The Mathematical Biology and Dynamical Systems Seminar presents Craig Nunemaker on ” Glycolytic hyperactivity as a driving force in the dysfunctional oscillatory behavior of pancreatic islets” on Tuesday, Nov. 14, from 3:05 to 4 p.m. in Morton 218.
Dr. Craig Nunemaker
Nunemaker is Associate Professor with the Diabetes Institute and the Department of Biomedical Sciences in the Heritage College of Osteopathic Medicine at Ohio University.
Abstract: Type 2 diabetes (T2D) is a costly and devastating metabolic disorder that affects over 25 million Americans. Insulin is crucial to maintaining normal metabolism and blood glucose levels. Insulin is only made by beta-cells within micro-organs in the pancreas called Islets of Langerhans. Identifying early pathological changes in these insulin-producing islets that contribute to the onset of T2D is important to intervening before the disease ensues. Two early signs of T2D before the onset of hyperglycemia are: (1) a condition of relative hyperinsulinemia caused by a shift to the left in the sensitivity of beta-cells to glucose (increased sensitivity), which results in increased insulin release during fasted conditions and potentially impaired insulin secretion in elevated glucose. (2) A disruption in pulsatile insulin secretion. Our data suggest that these two early signs of T2D both may be caused by excessive glycolytic activity. Specifically, we showed that islets isolated from diabetic (db/db) mice have left-shifted glucose sensitivity and disruptions in the pulsatile activity in 11mM (post-meal) glucose. However, when these islets are exposed to only 5mM glucose (near fasting) or when glycolytic rates are reduced, pulsatility is restored, glucose sensitivity is shifted back to normal, and insulin secretion is improved in the diabetic islets, while normal islets become inactive in 5mM glucose as expected. These data suggest that islets from diabetic mice may not display normal pulsatile function in normal fed conditions, but the capacity to generate such coordinated and rhythmic activity is still maintained. Our central hypothesis is that a disruption in normal islet pulsatility prior to T2D is due to excessive glycolytic activity in the beta-cell; thus reducing glycolytic enzyme activity will restore normal islet function before the disease progresses to hyperglycemia. Our work to date suggests that reducing excess glycolytic activity by partially blocking glucokinase enzyme activity can fully restore normal oscillations and insulin secretion in islets isolated from diabetic mice. This work provides unique insight into the pathology of islet dysfunction prior to developing T2D.
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