- About CURE
Peter C. Butler, MD
Professor and Chief, Division of Endocrinology, Diabetes, and Hypertension, Department of Medicine, David Geffen School of Medicine at UCLA
Dr. Butler is interested in the pathophysiology of islet dysfunction and b cell apoptosis in diabetes. Given the importance of close interaction between endocrine and exocrine pancreatic functions, he also studies the relationship between diabetes, pancreatitis and pancreatic cancer, and the actions of diabetes medications on pancreatitis and pancreatic cancer risk. Pancreatic duct glands (PDGs) have been hypothesized to give rise to pancreatic intraepithelial neoplasia (PanIN). Dr. Butler and his colleagues discover that treatment with the glucagon-like peptide (GLP)-1 analog, exendin-4, induced the expansion of PDGs with mucinous metaplasia and columnar cell atypia resembling low-grade PanIN in rats. In the pancreata of Pdx1-Cre; LSL-Kras(G12D) mice, (a state-of-the-art mouse model to study PanIN biology), exendin-4 led to acceleration of the disruption of exocrine architecture and chronic pancreatitis with mucinous metaplasia and increased formation of murine PanIN lesions. PDGs and PanIN lesions in rodent and human pancreata express the GLP-1 receptor. Further studies demonstrated that exendin-4 induced proproliferative signaling pathways in human pancreatic duct cells, PKA and mitogen-activated protein kinase phosphorylation of cAMP-responsive element-binding protein, and increased cyclin D1 expression. These GLP-1 effects were more pronounced in the presence of an activating mutation of Kras and were inhibited by metformin. These data reveal that GLP-1 mimetic therapy may induce focal proliferation in the exocrine pancreas and, in the context of exocrine dysplasia, may accelerate formation of neoplastic PanIN lesions and exacerbate chronic pancreatitis. In line with these conclusions, Dr Butler examined databases for adverse events associated with the dipeptidyl peptidase-4 inhibitor sitagliptin and the glucagon-like peptide-1 mimetic exenatide. The results of these studies are consistent with the animal studies indicating an increased risk for pancreatitis with GLP-1 based therapy (Gastroenterology. 2011; 141: 150-156). The findings also raise caution about the potential long-term actions of these drugs to promote pancreatic cancer.