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- Title
Stimulating Effect of the New Antidiabetic Compound EMD387008 on Muscle Glucose Uptake.
- Authors
Bozec-Hallakou, Sophie; Mésangeau, Didier; Doaré, Liliane; Durbin, Philippe
- Abstract
EMD387008, the first representative of a new class of antidiabetic drugs, is currently under clinical development for the treatment of T2DM. Skeletal muscle is the major site of insulin-stimulated glucose disposal and its insulin resistance is a contributing factor in the pathogenesis of T2DM. The effects of EMD387008 on muscle glucose uptake using in vitro and in vivo experimental models were investigated. In L6 muscle cell line: Cells were incubated with EMD387008 for 20h in absence of insulin and glucose uptake was measured (2-Deoxy-D [1,2-³H] glucose). EMD387008 increased significantly and in a dose-dependent manner the glucose uptake at 0.5mM 7.8±0.4, at 1mM 11.7±0.9 and at 2mM 12.8±0.8 vs 5.4±0.2pmol/min/mg protein in control group (p<0.01 Dunnett test). In isolated muscle: Glucose uptake was measured in EDL (extensor digitorum longus) muscle from GK diabetic rat after incubation of 2-Deoxy-D (1.2-³H) glucose without added insulin. Incubation with EMD387008 for 4h increased significantly muscle glucose uptake at the highest dose (2mM) (60±9.6 vs control 20.5±5.3nmol/g. 10min). In perfused hindlimb of Wistar rats: EMD 387008 increased muscle glucose uptake significantly and dose-dependently from 30µg/ml (AUC glucose 104.82 ±16.7 vs 5.13±5.06µmol/g.h in Wistar control group (p<0.001 Dunnett test n=9-10) after perfusion of 16mM of glucose with no insulin in the medium. In STZ treated rats: Muscle glucose consumption was assessed with (2-Deoxy-D (1.2-³H) glucose and Sokoloff method, after chronic treatment with EMD387008 for 45 days at 25, 50 and 100mg/kg po. From 50mg/kg, EMD387008 restored significantly the glucose consumption in soleus muscle 5.39±0.56 vs 3.71±0.3 in control STZ rats. In gastrocnemius muscle, EMD387008 induced a similar effect: 1.13±0.14 vs 0.7±0.05µmol/g.min in control STZ rats. The glucose lowering effect of EMD387008 observed in diabetic animals could partially be explained by an increase of muscle glucose uptake through an insulin-independent mechanism. The direct stimulation of muscle glucose uptake supports the promising profile of EMD387008 for the treatment of T2DM.
- Subjects
HYPOGLYCEMIC agents; SUGAR in the body; MUSCULOSKELETAL system; INSULIN resistance; TYPE 2 diabetes
- Publication
Diabetes, 2007, Vol 56, pA157
- ISSN
0012-1797
- Publication type
Article