Diabetes mellitus is a metabolic disorder marked by impaired insulin secretion and increased insulin resistance. Loss of pulsatile insulin secretion may be an early stage in this disorder. Our long-range hypothesis is that abnormal electrical oscillations, which might in turn reflect ion channel abnormalities and/or abnormal metabolic oscillations in the beta-cell, contributes to the abnormal secretion of diabetics. Dysfunctional activity of adenosine ATP-sensitive potassium channels (KATP channels) has been linked to insulin secretion abnormalities, however, a direct link between metabolic oscillations and rhythmic KATP channel activity has not been well established. KATP channel are hypothesized to reflect oscillatory changes in glucose metabolism and modulate spike-firing patterns in islets. To investigate the role of KATP channels in the generation and/or modulation of rhythms in metabolic and electrical activity, the mitochondrial membrane dye rhodamine 123 will be used as a measure of metabolic activity combined with electrophysiological techniques to simultaneously measure 9atterns of KATP channel or electrical activity. The role of calcium in metabolic and electrical processes will also be examined. These data will be used to construct and test a new mathematical model of islet electrical activity, based on slow metabolic rhythms acting through KATP channels.
