Unraveling the role of notch signaling in adult pancreatic beta cells

Insulin is a hormone required for glucose utilization by the body, and is only produced by the beta cells of the pancreas. In obesity, the body cannot properly respond to normal insulin levels, leading to a condition known as 'insulin resistance'. Insulin resistance has no symptoms by itself, as beta cells face the challenge of maintaining normal glucose levels by increasing insulin supply, but as beta cells progressively fail to meet the increased insulin demand, circulating glucose levels rise, resulting in the diagnosis of Type 2 Diabetes (T2D). T2D is very common in our society, as beta cells are a limited resource, unable to replicate themselves with high efficiency and with a finite ability to increase insulin production. The studies described in this application are designed to help understand the mechanisms responsible for beta cell adaptation to insulin resistance, and attempt to answer several key thus far inadequately addressed questions - why do these mechanisms fail, and can T2D progression be halted, even reversed, if beta cell function is preserved or beta cell replication can progress unimpeded? The project is centered on the study of signals that are required for pancreas formation during embryonic development, testing the hypothesis that these 'embryonic signals' are required for normal functioning of beta cells during adult life, and especially in conditions such as insulin resistance. The overall objective is to identify novel therapeutic targets and prevention strategies that prevent or treat T2D.