The objective of this project is to test the importance of oscillatory B-cell metabolism in insulin secretion, and to examine whether diminution of glycolytic oscillations, due to altered PFK isoform expression or regulation, may be responsible for the diminished insulin oscillations seen in islets from the GK rat, a non-obese model of NIDDM, and in islets from high fat/sucrose-fed (HFHS) Wistar rats.
The specific aims are to determine (i) how interference with oscillatory glycolysis affects the rise in the ATP/ADP ratio and the Ca2+ and insulin secretory response of the B-cell; (ii) whether other metabolizable secretagogues (e.g., glyceraldehyde or leucine plus glutamine) stimulate oscillatory insulin secretion by effects on oscillatory glycolysis and the ATP/ADP ratio or whether their metabolism is also intrinsically oscillatory, (iii) whether GK and HFHS Wistar islets have altered PFK isoform expression and kinetics and/or changes in the levels of regulatory metabolites that could account for diminished oscillations; (iv) whether a different magnitude or time course of rise in the ATP/ADP ratio occurs in GK and HFHS Wistar islets on glucose stimulation; (v) whether the diminished oscillations in insulin secretion in a population of GK or HFHS Wistar islets are due to a loss of synchrony.

National Institute of Health (NIH)
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Research Project (R01)
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Metabolism Study Section (MET)
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Laughlin, Maren R
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Boston University
Schools of Medicine
United States
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Richard, Ann-Marie T; Webb, Dominic-Luc; Goodman, Jessie M et al. (2007) Tissue-dependent loss of phosphofructokinase-M in mice with interrupted activity of the distal promoter: impairment in insulin secretion. Am J Physiol Endocrinol Metab 293:E794-801
Juntti-Berggren, Lisa; Webb, Dominic-Luc; Arkhammar, Per O G et al. (2003) Dihydroxyacetone-induced oscillations in cytoplasmic free Ca2+ and the ATP/ADP ratio in pancreatic beta-cells at substimulatory glucose. J Biol Chem 278:40710-6
Cunningham, Barbara A; Richard, Ann-Marie T; Dillon, Joseph S et al. (2003) Glucagon-like peptide 1 and fatty acids amplify pulsatile insulin secretion from perifused rat islets. Biochem J 369:173-8
Yaney, Gordon C; Fairbanks, Jamison M; Deeney, Jude T et al. (2002) Potentiation of insulin secretion by phorbol esters is mediated by PKC-alpha and nPKC isoforms. Am J Physiol Endocrinol Metab 283:E880-8
Deeney, J T; Kohler, M; Kubik, K et al. (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 276:36946-50
Faradji, R N; Havari, E; Chen, Q et al. (2001) Glucose-induced toxicity in insulin-producing pituitary cells that coexpress GLUT2 and glucokinase. Implications for metabolic engineering. J Biol Chem 276:36695-702
Porterfield, D M; Corkey, R F; Sanger, R H et al. (2000) Oxygen consumption oscillates in single clonal pancreatic beta-cells (HIT). Diabetes 49:1511-6
Liu, Y Q; Tornheim, K; Leahy, J L (1999) Glucose-fatty acid cycle to inhibit glucose utilization and oxidation is not operative in fatty acid-cultured islets. Diabetes 48:1747-53
Liu, Y Q; Tornheim, K; Leahy, J L (1998) Fatty acid-induced beta cell hypersensitivity to glucose. Increased phosphofructokinase activity and lowered glucose-6-phosphate content. J Clin Invest 101:1870-5
Liu, Y Q; Tornheim, K; Leahy, J L (1998) Shared biochemical properties of glucotoxicity and lipotoxicity in islets decrease citrate synthase activity and increase phosphofructokinase activity. Diabetes 47:1889-93

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