The Incretin Effect

The incretin effect is measured by a deliberately awkward experiment. A person drinks glucose while plasma glucose is tracked; on another day glucose is infused intravenously to reproduce that identical curve. The oral route produces far more insulin despite matched glycaemia, and the difference belongs to gut hormones released by nutrient arrival rather than to glucose itself. In healthy people it accounts for the majority of the insulin response to a meal, commonly quoted at between half and two thirds.

The two hormones responsible are GLP-1 from intestinal L-cells and GIP from K-cells, both cut within minutes by DPP-4. The isoglycaemic experiments that established the effect date to the 1960s; the finding that reshaped drug development came later. In type 2 diabetes the incretin effect is markedly blunted, with the insulinotropic action of GIP largely lost while GLP-1 keeps its effect at pharmacological concentrations. That asymmetry is why GLP-1 receptor agonists became glucose-lowering drugs and infused GIP did not, and why tirzepatide, a dual agonist reopening GIP, was a genuine surprise.

It follows that oral and intravenous glucose tolerance tests measure different physiology and their insulin data are not comparable. It also sets the ceiling on any intervention working by release of endogenous incretins rather than by supplying an agonist.

Incretin has drifted into a brand category for weight-loss injections generally, obscuring the mechanism. Two further inferences do not hold. A reduced incretin effect in type 2 diabetes is at least partly a consequence of hyperglycaemia rather than a proven cause of it. And DPP-4 inhibitors, which raise endogenous incretin concentrations only modestly, produce far smaller glycaemic and no meaningful weight effects: the same axis at very different exposure is a different drug class.