The long-term objectives of this proposal are 1) to define the role of phospholipases C and A2 in nutrient, receptor-mediated, and sulfonylurea-mediated insulin secretion by the islets of Langerhans; and 2) to determine the role of de novo synthesis of diacylglycerol from glucose in insulin secretion and hyperglycemia, since in Type II diabetes mellitus there is a blunted insulin response to glucose. The first hypothesis is that phospholipases C and A2 which are located at the plasma membrane of the beta-cells of islets of Langerhans, have a major role in initiating and regulating insulin secretion. The second hypothesis is that de novo synthesis of lysophosphatidic acid, phosphatidic acid and diacylglycerol from glucose has a role in glucose-induced insulin secretion and in the adaptation of beta-cells to hyperglycemia in vitro.
Aim #1 is to define the molecular mechanism whereby glucose and other secretagogues activate phospholipase C in insulin secretion and to test the working hypothesis that glucose is recognized by a site on the beta cell which is coupled to phospholipase C.
Aim #2 will define and characterize the role of phospholipase A2 in insulin secretion and identify the molecular mechanisms whereby the different classes of secretagogues stimulate and regulate arachidonic acid accumulation.
Aim #3 will test the hypothesis that de novo synthesis of lysophosphatidic acid, phosphatidic acid and diacylglycerol from glucose has a major role in insulin secretion and in the adaptation of islets to hyperglycemia in vitro; the study will define at the molecular levels the pathways involved and their regulation.

Agency
National Institute of Health (NIH)
Institute
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Type
Research Project (R01)
Project #
5R01DK043354-03
Application #
2142940
Study Section
Endocrinology Study Section (END)
Project Start
1991-07-15
Project End
1996-05-31
Budget Start
1993-09-01
Budget End
1996-05-31
Support Year
3
Fiscal Year
1993
Total Cost
Indirect Cost
Name
University of Pennsylvania
Department
Pathology
Type
Schools of Medicine
DUNS #
042250712
City
Philadelphia
State
PA
Country
United States
Zip Code
19104
Gao, Zhiyong; Young, Robert A; Li, Guizhu et al. (2003) Distinguishing features of leucine and alpha-ketoisocaproate sensing in pancreatic beta-cells. Endocrinology 144:1949-57
Gao, Zhiyong; Young, Robert A; Trucco, Matteo M et al. (2002) Protein kinase A translocation and insulin secretion in pancreatic beta-cells: studies with adenylate cyclase toxin from Bordetella pertussis. Biochem J 368:397-404
Westerlund, Johanna; Wolf, Bryan A; Bergsten, Peter (2002) Glucose-dependent promotion of insulin release from mouse pancreatic islets by the insulin-mimetic compound L-783,281. Diabetes 51 Suppl 1:S50-2
Zhu, Yuan; Xu, Gang; Patel, Arun et al. (2002) Cloning, expression, and initial characterization of a novel cytokine-like gene family. Genomics 80:144-50
Major, C D; Wolf, B A (2001) Interleukin-1beta stimulation of c-Jun NH(2)-terminal kinase activity in insulin-secreting cells: evidence for cytoplasmic restriction. Diabetes 50:2721-8
Gao, Z; Reavey-Cantwell, J; Young, R A et al. (2000) Synaptotagmin III/VII isoforms mediate Ca2+-induced insulin secretion in pancreatic islet beta -cells. J Biol Chem 275:36079-85
Xu, G G; Gao, Z Y; Borge Jr, P D et al. (2000) Insulin regulation of beta-cell function involves a feedback loop on SERCA gene expression, Ca(2+) homeostasis, and insulin expression and secretion. Biochemistry 39:14912-9
Xu, G G; Gao, Z Y; Borge Jr, P D et al. (1999) Insulin receptor substrate 1-induced inhibition of endoplasmic reticulum Ca2+ uptake in beta-cells. Autocrine regulation of intracellular ca2+ homeostasis and insulin secretion. J Biol Chem 274:18067-74
Gao, Z Y; Li, G; Najafi, H et al. (1999) Glucose regulation of glutaminolysis and its role in insulin secretion. Diabetes 48:1535-42
Major, C D; Gao, Z Y; Wolf, B A (1999) Activation of the sphingomyelinase/ceramide signal transduction pathway in insulin-secreting beta-cells: role in cytokine-induced beta-cell death. Diabetes 48:1372-80

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