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- Title
EMD387008, a New Antidiabetic Compound, Inhibits Hepatic Gluconeogenesis through Gluconeogenic Gene Regulation and AMPK Activation.
- Authors
Raynal, Sophie; Audet, Annick; MéSangeau, Didier; Durbin, Philippe; Augert, Guy
- Abstract
EMD387008 was previously shown to decrease hyperglycemia of diabetic rats partly by a gluconeogenesis inhibition. This 1st representative of a new class is currently under clinical development for T2DM treatment. The study objective was to investigate in vitro the mechanism of EMD387008-induced inhibition on hepatic gluconeogenesis. Isolated rat hepatocytes were incubated with various concentrations of EMD387008 (0.25mM to 1.5mM) for 18h and then for 3h in the presence of gluconeogenic precursors and AMPc/Dexamethasone. EMD387008 decreased significantly and dose-dependently glucose production with an IC50 of about 0.7mM. We investigated the mechanisms of action underlying the inhibition of hepatic glucose production by measuring EMD387008 effect on gene expression of PEPCK and G6Pase. Rat hepatoma H4IIE cells were serum-starved before adding EMD387008 at various concentrations (0.25mM to 2mM). G6Pase and PEPCK gene expression were stimulated by addition of AMPc/Dexa for 3h and measured by real-time PCR. Incubation with AMPc/Dexa resulted in a 2.7 fold increase in the expression of G6Pase. G6Pase expression level decreased to basal level when cells were incubated with 0.5mM of EMD387008. PEPCK expression is strongly increased in the presence of AMPc/Dexa. Incubation of H4IIE cells with EMD387008 at 1mM restored the induced-expression of PEPCK to basal levels. AMPK activation is described as a mechanism by which PEPCK and G6Pase gene expression could be regulated. The effect of EMD387008 on AMPK activation was studied by measuring the phosphorylation of the Thr 172 of the AMPK α subunit. EMD387008 dose-dependently promoted AMPK activation suggesting a link between this protein kinase activation, the down-regulation of PEPCK and G6Pase expression and the hepatic glucose production decrease. These results indicate that the EMD387008 glucose lowering effect shown in diabetic rat models could partially be explained by a hepatic glucose production inhibition. This also suggests that the EMD387008 effect involves AMPK activation and a subsequent downregulation of gluconeogenic genes expression.
- Subjects
HYPOGLYCEMIC agents; HYPERGLYCEMIA treatment; REGULATION of gluconeogenesis; DIABETES; GENETIC regulation
- Publication
Diabetes, 2007, Vol 56, pA157
- ISSN
0012-1797
- Publication type
Article