title: Direct regulation of glucose and not insulin on hepatic hexose-6-phosphate dehydrogenase and 11β-hydroxysteroid dehydrogenase type 1.
abstract: Abnormal hepatic gluconeogenesis contributes significantly to both fasting and non-fasting hyperglycemia of patients with type 2 diabetes. 11β-hydroxysteroid dehydrogenase type 1 (11β-HSD1) regulates the key hepatic gluconeogenic enzymes including phosphoenolpyruvate carboxykinase (PEPCK) and glucose-6-phosphatase (G6Pase) through the amplification of glucocorticoid receptor (GR) - mediated tissue glucocorticoid action, and is crucially dependent on hexose-6-phosphate dehydrogenase (H6PDH) - generating NADPH system. Here, we observed that compared with fasting state, H6PDH and 11β-HSD1 expression in livers were all increased under non-fasting state in both normal and diabetic rats, and the non-fasting diabetic group was the highest among the four experimental groups. Moreover, incubation of primary hepatocytes with increasing glucose caused dose-dependent increases in H6PDH, 11β-HSD1, GR, PEPCK and G6Pase expression. Also, glucose-6-phosphate (G6P) had a positive regulation on H6PDH and 11β-HSD1 in hepatocytes. In addition, primary hepatocytes treated with different doses of insulin in high glucose induced alteration of H6PDH and 11β-HSD1 while in low glucose there was no significant effect. These findings suggest that glucose instead of insulin directly regulates H6PDH and 11β-HSD1 and suppression of the two enzymes could be considered as an effective target for the treatment of type 2 diabetes.
authors.affiliation: Department of Pharmacology, School of Basic Medical Sciences, Jilin University, Changchun, China.
authors.forename: Zheng
authors.initials: Z
authors.lastname: Fan
authors.forename: Hongwei
authors.initials: H
authors.lastname: Du
authors.forename: Ming
authors.initials: M
authors.lastname: Zhang
authors.forename: Zhaojie
authors.initials: Z
authors.lastname: Meng
authors.forename: Li
authors.initials: L
authors.lastname: Chen
authors.forename: Yanjun
authors.initials: Y
authors.lastname: Liu
mesh_terms: D043205:11-beta-Hydroxysteroid Dehydrogenase Type 1 / Q000235:genetics / Q000378:metabolism*; D000818:Animals; D015153:Blotting, Western; D002237:Carbohydrate Dehydrogenases / Q000235:genetics / Q000378:metabolism*; D002478:Cells, Cultured; D003921:Diabetes Mellitus, Experimental / Q000378:metabolism; D003924:Diabetes Mellitus, Type 2 / Q000235:genetics / Q000378:metabolism*; D004195:Disease Models, Animal; D005215:Fasting; D015870:Gene Expression; D005943:Gluconeogenesis; D005947:Glucose / Q000494:pharmacology*; D019298:Glucose-6-Phosphate / Q000494:pharmacology; D022781:Hepatocytes / Q000201:enzymology / Q000378:metabolism; D006943:Hyperglycemia; D007328:Insulin / Q000494:pharmacology*; D008099:Liver / Q000201:enzymology* / Q000378:metabolism; D016133:Polymerase Chain Reaction; D051381:Rats
chemical_list: D007328:Insulin; D019298:Glucose-6-Phosphate; D002237:Carbohydrate Dehydrogenases; C020552:galactose-6-phosphate dehydrogenase; D043205:11-beta-Hydroxysteroid Dehydrogenase Type 1; D005947:Glucose