The pancreatic islet beta (B)-cell secretes insulin, and the hypothesis to be tested is that various forms of stress affects B-cell regulation and secretion in specific ways, and that stress responses are invoked which are protective of the B-cell. Secretion is altered when the sensitivity of the B-cell to glucose is reduced (desensitized), as in models of hyperglycemia and non-insulin-dependent diabetes mellitus (NIDDM). The B-cell may also be inhibited by other stress factors, such as cytokines, such that insulin secretion is reduced or absent, as in models of insulin-dependent diabetes mellitus (IDDM). The long-term goals of this study are to determine the signal transduction events and metabolic processes which participate in the onset of B-cell desensitization and the progression of events associated with stress responses and B-cell cytotoxicity. in vitro islet or B-cell models will be studied which mimic certain of the in vivo processes associated with forms of hyperglycemia /NIDDM or IDDM.
Aim (l) is to characterize the short and long-term desensitization/down-regulation of adenylyl cyclase in pancreatic islets during glucose-induced desensitization. Adenylyl cyclase activity and expression will be characterized in isolated islets and insulinoma cells.
Aim (2) is to define the stress response cellular mediators in B-cells. Stressors include: glucose (high or low concentrations), cytokines, heat shock and oxidative stress. Stress responses to be evaluated include: heat shock proteins, stress-activated protein kinases (SAPKs), heme oxygenase induction, adenosine monophosphate-mediated protein kinase (AMPK) and acetyl-CoA carboxylase activity, and antioxidant enzyme induction/activation. Future therapeutic strategies will benefit from increased awareness of the specific B-cell responses associated with stress.
Aim (3) is to characterize the activity and expression of phosphoinositide- and phosphatidylcholine-specific phospholipase C (PLC), during B-cell stress. PLC-derived diacylglycerol may mediate specific stress responses in B-cells related to shingomyelinase activation, ceramide production and nuclear transcription events.The importance of these studies is that novel signal transducing mechanisms will be explored in B-cells and characterized regarding their role in models of hyperglycemia and B-cell cytotoxicity. The results of these studies will increase our knowledge concerning regulatory pathways which participate in pathological as well as physiological processes associated with insulin release from the B- cell, and will lead to more complete understanding of diabetes mellitus for future therapeutic interventions involving cellular biology.
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