Searchable abstracts of presentations at key conferences in endocrinology
Endocrine Abstracts (2008) 15 S41

Aston University, Birmingham, UK.


The incretin concept refers to components of the entero-insular axis that enhance the insulin response to a meal. The incretin effect is mostly attributed to the gut hormones glucagon-like peptide-1 (GLP-1) and glucose-dependent insulinotropic polypeptide (GIP). The incretin effect is reduced in type 2 diabetes, and this appears to be due largely to reduced secretion of GLP-1. GLP-1 increases glucose-stimulated insulin secretion by pancreatic β-cells, reduces glucagon secretion from pancreatic α-cells in a glucose dependent manner, slows gastric emptying and exerts a satiety effect. Animal and in vitro studies have suggested that GLP-1 might also preserve or increase β-cell mass. Since the biological actions of GLP-1 remain essentially intact in type 2 diabetes, administration of extra GLP-1 is a potential therapeutic approach. However, GLP-1 is rapidly degraded by the enzyme dipepidyl peptidase IV (DPP-4) which breaks the peptide at the N2 alanine residue.

GLP-1 mimetics. To counter the effect of DPP-4, GLP-1 analogues have been developed with a different N2 residue that confers resistance to degradation by DPP-4. Additional modifications have been introduced to further extend the biological half-life. The first DPP-4 resistant GLP-1 analogue to be introduced was exenatide, introduced in the UK in 2007. This retains the biological effects of GLP-1, and twice daily subcutaneous injection typically enables a reduction in HbA1c approaching 1%, without causing significant hypoglycemia (except in combination with another insulin-releasing therapy) and accompanied by a reduction in body weight. Longer-acting formulations of exenatide and other prolonged-action GLP-1 mimetics such as liraglutide (GLP-1 linked to albumin via a fatty acid) are advanced in development. Nausea with these agents requires gradual dose titration, and emergence of antibodies in some patients has rarely affected efficacy.

DPP-4 inhibitors. To prevent the rapid degradation of endogenous GLP-1 and GIP, several inhibitors of DPP-4 (termed ‘gliptins’) have been developed. They reduce HbA1c, carry low risk of hypoglycemia and do not cause weight gain.

Sitagliptin was introduced in the UK in 2007, and other gliptins, notably vildagliptin, saxagliptin and alogliptin are near completion of pre-registration trials. As tablet preparations they are convenient to take, and fixed-dose combinations with metformin have been developed. Although DPP-4 is the CD26 receptor, immune side effects have not been reported.

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