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A proposal for the locus of metformin's clinical action: potentiation of the activation of pyruvate kinase by fructose-1,6-diphosphate

, : A proposal for the locus of metformin's clinical action: potentiation of the activation of pyruvate kinase by fructose-1,6-diphosphate. Medical Hypotheses 52(2): 89-93

Reduction of hepatic glucose output has been shown to be the chief basis for metformin's clinical benefit in diabetes, and the balance of the evidence suggests that this reflects inhibition of gluconeogenesis. Recent research with hepatocyte cell cultures demonstrates increased flux through pyruvate kinase in metformin-treated cells. An analysis of the conditions under which clinically relevant concentrations of metformin inhibit gluconeogenesis in hepatocyte cultures prompts the hypothesis that metformin potentiates the allosteric activation of pyruvate kinase by fructose-1,6-diphosphate. This model rationalizes several salient features of metformin's clinical activity: its ability to reduce hepatic triglyceride synthesis, its appetite-suppressant effect, and its failure to induce hypoglycemia.


PMID: 10340287

DOI: 10.1054/mehy.1997.0597

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