Actions of novel antidiabetic thiazolidinedione, T-174, in animal models of non-insulin-dependent diabetes mellitus (NIDDM) and in cultured muscle cells

Abstract

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-A^y) 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-A^y mice; T-174 was about 16 times more potent than pioglitazone.

3. The hypoglycaemic effect of exogenous insulin in KK-A^y 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-A^y 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-A^y 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 μM, 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.

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