7th Obesity & Endocrinology Specialists Congress

Biography

Biography: Caroline Bonner

Abstract

There are 60 million people with type 2 diabetes (T2D) in Europe. Obesity contributes to 65-80% of new cases of T2D. T2D is a complex metabolic disorder, the pathogenesis of which is not understood. Impaired insulin sensitivity, hyperglucagonemia, endogenous glucose production and islet cell dysfunction are major traits of the disease, but the sequence of events leading to hyperglycemia remains unclear. For decades, the mechanisms by which nutrients stimulate insulin secretion have been studied extensively, whilst the neighboring alpha (which secrete glucagon) have been ignored. A renewed interest in the regulation of glucagon secretion has been re-discovered since reports of elevated glucagon levels in T2D patients, by unexplained mechanisms. We have recently discovered SGLT2, which is specifically expressed in pancreatic alpha cells. Notably, inhibition of SGLT2 with dapagliflozin resulted in a marked increase (more than 83%) of glucagon secretion at glucose concentrations of 6 mM. Given the biochemical properties of SGLT2 (Km~6 mM), these data suggested that the SGLT2 glucose transporter is very effective in preventing hypoglycemia. Importantly, human islets co-treated with 15 mM glucose and dapagliflozin had no effect on glucagon secretion, thus suggesting that there are other glucose transporters (most likely the GLUTs) present on alpha cells, which are effective in hyperglycemia. Indeed, the specific expression and function of GLUT transporter proteins in human vs. rodent islets are conflicting and confusing. So given the known increased risk for T2D, understanding the complex pathways underlying glucose transport defects and islet hormone dysfunction in human should now become a priority for European healthcare.