Kendra Seckinger, Ph.D.

Pancreatic beta cell dysfunction and insulin resistance lead to Type 2 diabetes mellitus (T2DM). Beta cells secrete insulin in response to increased plasma glucose concentrations. Loss of glucose sensitivity, particularly during the acute rise in blood glucose following a meal, can lead to peripheral tissue damage during the onset of diabetes. One aspect of beta cell dysfunction that is not well understood is how glucose sensing is disrupted during the progression of T2DM. Glucokinase (GCK) is the primary glucose sensor in the beta cell because its activity is rate-limiting for insulin secretion. Previous work in my lab has shown that GCK is post-translationally activated by nitric oxide, and this is important because S-nitrosylated GCK increases glucose sensitivity. My thesis will investigate the activation and regulation of GCK to better understand glucose sensing dysfunction in beta cells. Aim 1 will determine the activation states of GCK suggested by its molecular structure using my novel quantitative GCK FRET biosensor. Aim 2 will quantify GCK activation and regulation in primary islets of healthy and diet-induced obese diabetic mice. My preliminary data show two distinct activation states for GCK. This proposal seeks critical information regarding GCK S-nitrosylation regulatory mechanisms in beta cells during the progression of T2DM.