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.

Agency
National Institute of Health (NIH)
Institute
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Type
Research Project (R01)
Project #
5R01DK025705-20
Application #
2733988
Study Section
Special Emphasis Panel (ZRG2-NTN (01))
Program Officer
Laughlin, Maren R
Project Start
1979-07-01
Project End
2001-06-30
Budget Start
1998-07-01
Budget End
1999-06-30
Support Year
20
Fiscal Year
1998
Total Cost
Indirect Cost
Name
State University of New York at Buffalo
Department
Pharmacology
Type
Schools of Dentistry
DUNS #
038633251
City
Buffalo
State
NY
Country
United States
Zip Code
14260
Laychock, Suzanne G; Tian, Yingrao; Sessanna, Shawn M (2003) Endothelial differentiation gene receptors in pancreatic islets and INS-1 cells. Diabetes 52:1986-93
Tian, Yingrao; Laychock, Suzanne G (2003) Prolactin regulates adenylyl cyclase and insulin secretion in rat pancreatic islets. Mol Cell Endocrinol 204:75-84
Srinivasan, Malathi; Laychock, Suzanne G; Hill, David J et al. (2003) Neonatal nutrition: metabolic programming of pancreatic islets and obesity. Exp Biol Med (Maywood) 228:15-23
Lee, B; Srinivasan, M; Aalinkeel, R et al. (2001) Mitochondrial-encoded gene regulation in rat pancreatic islets. Metabolism 50:200-6
Lee, B; Gai, W; Laychock, S G (2001) Proteasomal activation mediates down-regulation of inositol 1,4,5-trisphosphate receptor and calcium mobilization in rat pancreatic islets. Endocrinology 142:1744-51
Tian, Y; Laychock, S G (2001) Protein kinase C and calcium regulation of adenylyl cyclase in isolated rat pancreatic islets. Diabetes 50:2505-13
Srinivasan, M; Aalinkeel, R; Song, F et al. (2000) Adaptive changes in insulin secretion by islets from neonatal rats raised on a high-carbohydrate formula. Am J Physiol Endocrinol Metab 279:E1347-57
Laychock, S G; Duzen, J; Simpkins, C O (2000) Metallothionein induction in islets of Langerhans and insulinoma cells. Mol Cell Endocrinol 165:179-87
Lee, B; Laychock, S G (2000) Regulation of inositol trisphosphate receptor isoform expression in glucose-desensitized rat pancreatic islets: role of cyclic adenosine 3',5'-monophosphate and calcium. Endocrinology 141:1394-402
Lee, B; Jonas, J C; Weir, G C et al. (1999) Glucose regulates expression of inositol 1,4,5-trisphosphate receptor isoforms in isolated rat pancreatic islets. Endocrinology 140:2173-82

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