Journal
BIOCHEMICAL JOURNAL
Volume 403, Issue -, Pages 197-205Publisher
PORTLAND PRESS LTD
DOI: 10.1042/BJ20061209
Keywords
beta-cell; calcium oscillation; insulin secretion; NADPH; membrane potential; metabolism
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Funding
- NCRR NIH HHS [RR001395, P41 RR001395] Funding Source: Medline
- NHLBI NIH HHS [T32 HL-07224, T32 HL007224] Funding Source: Medline
- NIDDK NIH HHS [DK42600, DK 35914, DK 63984, R56 DK035914, R21 DK063984, R01 DK035914] Funding Source: Medline
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The present study was undertaken to determine the main metabolic secretory signals generated by the mitochondrial substrate MeS (methyl succinate) compared with glucose in mouse and rat islets and to understand the differences. Glycolysis and mitochondrial metabolism both have key roles in the stimulation of insulin secretion by glucose. Both fuels elicited comparable oscillatory patterns of Ca2+ and changes in plasma and mitochondrial membrane potential in rat islet cells and clonal pancreatic beta-cells (INS-1). Saturation of the Ca2+ signal occurred between 5 and 6 mM MeS, while secretion reached its maximum at 15 mM, suggesting operation of a K-ATP-channel-independent pathway. Additional responses to MeS and glucose included elevated NAD(P)H autofluorescence in INS-1 cells and islets and increases in assayed NADH and NADPH and the ATP/ADP ratio. Increased NADPH and ATP/ADP ratios occurred more rapidly with MeS, although similar levels were reached after 5 min of exposure to each fuel, whereas NADH increased more with MeS than with glucose. Reversal of MeS-induced cell depolarization by Methylene Blue completely inhibited MeS-stimulated secretion, whereas basal secretion and KCl-induced changes in these parameters were not affected. MeS had no effect on secretion or signals in the mouse islets, in contrast with glucose, possibly due to a lack of malic enzyme. The data are consistent with the common intermediates being pyruvate, cytosolic NADPH or both, and suggest that cytosolic NADPH production could account for the more rapid onset of MeS-induced secretion compared with glucose stimulation.
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