14.01.8 Glucagon-Like Peptide-1, Exenatide and Sitagliptin

Recently, there have been some very interesting findings relating to the treatment of diabetes, and they stem from the discovery of a new hormone, known as Glucagon-Like Peptide-1 (GLP-1). GLP-1 is produced by the gut, and has a major role in controlling glucose levels. GLP-1 stimulates insulin secretion, and inhibits glucagon secretion, both of which will lead to a decrease in glucose levels (Figure 14.4).

Figure 14.4 GLP-1, exenatide and sitagliptin (Copyright QUT, Sheila Doggrell)

This discovery led to a new treatment for diabetes, exenatide. Exenatide is a peptide agonist at GLP-1 receptors which mimics the effects of GLP-1, and so it stimulates insulin secretion while inhibiting glucagon secretion. Exenatide is used subcutaneously, prior to a meal. Exenatide is used when there is a lack of control of type 2 diabetes with treatment with metformin and a sulfonylurea (glibenclamide). In time, exenatide may replace these agents in the treatment of type 2 diabetes. Hypoglycemia is an unwanted effect with exenatide.

Glucagon-Like Peptide-1 (GLP-1) is broken down, which leads to inactivation, by the enzyme dipeptidyl peptidase-4 (DPP4). Sitagliptin is an inhibitor of dipeptidyl peptidase-4, and inhibition of the enzymes leads to the build up of GLP-1. Thus, the end result with sitagliptin is to mimic the effects of GLP-1 to increase insulin secretion and inhibit glucagon secretion. Sitagliptin is active after oral administration, and is increasingly often used in combination with other anti-diabetic drugs such as metformin or sulfonylurea (glibenclamide) or pioglitazone. Sitagliptin is capable to causing the adverse effect of hypoglycaemia but this occurs mainly when they are used with a sulfonylurea.