Issue: 2007 > February > review

Incretins: a new treatment option for type 2 diabetes?

P.H.L.M. Geelhoed-Duijvestijn


This article describes how the discovery of a protein almost 100 years ago led to a clinical treatment for
type 2 diabetes. Food intake, but also stimulation of the sympathetic nervous system (for example physical
exercise), stimulates the secretion of glucagon-likepeptide-1 (GLP-1), derived from the glucagon precursor proglucagon in the small intestine. GLP-1 stimulates the production and secretion of insulin, the release of somatostatin, glucose utilisation by increasing insulin sensitivity and in animal studies also β-cell function and expansion (proliferation). It inhibits glucagon release, gastric emptying, appetite and food intake via the central nervous system and in animal experiments also apoptosis of β-cells. Since GLP-1 has to be administered parenterally and its half-life is short, a long-acting GLP-1 receptor agonist (exenatide) and a long-acting GLP-1 analogue (liraglutide) have been developed as well as an inhibitor of DPP-IV (the
enzyme that breaks down endogenous GLP-1). Clinical
studies with exenatide and liraglutide as monotherapy
show a significant increase in the postprandial insulin concentration as well as a smaller increase in the postprandial glucose values. Adding these drugs to standard oral glucose-lowering medication shows
improvement in glucose and insulin concentrations and
HbA1c compared with adding placebo. The effect of
exenatide on HbA1c is the same as adding a long-acting
insulin analogue (glargine), but the increase in weight
after adding insulin is not seen after exenatide, where even a small decrease in weight is found. This is an important advantage, because most type 2 patients are already obese. Whether less β-cell apoptosis and maintenance of β-cell function occurs, as has been shown in animal studies, has to be awaited. Clinical studies with the oral dppiv inhibitors sitagliptin and vildagliptin show promising results, but are only published as abstracts at scientific meetings.