Actions of novel antidiabetic thiazolidinedione, T-174, in animal models of non-insulin-dependent diabetes mellitus (NIDDM) and in cultured muscle cells.
1. The antihyperglycaemic effect and the possible mechanism of action of T-174, a novel thiazolidinedione derivative, was determined in vivo and in vitro. 2. Oral administration of T-174 markedly improved hyperglycaemia, hyperinsulinaemia, hyperlipidaemia, and glucose intolerance in genetically obese and diabetic yellow KK (KK-Ay) mice (0.2-15.5 mg kg(-1) day(-1), for 7 days) and Zucker fatty rats (1.4-11.4 mg kg(-1) day(-1), for 6 days). The ED50 values for the glucose lowering action of T-174 and pioglitazone, another thiazolidinedione antidiabetic, were 1.8 and 29 mg kg(-1) day(-1), respectively in KK-Ay mice; T-174 was about 16 times more potent than pioglitazone. 3. The hypoglycaemic effect of exogenous insulin in KK-Ay mice was enhanced after the administration of T-174. A hyperinsulinaemic euglycaemic clamp study in Zucker fatty rats showed an amelioration of whole-body insulin resistance by the T-174 treatment. 4. Insulin-stimulated glucose metabolism was enhanced in adipocytes from KK-Ay mice treated with T-174. The insulin receptor number of the adipocytes was increased without a change in the affinity of the receptor. 5. The hypomagnesaemia in KK-Ay mice was completely restored by T-174. 6. In cultured L6 myotubes, glucose consumption and [3H]-2-deoxy-glucose transport were enhanced by T-174 (EC50; 6 and 4 microM, respectively). Combination of insulin with T-174 was additive to stimulate glucose disposal. 7. These results suggest that the antihyperglycaemic effect of T-174 was mediated by enhanced insulin action. This was associated with amelioration of the hypomagnesaemia and T-174 directly increased basal and insulin-stimulated glucose utilization by cultured muscle cells.
Arakawa
K
K
Discovery Research Laboratory, Tanabe Seiyaku Co., Ltd., Toda, Saitama, Japan.
Ishihara
T
T
Aoto
M
M
Inamasu
M
M
Saito
A
A
Ikezawa
K
K
D000818:Animals; D001786:Blood Glucose; D002478:Cells, Cultured; D003837:Deoxy Sugars / Q000493:pharmacokinetics; D003924:Diabetes Mellitus, Type 2 / Q000188:drug therapy*; D007004:Hypoglycemic Agents / Q000627:therapeutic use; D066298:In Vitro Techniques; D008297:Male; D051379:Mice; D018482:Muscle, Skeletal / Q000187:drug effects; D051381:Rats; D011924:Rats, Zucker; D013844:Thiazoles / Q000494:pharmacology / Q000627:therapeutic use*; D045162:Thiazolidinediones
D001786:Blood Glucose; D003837:Deoxy Sugars; D007004:Hypoglycemic Agents; D013844:Thiazoles; D045162:Thiazolidinediones; C089946:2,4-thiazolidinedione