Metabolic Fluxes and Stoichiometry of Glucose Metabolism

Abstract

I would like to comment on a recent article by Bertram et al. titled “Interaction of Glycolysis and Mitochondrial Respiration in Metabolic Oscillations of Pancreatic Islets”(1xInteraction of glycolysis and mitochondrial respiration in metabolic oscillations of pancreatic islets. Bertram, R., Satin, L.S., Pedersen, M.G., Luciani, D.S., and Sherman, A. Biophys. J. 2007; 92: 1544–1555Abstract | Full Text | Full Text PDF | PubMed | Scopus (51)See all References)(1).The article addresses two different types of oscillations of the membrane potential V and of [Ca2+]c, which are known to occur in the β-cells of pancreatic islets: fast electrical and slow glycolytic oscillations, and fast oscillations superimposed on slow ones (compound bursting). For this purpose, the authors modeled oxidative glucose metabolism of the β-cell (without lactate production). For glycolytic reactions, modified equations of Smolen (2xA model for glycolytic oscillations based on skeletal muscle phosphofructokinase kinetics. Smolen, P. J. Theor. Biol. 1995; 174: 137–148Crossref | PubMed | Scopus (45)See all References)(2) were applied, whereas for oxidative phosphorylation, a simplified M-K model (Magnus and Keizer (3xMinimal model of β-cell mitochondrial Ca2+ handling. Magnus, G. and Keizer, J. Am. J. Physiol. 1997; 273: C717–C733PubMedSee all References)(3)) was used. These new equations of glucose metabolism were combined with an earlier model published in 2004 (4xCalcium and glycolysis mediate multiple bursting modes in pancreatic islets. Bertram, R., Satin, L., Zhang, M., Smolen, P., and Sherman, A. Biophys. J. 2004; 87: 3074–3087Abstract | Full Text | Full Text PDF | PubMed | Scopus (86)See all References)(4), which contains V, [Ca2+]c, [Ca2+]ER, and [ADP]c as main variables. The underlying idea obviously was to show how phosphofructokinase (PFK, M-type)-driven glycolytic oscillations might interfere with oscillations of primarily V and [Ca2+]c. Their results show that the M-type PFK reaction is crucial for glycolytic oscillations, which, however, can be induced only at moderate values of JGK. When M-type PFK is reduced to 30% of total PFK, glycolytic oscillations are not possible and fast oscillations of [Ca2+]c prevail at JGK > 0.2.These results are not convincing, because the stoichiometry of oxidative glucose metabolism (in a given time interval, 6.0 mol of O2 are needed to form 6.0 mol of CO2 with 6.0 mol of H2O per mole of glucose utilized) is violated. The flux ratio, JO/JGK, deviates markedly from 6.0. In the relevant article, JO/JGK is only ∼0.76 (conditions of Fig. 2), 1.2 (Fig. 4), or 1.1 (Fig. 6). When these flux ratios were calculated, it was assumed that the mitochondria/cytosol volume ratio (κ = 0.07) was already included in calculations; if not, the above values would become reduced by a factor of 0.07.The following may argue against PFK-driven oscillations of glycolysis in β-cells: the PFK reaction can produce oscillations through a positive feed back of the products ADP (AMP) and fructose 1,6 bisphosphate concentration on enzyme catalytic activity. In the cytosol of the β-cell, however, most of [ADP]c produced originates from parallel, ATP-coupled reactions such as protein biosynthesis, insulin secretion, and ion transport. The PFK reaction consumes only ∼3.8% (5xMathematical simulation of membrane processes and metabolic fluxes of the pancreatic β-cell. Diederichs, F. Bull. Math. Biol. 2006; 68: 1779–1818Crossref | PubMed | Scopus (24)See all References)(5) of total ATP, which stems mainly from mitochondria and to a minor part from glycolysis (7.6% (5xMathematical simulation of membrane processes and metabolic fluxes of the pancreatic β-cell. Diederichs, F. Bull. Math. Biol. 2006; 68: 1779–1818Crossref | PubMed | Scopus (24)See all References)(5)). The kinetics of this large fraction of nonglycolytically produced ADP may control PFK and in this way may induce forced oscillations of glycolysis.