Actions of novel antidiabetic thiazolidinedione, T‐174, in animal models of non‐insulin‐dependent diabetes mellitus (NIDDM) and in cultured muscle cells
K Arakawa, T Ishihara, M Aoto… - British journal of …, 1998 - Wiley Online Library
K Arakawa, T Ishihara, M Aoto, M Inamasu, A Saito, K Ikezawa
British journal of pharmacology, 1998•Wiley Online Library1 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 …
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 …
- 1The antihyperglycaemic effect and the possible mechanism of action of T‐174, a novel thiazolidinedione derivative, was determined in vivo and in vitro.
- 2Oral 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.
- 3The 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.
- 4Insulin‐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.
- 5The hypomagnesaemia in KK‐Ay mice was completely restored by T‐174.
- 6In 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.
- 7These 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.
British Journal of Pharmacology (1998) 125, 429–436; doi:10.1038/sj.bjp.0702066
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