title: Dihydroxyacetone-induced oscillations in cytoplasmic free Ca2+ and the ATP/ADP ratio in pancreatic beta-cells at substimulatory glucose.
abstract: Glucose stimulation of pancreatic beta-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 beta-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.
authors.affiliation: Department of Molecular Medicine, The Rolf Luft Center for Diabetes Research, Karolinska Institutet, Karolinska Hospital, S-171 76 Stockholm, Sweden.
authors.forename: Lisa
authors.initials: L
authors.lastname: Juntti-Berggren
authors.forename: Dominic-Luc
authors.initials: DL
authors.lastname: Webb
authors.forename: Per O G
authors.initials: PO
authors.lastname: Arkhammar
authors.forename: Vera
authors.initials: V
authors.lastname: Schultz
authors.forename: Elke K H
authors.initials: EK
authors.lastname: Schweda
authors.forename: Keith
authors.initials: K
authors.lastname: Tornheim
authors.forename: Per-Olof
authors.initials: PO
authors.lastname: Berggren
mesh_terms: D000244:Adenosine Diphosphate / Q000378:metabolism; D000255:Adenosine Triphosphate / Q000378:metabolism; D000818:Animals; D002118:Calcium / Q000378:metabolism*; D004098:Dihydroxyacetone / Q000494:pharmacology*; D005947:Glucose / Q000378:metabolism / Q000494:pharmacology*; D007328:Insulin / Q000378:metabolism; D007425:Intracellular Membranes / Q000378:metabolism; D007515:Islets of Langerhans / Q000378:metabolism*; D008564:Membrane Potentials; D051379:Mice; D008928:Mitochondria / Q000378:metabolism; D009991:Oscillometry; D010179:Pancreas / Q000378:metabolism; D013050:Spectrometry, Fluorescence; D013997:Time Factors
chemical_list: D007328:Insulin; D000244:Adenosine Diphosphate; D000255:Adenosine Triphosphate; D005947:Glucose; D004098:Dihydroxyacetone; D002118:Calcium