Non-insulin-dependent diabetics have impaired glucose-dependent insulin secretion. Our general hypothesis is that abnormal islet beta-cell calcium channel activity is an intrinsic lesion that contributes to this secretory impairment. In normal islets, a rise in plasma glucose causes different beta-cell ion channels to interact to produce a characteristic pattern of membrane electrical activity called bursting. Bursting consists of cycles of rapid voltage spiking superimposed on slow depolaring voltage plateaus. Both the spikes and the plateaus are dependent on Ca channel activity and mediated the Ca uptake necessary for insulin release. However, the role of Ca channels and other ion channels in normal burst production is unclear. Our working hypothesis is that bursting results from the periodic slow inhibition or inactivation of Ca channel activity by membrane depolarization (Ca Channel Hypothesis). Alternatively, Ca influx may lead to the cyclic activation of Ca- activated potassium (K) channels (KCa Hypothesis) or ATP-sensitive K channels (Ca-KATP Hypothesis). The coupling between cell fuel metabolism and electrical activity is hypothesized to result from metabolite modulation of Ca and KATP channel activity. The feasibility of our diabetes hypothesis will be tested by determining whether abnormal Ca channel activity is a primary lesion in the db/db diabetic mouse model and can produce abnormal electrical activity and secretion by altering intracellular free [Ca]signalling. Ion channel recording techniques combined with a new type of experimental protocol, computer modelling of beta-cell electrical activity and intracellular free [Ca] measurements will be used to test these hypotheses in normal and diabetic mouse beta- cells.
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