The project's long term objective is to continue research on the role of glucose metabolism and calcium in stimulus-secretion coupling in insulin secretion. Glucose is the most potent insulin secretagogue and calcium is believed to be and important intracellular messenger in the pancreatic beta cell. Preliminary evidence that calcium may influence glucose metabolism, contractile proteins, protein phosphorylation and phospholipid metabolism in pancreatic in pancreatic islets and the relationships between these factors will be pursued. Mitochondrial glycerol phosphate dehydrogenase is a calcium-activated enzyme that is highly active in rat pancreatic islets and the enzyme is inhibited by diazoxide, and inhibitor of insulin release. Studies of this enzyme in human insulin secreting tissues will be continued. Studies will be continued that are designed to give clues about whether glucose stimulates discernable patterns of protein phosphorylation and of phospholipid metabolism in intact islets and how calcium may mediate these processes. Contractile proteins may power insulin granule movements within the beta cell. Pancreatic islets contain myosin light chain kinase, a calcium-calmodulin-activated enzyme that catalyzes phosphorylation of smooth muscle myosin enabling myosin ATPase to be activated by actin so contraction can occur. Studies are planned to partially characterize calcium-activated protein kinases in islets, including those that may catalyze phosphorylation of myosin. Juvenile (Type I) diabetes is caused by insulin deficiency due to beta cell destruction or malfunction. Whether the pathologic process originates in the beta cell or elsewhere in the body is unknown. Suspected causes of adult-onset (Type II) diabetes include insulin resistance, in which insulin production by the beta cell is unable to keep pace with the body's requirements, and also primary metabolic abnormalities of the beta cell. Since the exact causes of beta cell malfunction in these disorders are unknown, any research directed at elucidating the normal physiology of the beta cell is important in understanding its pathophysiology. In addition, a better understanding of beta cell metabolism may be helpful to researchers interested in preserving beta cells in tissue culture for therapeutic purposes, such as transplantation.
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