GLP-1 mimetic drugs and the risk of exocrine pancreatic disease: Cell and animal studies.

Abstract

Glucagon Like Peptide 1 (GLP-1) mimetic drugs or degradation inhibitors mimic the action of native GLP-1 as a incretin hormone and have become a common second line of therapy for Type 2 diabetes. However, an important clinical issue is whether these drugs increase the incidence of pancreatitis and pancreatic cancer. This paper reviews the physiology of GLP-1 including its synthesis, secretion and action of the peptide. Reported effects of the mimetic drugs on the exocrine pancreas in animal studies are also reviewed. GLP-1 is synthesized in a specific class of enteroendocrine cell, the L-cell, by post-translational processing of proglucagon. It is released in response to the presence of nutrients in the small intestine and stimulates vagal afferent nerve endings as well as entering the blood where it is rapidly degraded by dipeptidyl peptidase IV. Its actions are mediated by specific G-protein coupled receptors. The major target tissues are the pancreatic islet beta cells, the brain and the heart but GLP-1 also affects gastrointestinal motility and secretion including the exocrine pancreas where its major systemic action is to inhibit secretion. In some animal, as well as human studies, the GLP-1 mimetic drugs are associated with pancreatitis or precursor lessions to pancreatic cancer but a mechanism is not clear. The most common occurrence of pathology in rodents is when the drugs are combined with a high fat diet. There is nothing in the physiology of GLP-1 or animal toxicology studies to support a mechanism of action or a major concern about the action of GLP-1 mimetic drugs on the exocrine pancreas. Further studies are warranted using animal models of disease and high fat diets.