Treatments for Type 2 Diabetes

G lucagon-like peptide-1 (GLP-1) is produced by the proglucagon gene in L-cells of the small intestine in response to nutrients.1 It is an incretin – a gut hormone – that is responsible for the greater insulin response to oral versus IV glucose.2 Its major mechanism of action occurs through stimulation of glucose-dependent insulin release from the pancreatic islets. In addition to its insulinotropic effects, GLP-1 is thought to exert glucose-lowering effects by slowing gastric emptying,3 inhibiting inappropriate glucagon release,4 stimulating betacell proliferation5 and differentiation,6 as well as improving satiety7 (Table 1). In type 2 diabetes, GLP-1 levels are decreased,8 insulin secretion is delayed and diminished and gastric emptying is paradoxically accelerated.9 Glucagon levels are also inappropriately elevated in the fasting state and lack normal postprandial suppression.10 Agents that increase GLP-1 activity may help to correct these abnormalities. In clinical trials, GLP-1 effects are evident regardless of the duration or severity of diabetes.11 Modulating GLP-1 levels and GLP-1 activity through administration of the native hormone, analogues and mimetics, or by inhibiting its degradation, has become a major focus of investigation to develop treatments for type 2 diabetes. GLP-1 binds to a seven-transmembrane G-protein-coupled receptor of a subfamily that includes receptors for secretin, vasoactive intestinal peptide (VIP) and gastric inhibitory peptide.12 The receptor is found on pancreatic periductal and beta-cells, as well as the kidney, heart, stomach and brain.13 Glucagon-like peptide receptor (GLP-1R) knockout mice have fasting hyperglycemia and abnormal glucose tolerance but are not obese.14 GLP-1 exhibits a relatively short half-life of 1 to 2 minutes that necessitates continuous infusion to achieve steady-state in pharmacologic studies.15 This is attributed to N-terminal degradation by the enzyme dipeptidyl peptidase IV (DPPIV).1 Mice lacking DPP-IV exhibit reduced food intake, improved insulin sensitivity and attenuated decline in beta-cell mass.16 Current research focuses on agents that increase GLP-1 via inhibition of DPP-IV and on GLP-1 analogues that are resistant to DPP-IV degradation.