BADER- Barbara Corkey

Barbara Corkey, Ph.D.

Molecular Coupling of Fuel Metabolism to Cell Function

The main main goal of work in the Corkey laboratory is to determine how fuels generate the signals to modulate exocytosis, electrical activity, metabolism and gene expression and involves assessment of the regulation of mitochondrial energy coupling and the influence of metabolites on intracellular signal transduction in adipocytes, pancreatic b-cells and human fibroblasts. Recent emphasis has been on the signaling consequences of cellular energy state, the influence of fatty acids on protein kinases and the role of fatty acids and long chain acyl CoA esters on signal transduction, Ca²⁺ and H⁺ handling and respiration. Projects are underway to compare the consequences of growing cells under diabetes-like conditions with cells obtained from model animals. Work has also begun evaluating the mechanism of autoimmune -cell destruction in insulin dependent diabetes with a particular focus on cytokine-mediated signal transduction and cell destruction. A new and exciting area that we have embarked on, in collaboration with other faculty members at Boston University, involves studies on the roles of insulin resistance and obesity in the development of dyslipidemias and Type II diabetes. A multi-dimensional approach is being used to explore this problem, using pancreatic islets, skeletal muscle, and adipose tissue, in a variety of animal models of NIDDM and tissues obtained from defined human sub-populations, including minority groups and women. The techniques employed in this laboratory include microscope-based single cell digital imaging of intracellular free Ca²⁺, Mg²⁺, pH and membrane potential, fluorescence monitoring of the same parameters in cell suspensions or whole perifused tissues, protein chemistry and enzyme analysis, and metabolite determination by chromatographic, NMR and enzymatic methods. Work is done in collaboration with scientists at Boston Medical Center, Harvard, the Karolinska Institute, the Universities of Montreal, Pennsylvania and Texas.

References:

1. Segall, L., Lameloise, N., Assimacopoulos-Jeannet, F., Roche, E., Corkey, P., Thumelin, S., Corkey, B. E. And Prentki, M. (1999) Lipid rather than glucose metabolism is implicated in altered insulin secretion caused by oleate in INS-1 cells. Am. J. Physiol. 277:E521-528.

2. Brown, H., Meister, B., Deeney, J. T., Rhodes, C. J., Seino, S., Corkey, B. E., Berggren, P.-O. and Fried, G. (2000) Synaptotagmin isoforms in pancreatic endocrine cells—Distinct compartmentalization and role in exocytosis. Diabetes 49:383-391.

3. Deeney, J. T., Rhodes, C. J., Prentki, M., Berggren, P.-O. and Corkey, B. E. (2000) Acute stimulation with long chain acyl CoA enhances exocytosis of insulin in permeabilized pancreatic clonal ß-cells (HIT T-15). J. Biol. Chem. 275:9363-9368.

4. Farfari, S., Assimacopoulos-Jeannet, F., Schultz, V., Corkey, B. E. and Prentki, M. (2000) Glucose regulated anaplerosis and cataplerosis in pancreatic ß-cells. Diabetes 40:718-726.

5. Yaney, G. C., Korchak, H. M. and Corkey, B. E. (2000) Long chain acyl CoA regulation of protein kinase C and fatty acid potentiation of glucose-stimulated insulin secretion in clonal ß-cells. Endocrinology 141:1989-1998.

6. Guo, W., Kirkland, J. L., Corkey, B. E. and Hamilton, J. A. (2000) Esterification of free fatty acids in adipocytes: A comparison between octanoate and oleate. Biochem. J. 349:463-471.

7. Porterfield, D. M., Corkey, R. F., Sanger, R. H., Tornheim, K., Smith, P. J. S. and Corkey, B. E. (2000) Oxygen Consumption Oscillates in Single Clonal Pancreatic ß-Cells. Diabetes 49:1511-1516.

8. Dillon, J. S., Yaney, G. C., Chipkin, S., Voilley, N., Bliss, C. R., Schultz, V., Schuit, F. C., Prentki, M. and Corkey, B. E. (2000) Dehydroepiandrosterone sulfate (DHEAS) and ß-cell function: Enhanced glucose-induced insulin secretion and altered gene expression in rodent pancreatic ß-cells. Diabetes 49:2012-20.

9. Yaney, G. C., Civelek, V. N., Dillon, J. S., Cunningham, B. A., Hamilton, J. A., Korchak, H. M., Tornheim, K., Corkey, B. E. and Boyd, A. E., III (2001) Glucagon-like peptide-1 stimulates lipolysis in clonal pancreatic ß-cells. Diabetes 50:56-62.

10. Caserta, F., Civelek, V. N., Prentki, M., McGarry, J. D., Corkey, B. E., Hamilton, J. A. and Kirkland, J. L. (2001) Fat depot origin affects fatty acid handling in cultured rat and human preadipocytes. Am J. Physiol. 280:E238-47.

11. Korchak, H. M., Corkey, B. E., Yaney, G. C. and Kilpatrick, L. E. (2001) Negative regulation of ligand-initiated Ca²⁺ uptake by ßII-PKC in differentiated HL60 cells. Am. J. Physiol. 281:C514-523.

12. Faradji, R. N., Havari, E., Chen, Q., Gray, J., Tornheim, K., Corkey, B. E., Mulligan, R. C. and Lipes, M. A. (2001) Glucose-induced toxicity in insulin-producing pituitary cells coexpressing GLUT2 and glucokinase: Implications for metabolic engineering. J. Biol. Chem. 276:36695-36702.

13. Hamilton, J. A., Johnson, R., Corkey, B. E. and Kamp, F. (2001) Fatty acid transport: the diffusion mechanism in model and biological membranes. J. Mol. Neurosci. 16:99-108.

14. Deeney, J.T., Köhler, M., Kubik, K., Brown, G., Schultz, V., Tornheim, K., Corkey, B. E. and Berggren, P.-O. (2001) Glucose-Induced Metabolic Oscillations Parallel Those of Ca ²⁺ and Insulin Release in Clonal Insulin-Secreting Cells; A Multiwell Approach to Oscillatory Cell Behavior. J. Biol. Chem. 276:36946-36950.

15. Han, J., Farmer, S. R., Kirkland, J. L., Corkey, B. E., Yoon, R., Pirtskhalava, T, Ito, Y. and Guo, W. (2002) Octanoate Attenuates Adipogenesis in 3T3-L1 Preadipocytes. J. Nutr. 132:904-910.

16. Alarcon, C., Wicksteed, B., Prentki, M., Corkey, B. E. and Rhodes, C. J. (2002) Succinate is a preferential metabolic stimulus-coupling signal for glucose-induced proinsulin biosynthesis translation. Diabetes 51:2496-2504.

17. Yaney, G. C., Korchak, H. M. And Corkey, B. E. (2002) Potentiation of Insulin Secretion by Phorbol Esters is Mediated by PKC-a and nPKC isoforms. Am. J. Physiol. Endocrinol Metab. 283:E880-888.

18. Cunningham, B. A., Richard, A.-M., Dillon, J. S., Daley, J. T., Civelek, V. N., Deeney, J. T., Yaney, G. C., Corkey, B. E. and Tornheim, K. (2003) Glucagon-like peptide 1 and fatty acids amplify oscillatory insulin secretion from perifused rat islets. Biochem. J. 369:173-178.

19. Kamp, F., Guo, W., Souto, R., Pilch, P. F., Corkey, B. E. and Hamilton, J. A. (2003) Rapid flip-flop of oleic acid across the plasma membrane of adipocytes. J. Biol. Chem. 278:7988-7995.

20. Yaney GC, Corkey BE. Fatty acid metabolism and insulin secretion in pancreatic beta cells. Diabetologia. 2003;46:1297-312.

21. Branstrom R, Aspinwall CA, Valimaki S, Ostensson CG, Tibell A, Eckhard M, Brandhorst H, Corkey BE, Berggren PO, Larsson O. Long-chain CoA esters activate human pancreatic beta-cell KATP channels: potential role in Type 2 diabetes. Diabetologia. 2004;47:277-83.






			Barbara Corkey, Ph.D. Molecular Coupling of Fuel Metabolism to Cell Function The main main goal of work in the Corkey laboratory is to determine how fuels generate the signals to modulate exocytosis, electrical activity, metabolism and gene expression and involves assessment of the regulation of mitochondrial energy coupling and the influence of metabolites on intracellular signal transduction in adipocytes, pancreatic b-cells and human fibroblasts. Recent emphasis has been on the signaling consequences of cellular energy state, the influence of fatty acids on protein kinases and the role of fatty acids and long chain acyl CoA esters on signal transduction, Ca²⁺ and H⁺ handling and respiration. Projects are underway to compare the consequences of growing cells under diabetes-like conditions with cells obtained from model animals. Work has also begun evaluating the mechanism of autoimmune -cell destruction in insulin dependent diabetes with a particular focus on cytokine-mediated signal transduction and cell destruction. A new and exciting area that we have embarked on, in collaboration with other faculty members at Boston University, involves studies on the roles of insulin resistance and obesity in the development of dyslipidemias and Type II diabetes. A multi-dimensional approach is being used to explore this problem, using pancreatic islets, skeletal muscle, and adipose tissue, in a variety of animal models of NIDDM and tissues obtained from defined human sub-populations, including minority groups and women. The techniques employed in this laboratory include microscope-based single cell digital imaging of intracellular free Ca²⁺, Mg²⁺, pH and membrane potential, fluorescence monitoring of the same parameters in cell suspensions or whole perifused tissues, protein chemistry and enzyme analysis, and metabolite determination by chromatographic, NMR and enzymatic methods. Work is done in collaboration with scientists at Boston Medical Center, Harvard, the Karolinska Institute, the Universities of Montreal, Pennsylvania and Texas. References: 1. Segall, L., Lameloise, N., Assimacopoulos-Jeannet, F., Roche, E., Corkey, P., Thumelin, S., Corkey, B. E. And Prentki, M. (1999) Lipid rather than glucose metabolism is implicated in altered insulin secretion caused by oleate in INS-1 cells. Am. J. Physiol. 277:E521-528. 2. Brown, H., Meister, B., Deeney, J. T., Rhodes, C. J., Seino, S., Corkey, B. E., Berggren, P.-O. and Fried, G. (2000) Synaptotagmin isoforms in pancreatic endocrine cells—Distinct compartmentalization and role in exocytosis. Diabetes 49:383-391. 3. Deeney, J. T., Rhodes, C. J., Prentki, M., Berggren, P.-O. and Corkey, B. E. (2000) Acute stimulation with long chain acyl CoA enhances exocytosis of insulin in permeabilized pancreatic clonal ß-cells (HIT T-15). J. Biol. Chem. 275:9363-9368. 4. Farfari, S., Assimacopoulos-Jeannet, F., Schultz, V., Corkey, B. E. and Prentki, M. (2000) Glucose regulated anaplerosis and cataplerosis in pancreatic ß-cells. Diabetes 40:718-726. 5. Yaney, G. C., Korchak, H. M. and Corkey, B. E. (2000) Long chain acyl CoA regulation of protein kinase C and fatty acid potentiation of glucose-stimulated insulin secretion in clonal ß-cells. Endocrinology 141:1989-1998. 6. Guo, W., Kirkland, J. L., Corkey, B. E. and Hamilton, J. A. (2000) Esterification of free fatty acids in adipocytes: A comparison between octanoate and oleate. Biochem. J. 349:463-471. 7. Porterfield, D. M., Corkey, R. F., Sanger, R. H., Tornheim, K., Smith, P. J. S. and Corkey, B. E. (2000) Oxygen Consumption Oscillates in Single Clonal Pancreatic ß-Cells. Diabetes 49:1511-1516. 8. Dillon, J. S., Yaney, G. C., Chipkin, S., Voilley, N., Bliss, C. R., Schultz, V., Schuit, F. C., Prentki, M. and Corkey, B. E. (2000) Dehydroepiandrosterone sulfate (DHEAS) and ß-cell function: Enhanced glucose-induced insulin secretion and altered gene expression in rodent pancreatic ß-cells. Diabetes 49:2012-20. 9. Yaney, G. C., Civelek, V. N., Dillon, J. S., Cunningham, B. A., Hamilton, J. A., Korchak, H. M., Tornheim, K., Corkey, B. E. and Boyd, A. E., III (2001) Glucagon-like peptide-1 stimulates lipolysis in clonal pancreatic ß-cells. Diabetes 50:56-62. 10. Caserta, F., Civelek, V. N., Prentki, M., McGarry, J. D., Corkey, B. E., Hamilton, J. A. and Kirkland, J. L. (2001) Fat depot origin affects fatty acid handling in cultured rat and human preadipocytes. Am J. Physiol. 280:E238-47. 11. Korchak, H. M., Corkey, B. E., Yaney, G. C. and Kilpatrick, L. E. (2001) Negative regulation of ligand-initiated Ca²⁺ uptake by ßII-PKC in differentiated HL60 cells. Am. J. Physiol. 281:C514-523. 12. Faradji, R. N., Havari, E., Chen, Q., Gray, J., Tornheim, K., Corkey, B. E., Mulligan, R. C. and Lipes, M. A. (2001) Glucose-induced toxicity in insulin-producing pituitary cells coexpressing GLUT2 and glucokinase: Implications for metabolic engineering. J. Biol. Chem. 276:36695-36702. 13. Hamilton, J. A., Johnson, R., Corkey, B. E. and Kamp, F. (2001) Fatty acid transport: the diffusion mechanism in model and biological membranes. J. Mol. Neurosci. 16:99-108. 14. Deeney, J.T., Köhler, M., Kubik, K., Brown, G., Schultz, V., Tornheim, K., Corkey, B. E. and Berggren, P.-O. (2001) Glucose-Induced Metabolic Oscillations Parallel Those of Ca ²⁺ and Insulin Release in Clonal Insulin-Secreting Cells; A Multiwell Approach to Oscillatory Cell Behavior. J. Biol. Chem. 276:36946-36950. 15. Han, J., Farmer, S. R., Kirkland, J. L., Corkey, B. E., Yoon, R., Pirtskhalava, T, Ito, Y. and Guo, W. (2002) Octanoate Attenuates Adipogenesis in 3T3-L1 Preadipocytes. J. Nutr. 132:904-910. 16. Alarcon, C., Wicksteed, B., Prentki, M., Corkey, B. E. and Rhodes, C. J. (2002) Succinate is a preferential metabolic stimulus-coupling signal for glucose-induced proinsulin biosynthesis translation. Diabetes 51:2496-2504. 17. Yaney, G. C., Korchak, H. M. And Corkey, B. E. (2002) Potentiation of Insulin Secretion by Phorbol Esters is Mediated by PKC-a and nPKC isoforms. Am. J. Physiol. Endocrinol Metab. 283:E880-888. 18. Cunningham, B. A., Richard, A.-M., Dillon, J. S., Daley, J. T., Civelek, V. N., Deeney, J. T., Yaney, G. C., Corkey, B. E. and Tornheim, K. (2003) Glucagon-like peptide 1 and fatty acids amplify oscillatory insulin secretion from perifused rat islets. Biochem. J. 369:173-178. 19. Kamp, F., Guo, W., Souto, R., Pilch, P. F., Corkey, B. E. and Hamilton, J. A. (2003) Rapid flip-flop of oleic acid across the plasma membrane of adipocytes. J. Biol. Chem. 278:7988-7995. 20. Yaney GC, Corkey BE. Fatty acid metabolism and insulin secretion in pancreatic beta cells. Diabetologia. 2003;46:1297-312. 21. Branstrom R, Aspinwall CA, Valimaki S, Ostensson CG, Tibell A, Eckhard M, Brandhorst H, Corkey BE, Berggren PO, Larsson O. Long-chain CoA esters activate human pancreatic beta-cell KATP channels: potential role in Type 2 diabetes. Diabetologia. 2004;47:277-83.