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J. Biol. Chem., Vol. 278, Issue 42, 40710-40716, October 17, 2003

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Dihydroxyacetone-induced Oscillations in Cytoplasmic Free Ca²⁺ and the ATP/ADP Ratio in Pancreatic -Cells at Substimulatory Glucose^*

Lisa Juntti-Berggren  , Dominic-Luc Webb   ¶, Per O.G. Arkhammar  ||, Vera Schultz **, Elke K. H. Schweda , Keith Tornheim **  and Per-Olof Berggren 

From the Department of Molecular Medicine, The Rolf Luft Center for Diabetes Research, Karolinska Institutet, Karolinska Hospital, S-171 76 Stockholm, Sweden, the ^**Department of Biochemistry, Boston University School of Medicine, Boston, Massachusetts 02118, and the Clinical Research Centre, Karolinska Institutet and University College of South Stockholm, Novum, S-141 86 Huddinge, Sweden

Glucose stimulation of pancreatic -cells causes oscillatory influx of Ca²⁺, leading to pulsatile insulin secretion. We have proposed that this is due to oscillations of glycolysis and the ATP/ADP ratio, which modulate the activity of ATP-sensitive K⁺ channels. We show here that dihydroxyacetone, a secretagogue that feeds into glycolysis below the putative oscillator phosphofructokinase, could cause a single initial peak in cytoplasmic free Ca²⁺ ([Ca²⁺]_i) but did not by itself cause repeated oscillations in [Ca²⁺]_i in mouse pancreatic -cells. However, in the presence of a substimulatory concentration of glucose (4 mM), dihydroxyacetone induced [Ca²⁺]_i oscillations. Furthermore, these oscillations correlated with oscillations in the ATP/ADP ratio, as seen previously with glucose stimulation. Insulin secretion in response to dihydroxyacetone was transient in the absence of glucose but was considerably enhanced and somewhat prolonged in the presence of a substimulatory concentration of glucose, in accordance with the enhanced [Ca²⁺]_i response. These results are consistent with the hypothesized role of phosphofructokinase as the generator of the oscillations. Dihydroxyacetone may affect phosphofructokinase by raising the free concentration of fructose 1,6-bisphosphate to a critical level at which it activates the enzyme autocatalytically, thereby inducing the pulses of phosphofructokinase activity that cause the metabolic oscillations.

Received for publication, July 29, 2003

^* This work was supported by the Swedish Research Council, Berth von Kantzows Foundation, Novo Nordisk Foundation, Karolinska Institutet, the Swedish Diabetes Association, Juvenile Diabetes Research Foundation Grant 1-2002-372, and United States Public Health Service Grants DK58508, DK35914, and DK53064. The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

These authors contributed equally to this work.

^¶ Supported in part by the Lars Hiertas Minne and Kungliga Fysiografiska Sallskapet.

^|| Present address: Novo Nordisk A/S, Novo Alle, DK 2880, Bagsvaerd, Denmark.

To whom correspondence should be addressed: Boston University School of Medicine, 650 Albany St., Rm. 815, Boston, MA 02118. E-mail: tornheim{at}bu.edu.

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