Essay for the 2011 CIHR/CMAJ award: glucagon-like peptides for metabolic and gastrointestinal disorders

Type 2 diabetes arises as a result of insufficient insulin production, commonly in the setting of impaired insulin action. Type 2 diabetes and obesity are major health problems that often affect the same patient. These conditions are increasing in prevalence and are associated with substantial health care costs, impaired quality of life, and considerable morbidity and mortality. The available treatments for these metabolic disorders have traditionally been complicated by incomplete efficacy, the need for frequent and expensive self-monitoring of blood glucose levels and associated adverse effects such as weight gain and hypoglycemia. Because the successful treatment of diabetes is directly associated with a decrease in its related complications, improvements in controlling blood glucose levels lead directly to enhanced quality of life for patients with diabetes.

I have studied how gastrointestinal hormones control the ingestion, absorption and disposal of nutrients for more than 25 years. In 1987, as a research fellow funded by the Medical Research Council, I described the action of a novel peptide hormone, glucagon-like peptide-1 (GLP-1), on insulin-producing islet cells.1 Glucagon-like peptide-1 directly stimulates the synthesis and secretion of insulin from islet cells. These findings yielded a new area for biologic investigation, namely the physiologic relevance and biologic activity of GLP-1 and related peptides. Since that discovery, my research has delineated how GLP-1 acts in the body to control the growth and survival of islet β cells, the regulation of food intake and body weight, and the function and survival of cardiovascular tissues.2^–4 My work has shown how this hormone works in the immune system and in the control of postprandial lipid metabolism.5^,6 The Drucker laboratory has generated novel mouse models lacking GLP-1 activity, permitting the delineation of the endogenous physiologic importance of the GLP-1 system in multiple tissues.7^–9 My work also described the importance of the enzyme that degrades GLP-1, dipeptidyl peptidase-4 (DPP-4), showing that genetic elimination of DPP-4 produces healthy mice with improved insulin secretion and better glucose control.10

As a result of these studies and related investigations by other leading scientists, the pharmaceutical industry has developed two new classes of drugs to treat type 2 diabetes, which are based on the potentiation of GLP-1 activity.11 The first approved GLP-1 receptor agonist, exendin-4, was discovered by John Eng, and my team and I cloned the gene encoding the protein.12 The Drucker laboratory has published numerous papers showing the glucoregulatory and metabolic actions of GLP-1 in experimental models of diabetes. Because exendin-4 must be injected twice daily, and because a more recently approved agent, liraglutide, requires injection only once daily, I led the first Phase III trial of a once-weekly version of exendin-4. This drug, exenatide, has been approved for use in Europe, with approval in North America expected soon.13

A second class of drugs based on GLP-1 activity, the DPP-4 inhibitors, was approved in 2007. These drugs lower blood glucose levels by inhibiting the enzymatic breakdown of GLP-1, thereby prolonging its action. Multiple DPP-4 inhibitors, which can be taken once daily in tablet form, have been approved for the treatment of diabetes.