GLP-1–Based Therapies and the Exocrine Pancreas: More Light, or Just More Heat?
- Department of Diabetic Medicine, University of Bristol, Bristol, U.K.
- Corresponding author: Edwin A.M. Gale, edwin.gale{at}bristol.ac.uk.
GLP-1–based therapies are the most promising new treatment for type 2 diabetes to have been introduced in recent years. Long-term outcome studies are not yet available, but in the interim they have cleared many—although not all—of the hurdles for acceptability, efficacy, and safety. GLP-1 is a proglucagon-derived peptide secreted from the L cells of the gut in response to food. It is rapidly inactivated by dipeptidyl peptidase-4 (DPP-4) enzymes following secretion. The fraction of intact GLP-1 that survives enzymatic degradation boosts the insulin response to oral glucose, accounting for much of the incretin effect. Inhibition of DPP-4 enhances the physiological GLP-1 response to food and lowers circulating glucose without inducing hypoglycemia. The long-term consequences of inhibition of DPP-4—a widely distributed protease whose substrates include neuropeptides and chemokines—are unknown, but the safety profile of this class of agent currently appears favorable (1).
Native GLP-1 has a short half-life in the circulation and is therefore unsuitable for clinical use. This has prompted development of analogs that are both resistant to degradation and appropriate for use at pharmacological doses. These have proved remarkably effective in reducing body weight as well as plasma glucose and have been particularly useful in obese individuals who might otherwise have been candidates for bariatric surgery. The main side effects that have been reported are nausea and vomiting, and in some cases they are so severe as to lead to circulatory collapse and cardiovascular or renal problems (2). Animal safety studies with liraglutide have identified a higher than expected number of cases of a rare C-cell carcinoma of the thyroid (3), and acute pancreatitis has been reported in humans treated with liraglutide or exenatide (4).
GLP-1 receptors are abundant on pancreatic β-cells, an observation that gave rise to the hope that GLP-1–based therapies would induce pancreatic β-cell …
