The broad long term objectives of the research are to understand in detain the mechanisms by which glucose stimulates insulin secretion. In its action to stimulate insulin release, glucose depolarizes the cell by closing ATP-sensitive K+ channels (KATP channels) and thereby increases the rate of Ca2+ entry into the cell via activation of voltage- dependent Ca2+ channels. The raised intracellular Ca2+ concentration (Ca2+)i stimulates insulin secretion. This pathway of glucose signaling is described as the KATP-channel dependent pathway. However, glucose has at least one other effect by which it powerfully augments the released caused by increased (Ca2+)i. This is due to a KATP channel-independent pathway of glucose signaling. In this study, the emphasis will be on the latter pathway and the mechanisms by which is augments release. There is strong evidence that the KATP channel-independent augmentation of insulin release by glucose is responsible for the second phases of glucose stimulated insulin release and also for time dependent potentiation (TDP). Mechanistically, there is evidence that the augmentation pathway may be due to a glucose induced build up of malonyl CoA, inhibition of carnitine palmitoyl transferase I and of fatty acid oxidation, and a consequent increase in cytosolic long chain acyl CoA ester build up. As there is considerable evidence that also links TDP to the activation of PKC isoforms, the putative role of PK isoforms in the mechanism of glucose augmentation will be studied. Finally, as the signaling pathways of stimulation and augmentation exert their final effects on exocytosis, the mechanisms of exocytosis will be studied. The work, which include measurements of insulin secretion, the translocation and activity of PKC isoforms, and studies on docking, priming and exocytosis of secretory granules, will be performed on b-cell lines and rodent islets. The information gained on these mechanisms by which glucose stimulates insulin secretion will be of value in the understanding and treatment of those diseases in which insulin release is defective, whether the defect results in hypo- or hyper-insulinemia.
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