Amelioration by KRP-297, a new thiazolidinedione, of impaired glucose uptake in skeletal muscle from obese insulin-resistant animals.
We examined the effect of KRP-297, a new thiazolidinedione derivative, on glucose uptake in the soleus muscle of two animal models of insulin resistance that show moderate (ob/ob mice) and severe (db/db mice) hyperglycemia. Insulin-stimulated 2-deoxyglucose (2DG) uptake in soleus muscle was 53.8% lower in ob/ob mice versus lean mice (P < .05). When administered to ob/ob mice, KRP-297 (0.3 to 10 mg/kg) decreased plasma glucose and insulin levels and improved the impaired insulin-stimulated 2DG uptake in soleus muscle in a dose-dependent manner. Soleus muscle from db/db mice exhibited defects in both basal (35.0% decrease, P < .01) and insulin-stimulated (50.5% decrease, P < .01) 2DG uptake. These defects were improved by treatment with KRP-297 (0.3 to 10 mg/kg). Moreover, KRP-297 prevented severe hyperglycemia and the marked decrease in pancreatic insulin content in db/db mice. These results suggest that KRP-297 treatment is useful to prevent the development of diabetic syndromes in addition to ameliorating the impaired glucose transport in skeletal muscle.
Murakami
K
K
Central Research Laboratories, Kyorin Pharmaceutical Co Ltd, Tochigi, Japan.
Tsunoda
M
M
Ide
T
T
Ohashi
M
M
Mochizuki
T
T
D000818:Animals; D001786:Blood Glucose / Q000378:metabolism; D005947:Glucose / Q000378:metabolism*; D007004:Hypoglycemic Agents / Q000494:pharmacology*; D007333:Insulin Resistance; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018482:Muscle, Skeletal / Q000378:metabolism*; D009765:Obesity / Q000097:blood / Q000378:metabolism*; D013844:Thiazoles / Q000494:pharmacology*; D053778:Thiazolidines
D001786:Blood Glucose; D007004:Hypoglycemic Agents; D013844:Thiazoles; D053778:Thiazolidines; C116017:5-((2,4-dioxo-5-thiazolidinyl)methyl)-2-methoxy-N-((4-(trifluoromethyl)phenyl)methyl)benzamide; D005947:Glucose