The objective of this project is to test the importance of oscillatory B-cell metabolism in insulin secretion, and to examine whether diminution of glycolytic oscillations, due to altered PFK isoform expression or regulation, may be responsible for the diminished insulin oscillations seen in islets from the GK rat, a non-obese model of NIDDM, and in islets from high fat/sucrose-fed (HFHS) Wistar rats.
The specific aims are to determine (i) how interference with oscillatory glycolysis affects the rise in the ATP/ADP ratio and the Ca2+ and insulin secretory response of the B-cell; (ii) whether other metabolizable secretagogues (e.g., glyceraldehyde or leucine plus glutamine) stimulate oscillatory insulin secretion by effects on oscillatory glycolysis and the ATP/ADP ratio or whether their metabolism is also intrinsically oscillatory, (iii) whether GK and HFHS Wistar islets have altered PFK isoform expression and kinetics and/or changes in the levels of regulatory metabolites that could account for diminished oscillations; (iv) whether a different magnitude or time course of rise in the ATP/ADP ratio occurs in GK and HFHS Wistar islets on glucose stimulation; (v) whether the diminished oscillations in insulin secretion in a population of GK or HFHS Wistar islets are due to a loss of synchrony.
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