Glucose Mediated Regulation of Beta Cell Proliferation

The pancreatic beta cell, as the sole source of circulating insulin, is indispensible for normal glucose metabolism. All forms of diabetes are characterized by insufficient insulin to meet metabolic needs, and inadequate beta cell mass is present in most forms of diabetes. Beta cell regenerative therapies provide one potential avenue for the prevention or cure of diabetes. Study of the pathways and mechanisms involved in endogenous beta cell proliferation can provide important clues to how regeneration occurs. Glucose is one important regulator of beta cell replication. Here we review the published literature investigating the effect of glucose on beta cell proliferation, and then describe the data supporting various known mechanisms of action. First, in vitro studies on fetal and adult beta cells from rodents and humans are reviewed. Next, we review evidence that circulating blood glucose regulates beta cell proliferation in living animals. These studies encompass a variety of in vivo models, including dietary manipulation, partial pancreatectomy, intravenous infusion of glucose, islet transplantation, and studies on diabetic hyperglycemia. Finally, mechanistic studies, both in vitro and in vivo, point to several different mitogenic pathways activated by glucose. Especially prominent are insulin signaling pathway members, glucose metabolism, and glucose impact on signaling by other growth factors. Multiple unanswered questions remain, and are highlighted throughout. With today's technologies we can now address questions first raised in the early 1900s, and hopefully develop new approaches to assuage the devastation of clinical diabetes.