dependent insulinotropic polypeptide
• Beta cell function
• Dual incretin agonist

• Campbell JE, Drucker DJ. "Pharmacology, physiology, and mechanisms of incretin hormone action." Cell Metabolism 17(6):819–837 (2013).