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- Title
EMD387008, a New Antidiabetic Compound, Inhibits Hepatic Lactate Gluconeogenesis in Zucker Diabetic Fatty (ZDF) Rats: a Carbon-13 NMR Study.
- Authors
Baverel, G.; Collidor, N.; Konecni, L.; Audet, A.; Mésangeau, D.; Pinteur, C.; Martin, G.; Gauthier, C.
- Abstract
EMD387008, the first representative of a new class of antidiabetic drugs, has been previously shown to decrease hyperglycemia in diabetic animal models. It is currently under clinical development for the treatment of Type 2 diabetes. The objective of this study was to investigate in vitro the activity of EMD387008 on hepatic gluconeogenesis, which contributes to hyperglycemia in diabetes. Precision-cut liver slices from adult male ZDF rats were incubated in oxygenated Krebs-Henseleit medium with variously [sup 13]C-labeled lactates (5 mM) or with 5 mM unlabeled lactate plus 25 mM [sup 13]C-bicarbonate. Substrate removal (lactate and glycogen) and product formation were measured by enzymatic and [sup 13]C-NMR spectroscopy methods. In slices from fasted lean ZDF rats, EMD387008 dose-dependently inhibited [sup 13]C-glucose synthesis from [2-[sup 13]C]-lactate (IC50 5.6mM). The labelling patterns of the glucoses synthesized from [1-[sup 13]C]-, [2-[sup 13]C]- and [3-[sup 13]C]-lactate as well as from lactate plus [sup 13]C-bicarbonate indicated that lactate gluconengenesis involved not only the passage of carbons through pyruvate carboxylase and the reversible equilibration of oxaloacetate with fumarate but also pyruvate dehydrogenase and the entire tricarboxylic acid cycle. In slices from fed diabetic ZDF rats, 6mM of EMD387008 inhibited lactate consumption by 70%, glucose production by 30% and the synthesis of all the [sup 13]C-labeled glucose carbons from all [sup 13]C-labeled substrates by 73, 76, 72 and 67%, respectively, but did not change glycogen degradation. EMD387008 also caused a reduction of cellular ATP levels and of [sup 13]CO[sub 2] production from [sup 13]C-lactates but increased the beta-hydroxybutyrate/acetoacetate ratio, which reflects the mitochondrial redox state. These results show that EMD387008 produced a strong reduction of hepatic glucose production that could be partially explained by a decrease in mitochondrial redox potential. The gluconeogenesis inhibition could contribute to the glucose lowering effect of EMD387008 observed in diabetic rat models.
- Publication
Diabetes, 2007, Vol 56, pA157
- ISSN
0012-1797
- Publication type
Academic Journal