Mathematical model of beta-cell glucose metabolism and insulin release. I. Glucokinase as glucosensor hypothesis.
To quantitatively test the theory that glucokinase controls the rate of glucose metabolism and therefore the rate of insulin secretion, a minimal mathematical model of glycolysis in the pancreatic beta-cell was developed. The model represents our current hypothesis of how the normal beta-cell transduces the glucose signal. In this report, the model was used to address questions regarding the control strength of transport, hexokinase, glucose-6-phosphatase, and phosphofructokinase in the metabolism of glucose. The hypothesis that fructose 6-phosphate and a protein regulator modulate glucokinase activity was evaluated by simulation analysis, as was the possibility that glucose-6-phosphatase, working in concert with phosphofructokinase, can modulate the glucose-sensing system. It was found that, in the absence of glucose-6-phosphatase, transport, hexokinase, and phosphofructokinase do not greatly influence the rate of glucose metabolism unless their activities are dramatically altered from the measured values. Glucose metabolism was profoundly affected by the activity of glucokinase. However, in the presence of glucose-6-phosphatase, the ratio of glucose-6-phosphatase to phosphofructokinase activities was a very important parameter, and this potential control mechanism deserves more attention. The results further support the notion that glucokinase is indeed the glucosensor of the beta-cell and that modeling the system in toto provides quantitative evaluation needed to interpret the experimental tests of hypotheses.
Sweet
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IR
Department of Biochemistry and Biophysics, University of Pennsylvania, Philadelphia 19104, USA.
Matschinsky
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FM
D000818:Animals; D001692:Biological Transport; D005636:Fructosephosphates / Q000494:pharmacology; D005941:Glucokinase / Q000037:antagonists & inhibitors / Q000502:physiology*; D005947:Glucose / Q000378:metabolism*; D005952:Glucose-6-Phosphatase / Q000494:pharmacology; D006593:Hexokinase / Q000502:physiology; D006706:Homeostasis; D006801:Humans; D007328:Insulin / Q000378:metabolism*; D007515:Islets of Langerhans / Q000378:metabolism*; D008356:Mannoheptulose / Q000494:pharmacology; D008954:Models, Biological; D010732:Phosphofructokinase-1 / Q000494:pharmacology; D010766:Phosphorylation; D015398:Signal Transduction
D005636:Fructosephosphates; D007328:Insulin; D008356:Mannoheptulose; C027618:fructose-6-phosphate; D006593:Hexokinase; D010732:Phosphofructokinase-1; D005941:Glucokinase; D005952:Glucose-6-Phosphatase; D005947:Glucose