Computer modeling identifies glucokinase as glucose sensor of pancreatic beta-cells

Garfinkel, David; Garfinkel, Lillian; Meglasson, M. D.; Matschinsky, Franz M.

doi:10.1152/ajpregu.1984.247.3.r527

Cited by 10 publications

(11 citation statements)

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“…The low-affinity component of glucose usage has sigmoidal kinetics with a Hill coefficient value of 1.5, indicating cooperative rate dependence on glucose concentration (Table I) . 30,56 Results from a number of less comprehensive studies support these observations. 'g*23,62 Usage of [5-3H]mannose by isolated islets of rats also occurs with two kinetic components similar to those for metabolism of glucose.…”

Section: Metabolic Fate Of Glucose In Pancreatic Isletsmentioning

confidence: 93%

Pancreatic islet glucose metabolism and regulation of insulin secretion

Meglasson

Matschinsky

1986

Diabetes Metab. Rev.

484

345

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Section: Metabolic Fate Of Glucose In Pancreatic Isletsmentioning

confidence: 93%

Pancreatic islet glucose metabolism and regulation of insulin secretion

Meglasson

Matschinsky

1986

Diabetes Metab. Rev.

484

345

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“…Mannose stimulates the secretion of insulin by pancreatic islet fl-cells. Analysis of their sugar utilization curves (Garfinkel et al, 1984) by using Eadie-Hofstee plots or non-linear regression reveals a high-affinity component that is ascribed to hexokinase.…”

Section: Substrates and Michaelis Constantsmentioning

confidence: 99%

Kinetic properties of hexokinase as assembled with a microcomputer data base

Garfinkel

Matsiras

et al. 1987

Biochemical Journal

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We have constructed a relational data base containing the kinetic properties of the isoenzymes of hexokinase using the Knowledgeman data-base program on an IBM PC microcomputer. The natural subunit of this data base is the refereed publication, 165 of which were included. Reported values for the Mr (approx. 97,000) are in good agreement, but this agreement becomes progressively worse as one examines the Km values for glucose and ATP and the Ki for glucose 6-phosphate, where the reported values are spread over three orders of magnitude. Some quantities are very thinly or unreliably determined. Experimental conditions, especially free Mg2+ concentration, are rarely close to physiological. Reasons for the spread or uncertainty of numbers, and the distinctions that can be made between isoenzymes despite this spread, are discussed.

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“…Recently, however, Matschinsky et al proposed that the anomeric specificity of hexose metabolism in islet cells is attributable to a limited preference of glucokinase for the ct-anomer of either D-glucose or D-mannose [9,10]. The latter claim was considered in the framework of the concept that glucokinase would act as a glucoreceptor in the pancreatic B-cell [11,12].In the present report, we will review recent experimental findings which clearly indicate that glucokinase is not the enzyme responsible for the anomeric specificity of glucose metabolism in islet cells. …”

mentioning

confidence: 99%

Glucokinase is not the pancreatic B-cell glucoreceptor

Malaisse¹,

Sener²

1985

Diabetologia

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Summary. A series of recent experimental findings are reviewed to indicate that glucokinase does not represent the pancreatic B-cell glucoreceptor.(1) Whether in liver, pancreatic islet or insulin-producing tumoral cell homogenates, glucokinase fails to yield a higher reaction velocity with a-than r-D-glucose. (2) At a high glucose concentration (40 mmol/1), when the phosphorylation of glucose by glucokinase is indeed higher with r-than a-D-glucose, no preference for r-D-glucose is observed in intact islets, as judged from the utilization of D-[5-3H]glucose, production of lactic acid, oxidation of D-[u-laC]glucose, net uptake of 45Ca or release of insulin. (3) The glucose 6-phosphate content of intact islets is higher in the presence oft-than a-D-glucose. (4) At a low glucose concentration (3.3 mmol/1), when the participation of glucokinase to hexose phosphorylation is minimal, a-D-glucose is still better metabolized and stimulates both 45Ca net uptake and insulin release more efficiently than r-D-glucose, despite the fact that hexokinase yields a higher reaction velocity with r-than a-Dglucose. (5) (6) In islets removed from fasted rats, the rate of glycolysis is more severely decreased than expected from the repression of glucokinase. (7) The metabolism of glucose in tumoral insulin-producing cells differs, in several respects, from that in normal pancreatic islets, although the pattern of hexokinase and glucokinase activities is similar in these two types of cells. All these observations point to the participation of regulatory sites distal to glucose phosphorylation in the control of glucose metabolism in islet cells. Key words:Pancreatic islets, insulin-producing tumoral cells, glucose anomers, glucokinase, hexokinase.In the 1972 Minkowski Lecture [1], a model was presented for the stimulation of insulin release by nutrient secretagogues and its modulation by polypeptide and adrenergic hormones. The model aimed at illustrating how changes in either the fluxes and intracellular distribution of calcium or generation of cyclic AMP may provide a multifactorial regulation for a single process of release, as mediated by the microtubular-microfilamentous effector system. In addition, it was briefly proposed, at variance with a current view at that time [2,3], "that glucose has to be transported and metabolized in the B cell in order to stimulate insulin secretion". In further work, my colleagues and I concentrated mainly on the validity of the latter proposal. We eventually reached the conclusion that the insulinotropic action of nutrient secretagogues indeed reflects their capacity to augment oxidative fluxes in the islet cells, this being defined as the fuel hypothesis [4] or fuel concept [5] for insulin release.One of the essential arguments in support of this fuel concept consisted of the finding that the higher insulinotropic capacity of the a-than fl-anomer of either Dglucose or D-mannose coincides with a higher rate of glycolysis in pancreatic islets exposed to the a-as distinct from fl-anomer of these two ...

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Computer modeling identifies glucokinase as glucose sensor of pancreatic beta-cells

Cited by 10 publications

References 0 publications

Pancreatic islet glucose metabolism and regulation of insulin secretion

Pancreatic islet glucose metabolism and regulation of insulin secretion

Kinetic properties of hexokinase as assembled with a microcomputer data base

Glucokinase is not the pancreatic B-cell glucoreceptor

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