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Diabetes 52:394-402, 2003
© 2003 by the American Diabetes Association, Inc.
Differential Effects of Glucose and Glyburide on Energetics and Na+ Levels of ßHC9 Cells
Nuclear Magnetic Resonance Spectroscopy and Respirometry Studies
1 Diabetes Research Center and Department of Biochemistry and Biophysics, University of Pennsylvania School of Medicine, Philadelphia, Pennsylvania
2 Division of Metabolism, Children’s Hospital of Philadelphia, Philadelphia, Pennsylvania
3 Pharmacological Research 1, Novo Nordisk, Bagsvaerd, Denmark
In the present study, noninvasive 31P and 23Na+–nuclear magnetic resonance (NMR) technology and respirometry were used to compare the effect of high glucose (30 mmol/l) with the effect of the antidiabetic sulfonylurea (SU) compound glyburide (GLY) on energy metabolism, Na+ flux, insulin, and cAMP release of continuously superfused ß-HC9 cells encapsulated in microscopic agarose beads. Both high glucose and GLY increased oxygen consumption in ß-HC9 cells (15–30%) with a maximal effect at 8 mmol/l for glucose and at 250 nmol/l for GLY. At the same time, insulin release from ß-cells increased by 15- and 25-fold with high glucose or GLY, respectively. The P-creatine (PCr) level was greatly increased and inorganic phosphate (Pi) was decreased with 30 mmol/l glucose in contrast to the decreased level of PCr and increased Pi with GLY. ATP levels remained unchanged during both interventions. Studies on isolated mitochondria of ß-HC9 cells showed that GLY added to mitochondria oxidizing glutamine or glutamate abolished the stimulation of respiration by ADP (state 3) meanwhile leaving state 3 respiration unchanged during oxidation of other substrates. Exposure of ß-HC9 cells to 5 mmol/l glucose decreased intracellular Na+ levels monitored by 23Na+-NMR spectroscopy and 30 mmol/l glucose resulted in a further decrease in cytosolic Na+. In contrast, Na+ increased when 1 µmol/l GLY was added to the perfusate containing 5 mmol/l glucose. These data support the hypothesis that glucose activates the ß-cell through a "push mechanism" due to substrate pressure enhancing fuel flux, energy production, and extrusion of Na+ from the cells in contrast to SU receptor (SUR)-1 inhibitors, which may modify intermediary and energy metabolism secondarily through a "pull mechanism" due to higher energy demand resulting from increased ion fluxes and the exocytotic work load.
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