Abstract

The working hypothesis to be tested is that phospholipases C and A2 have a major role in initiating and regulating insulin secretion. According to the hypothesis, glucose is recognized at the plasma membrane by a protein that would then be coupled to phospholipase C. The identity of this protein is unknown but possible candidates include the glucose transporter, a putative glucose receptor, or an enzyme of glycolysis.
Aim #1 is to define the molecular mechanism whereby glucose and other secretagogues activate phospholipase C in insulin secretion.
Aim#2 is to determine whether novel inositol phospholipids (PIP3) are present in islets and insulin-secreting cells, and whether they have a role in insulin secretion.
Aim #3 will define and characterize the role of phospholipase A2 and arachidonic acid accumulation in insulin secretion. Preliminary data show that the muscarinic agonist carbachol stimulates phospholipase A2 and glucose may activate diacylglycerol (DAG) lipase and arachidonate may affect voltage- dependent Ca++ influx.

  Funding Agency

Agency
National Institute of Health (NIH)
Institute
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Type
Modified Research Career Development Award (K04)
Project #
5K04DK002217-02
Application #
2134033
Study Section
Endocrinology Study Section (END)
Project Start
1994-01-01
Project End
1998-12-31
Budget Start
1995-01-01
Budget End
1995-12-31
Support Year
2
Fiscal Year
1995
Total Cost
Indirect Cost

  Institution

Name
University of Pennsylvania
Department
Pathology
Type
Schools of Medicine
DUNS #
042250712
City
Philadelphia
State
PA
Country
United States
Zip Code
19104

  Publications

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
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
Jolly-Tornetta, C; Gao, Z Y; Lee, V M et al. (1998) Regulation of amyloid precursor protein secretion by glutamate receptors in human Ntera 2 neurons. J Biol Chem 273:14015-21
Konrad, R J; Dean, R M; Young, R A et al. (1996) Glucose-induced tyrosine phosphorylation of p125 in beta cells and pancreatic islets. A novel proximal signal in insulin secretion. J Biol Chem 271:24179-86
Chen, M; Yang, Z; Naji, A et al. (1996) Identification of calcium-dependent phospholipase A2 isoforms in human and rat pancreatic islets and insulin secreting beta-cell lines. Endocrinology 137:2901-9
Konard, R J; Stoller, J Z; Gao, Z Y et al. (1996) Eicosapentaenoic acid (C20:5) augments glucose-induced insulin secretion from beta-TC3 insulinoma cells. Pancreas 13:253-8
Gao, Z; Konrad, R J; Collins, H et al. (1996) Wortmannin inhibits insulin secretion in pancreatic islets and beta-TC3 cells independent of its inhibition of phosphatidylinositol 3-kinase. Diabetes 45:854-62
Rothenberg, P L; Willison, L D; Simon, J et al. (1995) Glucose-induced insulin receptor tyrosine phosphorylation in insulin-secreting beta-cells. Diabetes 44:802-9
Alter, C A; Wolf, B A (1995) Identification of phosphatidylinositol 3,4,5-trisphosphate in pancreatic islets and insulin-secreting beta-cells. Biochem Biophys Res Commun 208:190-7
Major, C; Wolf, B A (1994) Quantitation of the fatty acid composition of phosphatidic acid by capillary gas chromatography electron-capture detection with picomole sensitivity. J Chromatogr B Biomed Appl 658:233-40

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