Is the glucose‐induced stimulation of glycolysis in pancreatic islets attributable to activation of phosphofructokinase by fructose 2,6‐bisphosphate?

Malaisse, Willy; Malaisse‐Lagae, Francine; Sener, Abdullah; Schaftingen, Emile Van; Hers, Henri‐Géry

doi:10.1016/0014-5793(81)80722-3

Cited by 25 publications

(20 citation statements)

References 11 publications

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“…Phosphofructokinases from muscle (9) and from pancreatic islets (20) are also highly sensitive to the action of fructose 2,6-bisphosphate, which increases their affinity for fructose 6-phosphate. Preliminary experiments performed with purified yeast phosphofructokinase (kindly provided by E. Hofmann, Leipzig) have also revealed a large stimulatory effect of fructose 2,6-bisphosphate, but ofa more complex type in which there were changes of both Km and Vma.…”

Section: Discussionmentioning

confidence: 99%

Control of liver 6-phosphofructokinase by fructose 2,6-bisphosphate and other effectors.

Schaftingen¹,

Jett²,

Hue³

et al. 1981

Proc. Natl. Acad. Sci. U.S.A.

209

122

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Rat liver 6-phosphofructokinase (ATP-D-fructose-6-phosphate 1-phosphotransferase, EC 2.7.1.11) was partially purified free of interfering enzymes by a rapid procedure. Fructose 2,6-bisphosphate, at micromolar concentrations, greatly stimulated the enzyme by increasing its affinity for fructose 6-phosphate and relieving the inhibition by ATP. Its action was synergistic with that of AMP. As a stimulator of liver phosphofructokinase, fructose 2,6-bisphosphate was approximately 1000-and 2500-fold more efficient than fructose 1,6-bisphosphate and glucose 1,6-bisphosphate, respectively. The concentration at which a half-maximal effect was obtained with the hexose bisphosphates was dependent upon the experimental conditions. It was relatively high at physiological concentrations of substrates, AMP, and Pi, and under these conditions the positive effect of fructose 1,6-bisphosphate was no longer detectable. This was probably due to the negative effect of fructose 1,6-bisphosphate as a reaction product inhibitor. It is concluded that fructose 2,6-bisphosphate rather than fructose 1,6-bisphosphate controls, in association with other effectors, the activity of phosphofructoldnase in the liver.There is a general agreement in the literature that 6-phosphofructokinase (ATP:D-fructose-6-phosphate l-phosphotransferase, EC 2.7.1.11) plays a major role in the control ofglycolysis in nearly all types of cells (1-6). The activity of this enzyme is controlled by several metabolites, most notably its two substrates, fructose 6-phosphate and ATP. The rate of the reaction is a sigmoidal function of fructose 6-phosphate concentration, and the saturation curve is shifted to the left in the presence of positive effectors, among which fructose 1,6-bisphosphate (7,8), the product of the reaction, and AMP are currently believed to play a major role. Negative effectors such as ATP and citrate have the opposite effect. The rate ofthe reaction plotted as a function of ATP concentration exhibits a typical inhibition by excess substrate. This inhibition is relieved by the positive effectors and by large concentrations of fructose 6-phosphate, whereas it is intensified by the negative effectors.Fructose 2,6-bisphosphate is a newly recognized, extremely effective, positive effector of liver and muscle phosphofructokinase (9). Its concentration in the liver is greatly increased under conditions in which glycolysis is active and is decreased by glucagon (10). It has also been found to inhibit, at micromolar concentrations, liver and muscle fructose-1,6-bisphosphatase (11). It therefore appears to be a major regulator of both glycolysis and gluconeogenesis in the liver. The purpose of the present work was to investigate the action of fructose 2,6-bisphosphate on the kinetics of liver phosphofructokinase and to compare it to that of its isomers fructose 1,6-bisphosphate and glucose 1,6-bisphosphate and that of AMP. When the effect of fructose 1,6-bisphosphate was examined, pyruvate kinase (20 ,g/ml) and lactate dehydrogenase (25 Mg/ ml) were u...

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Section: Discussionmentioning

confidence: 99%

Control of liver 6-phosphofructokinase by fructose 2,6-bisphosphate and other effectors.

Schaftingen¹,

Jett²,

Hue³

et al. 1981

Proc. Natl. Acad. Sci. U.S.A.

209

122

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“…Haller and Lewis demonstrated additionally that excess peripheral glucose depletes cells of oxidative substrates in muscle metabolism (16). Concerning insulin secretion of the pancreatic ␤ cell (17), a coincidence between reduced PFK1 activity and impaired insulin secretion has been described in vitro (18,19), but was explained by primary phosphate depletion and consequently impaired secretion in the particular experimental setup used. Recently, Yaney and coworkers (20) demonstrated the presence of all three isotypes of PFK1 in rat-derived ␤ cell lines and islets at the protein level.…”

Section: Introductionmentioning

confidence: 99%

Deficiency of phosphofructo-1-kinase/muscle subtype in humans impairs insulin secretion and causes insulin resistance.

Ristow¹,

Vorgerd²,

Möhlig³

et al. 1997

J. Clin. Invest.

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Non-insulin-dependent diabetes mellitus (NIDDM) is caused by peripheral insulin resistance and impaired ␤ cell function. Phosphofructo-1-kinase (PFK1) is a rate-limiting enzyme in glycolysis, and its muscle subtype (PFK1-M) deficiency leads to the autosomal recessively inherited glycogenosis type VII Tarui's disease. It was evaluated whether PFK1-M deficiency leads to alterations in insulin action or secretion in humans.A core family of four members was evaluated for PFK1-M deficiency by DNA and enzyme-activity analyses. All members underwent oral and intravenous glucose tolerance tests (oGTT and ivGTT) and an insulin-sensitivity test (IST) using octreotide.Enzyme PFK1-M deficiency causes impaired insulin secretion in response to glucose, demonstrating its participation in islet glucose metabolism, and peripheral insulin resistance. These combined metabolic sequelae of PFK-1 deficiency identify it as a candidate gene predisposing to NIDDM. ( J.

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“…In the liver, fructose-2,6-P2 also inhibits the activity of fructose-l,6-P2 bisphosphatase [7]. A salient feature of the effect of fructose-2,6-P2 upon phosphofructokinase activity consists in the fact that the activator enhances the reaction velocity at non-saturating concentrations of fructose-6-P, but fails to augment the maximal velocity recorded at a saturating concentration of fructose-6-P [8]. In the liver, the activator is formed from fructose-6-P and ATP in a reaction catalyzed by a novel enzyme, fructose-6-P,2-kinase [9][10][11].…”

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confidence: 99%

The glycolytic cascade in pancreatic islets

Malaisse¹,

Malaisse‐Lagae²,

Sener³

1982

Diabetologia

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Is the glucose‐induced stimulation of glycolysis in pancreatic islets attributable to activation of phosphofructokinase by fructose 2,6‐bisphosphate?

Cited by 25 publications

References 11 publications

Control of liver 6-phosphofructokinase by fructose 2,6-bisphosphate and other effectors.

Control of liver 6-phosphofructokinase by fructose 2,6-bisphosphate and other effectors.

Deficiency of phosphofructo-1-kinase/muscle subtype in humans impairs insulin secretion and causes insulin resistance.

The glycolytic cascade in pancreatic islets

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