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Opposite effects of a glucokinase activator and metformin on glucose-regulated gene expression in hepatocytes

Lookup NU author(s): Dr Ziad Al-Oanzi, Sofia Fountana, Tabassum Moonira, Dr Susan Tudhope, John Petrie, Ahmed Alshawi, Dr Gillian Patman, Dr Catherine Arden, Professor Helen Reeves, Professor Loranne Agius

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This is the authors' accepted manuscript of an article that has been published in its final definitive form by Wiley-Blackwell, 2017.

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Abstract

Aim: Small molecule activators of glucokinase (GKAs) have been extensively explored as potential anti-hyperglycaemic drugs for type 2 diabetes (T2D). Several GKAs were remarkably effective at lowering blood glucose during early therapy but then lost their glycaemic efficacy chronically during clinical trials. We used rat hepatocytes to test the hypothesis that GKAs raise hepatocyte glucose 6-phosphate, (G6P, the glucokinase product) and down-stream metabolites with consequent repression of the liver glucokinase gene (Gck). We compared a GKA with metformin, the most widely prescribed drug for T2D. Results: Treatment of hepatocytes with 25mM glucose raised cell G6P concomitantly with Gck repression and induction of G6pc (glucose 6-phosphatase) and Pklr (pyruvate kinase). A GKA mimicked high glucose by raising G6P and fructose-2,6-bisphosphate, a regulatory metabolite, causing a left-shift in glucose responsiveness on gene regulation. Fructose like the GKA repressed Gck but modestly induced G6pc. 2-Deoxyglucose, which is phosphorylated by glucokinase, but not further metabolised caused Gck repression but not G6pc induction, implicating the glucokinase product in Gck repression. Metformin counteracted the effect of high glucose on the elevated G6P and fructose 2,6-bisphosphate and on Gck repression, recruitment of Mlx-ChREBP to the G6pc and Pklr promoters and induction of these genes. Conclusions: 1. Elevation in hepatocyte G6P and downstream metabolites with consequent liver Gck repression is a potential contributing mechanism to the loss of GKA efficacy during chronic therapy. 2. Cell metformin loads within the therapeutic range attenuate the effect of high glucose on G6P and on glucose-regulated gene expression.


Publication metadata

Author(s): Al-Oanzi ZH, Fountana S, Moonira T, Tudhope SJ, Petrie JL, Alshawi A, Patman G, Arden C, Reeves HL, Agius L

Publication type: Article

Publication status: Published

Journal: Diabetes, Obesity and Metabolism

Year: 2017

Volume: 19

Issue: 8

Pages: 1078-1087

Print publication date: 01/08/2017

Online publication date: 16/02/2017

Acceptance date: 11/02/2017

ISSN (print): 1462-8902

ISSN (electronic): 1463-1326

Publisher: Wiley-Blackwell

URL: http://dx.doi.org/10.1111/dom.12910

DOI: 10.1111/dom.12910


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