Insulin secretion from beta cells of islets of Langerhans is mediated by second messengers such as cyclic AMP, cyclic CMP, calcium, inositol trisphosphate, diacylglycerol, and fatty acids. Nitric oxide generated from L-arginine by nitric oxide synthase is a recently identified mediator of cell activity. Normally, glucose stimulates insulin secretion. However, continuous glucose stimulation leads to a desensitization of the beta cell secretory response. Nitric oxide may also support insulin release under normal conditions, but in high concentrations induces cytotoxicity. In this project, freshly isolated islets, and in vitro models of glucose- induced beta cell desensitization mimicking non-insulin dependent diabetes mellitus (NIDDH), and cytokine-induced nitric oxide toxicity mimicking insulin -dependent diabetes mellitus (IDDM) will be investigated for the role of specific second messengers and metabolic pathways in beta cell function. Nitric oxide synthases will be characterized and various pharmacological agents investigated for possible protective activity against nitric oxide cytotoxicity. These studies will also determine whether heterologous desensitization of adenylate cyclase accounts in part for desensitization of insulin release, glucagon sensitivity and glycogen metabolism. The role of adenylate cyclase in mediating the beta cell responses to atrial natriuretic factor (ANF) receptor stimulation will be explored in order to define the role of cyclic GMP and cyclic AMP. Subtypes of ANF receptors will be characterized. The role of myo-inositol transport, Na+,K+-ATPase activity, phospholipase C and inositol trisphosphate production in glucose desensitization will also be determined since these cell activities play an important role in mobilizing and maintaining cellular Ca2+ levels and secretion. Whether the polyol pathway affects phosphoinositide pathway function and secretion during desensitization will be determined. Increased understanding of the signal-transduction mechanisms which modulate insulin secretion under normal conditions and in models of diabetes mellitus, and of the pharmacological interventions which may defuse cytotoxic events, will increase our knowledge of and ability to overcome diabetes mellitus.

Agency
National Institute of Health (NIH)
Institute
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Type
Research Project (R01)
Project #
5R01DK025705-17
Application #
2137775
Study Section
Metabolism Study Section (MET)
Project Start
1979-07-01
Project End
1997-06-30
Budget Start
1995-07-01
Budget End
1996-06-30
Support Year
17
Fiscal Year
1995
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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