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Phlorizin treatment of diabetic rats paratially reverses the abnormal expression of genes involved in hepatic glucose metabolism

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Brichard, Sonia [UCL] Henquin, Jean-Claude [UCL] Girard, Jean

Liver insulin resistance and glucagon-stimulated hepatic glucose production are characteristics of the diabetic state. To determine the potential role of glucose toxicity in these abnormalities, we examined whether phlorizin treatment of streptozotocin-diabetic rats resulted in altered expression of genes involved in key steps of hepatic glucose metabolism. By inhibiting renal tubular glucose reabsorption, phlorizin infusion to diabetic rats induced normoglycaemia, did not significantly alter low circulating insulinaemia, but caused a marked decrease in hyperglucagonaemia. Glucokinase and L-type pyruvate kinase mRNA levels were reduced respectively by 90% and 70% in fed diabetic rats, in close correlation with changes in enzyme activities. Eighteen days of phlorizin infusion partially restored glucokinase mRNA and activity (40% of control levels), but had no effect on L-type pyruvate kinase mRNA and activity. In contrast to the glycolytic enzymes, mRNA and activity of the gluconeogenic enzyme, phospoenolpyruvate carboxykinase were increased (10- and 2.2-fold, respectively) in fed diabetic rats. Phlorizin administration decreased phospoenolpyruvate carboxykinase mRNA to values not different from those in control rats, while phospoenolpyruvate carboxykinase activity remained 50% higher than that in control rats. The 50% rise in liver glucose transporter (GLUT 2) mRNA and protein, produced by diabetes, was also corrected by phlorizin treatment. In conclusion, we propose that phlorizin treatment of diabetic rats may induce a partial shift of the predominating gluconeogenesis, associated with hepatic glucose overproduction, into glycolysis, by correction of impaired pre-translational regulatory mechanisms. This could be essentially mediated through improved pancreatic alpha-cell function and subsequent lowering of hyperglucagonaemia. These observations suggest that glucagon-stimulated hepatic glucose production may result, in part, from glucose toxicity.

Document type Article de périodique (Journal article) – Article de recherche
Access type Accès restreint
Publication date 1993
Language Anglais
Journal information "Diabetologia : clinical and experimental diabetes and metabolism" - Vol. 36, no. 4, p. 292-298 (1993)
Peer reviewed yes
Publisher Springer ((Germany) Heidelberg)
issn 0012-186X
e-issn 1432-0428
Publication status Publié
Affiliations UCL - (SLuc) Service d'endocrinologie et de nutrition
UCL - MD/FSIO - Département de physiologie et pharmacologie
Keywords Diabetes-Mellitus ; Phlorhizin ; Glucagon ; Hepatic Glucose Metabolism ; Gene Expression
Links
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Bibliographic reference Brichard, Sonia ; Henquin, Jean-Claude ; Girard, Jean. Phlorizin treatment of diabetic rats paratially reverses the abnormal expression of genes involved in hepatic glucose metabolism. In: Diabetologia : clinical and experimental diabetes and metabolism, Vol. 36, no. 4, p. 292-298 (1993)
Permanent URL http://hdl.handle.net/2078.1/145883