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 e ect 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 71 day 71 , for 7 days) and Zucker fatty rats (1.4 ± 11.4 mg kg 71 day 71 , for 6 days). The ED 50 values for the glucose lowering action of T-174 and pioglitazone, another thiazolidinedione antidiabetic, were 1.8 and 29 mg kg 71 day 71 , respectively in KK-A y mice; T-174 was about 16 times more potent than pioglitazone. 3 The hypoglycaemic e ect 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 a nity 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 [ 3 H]-2-deoxy-glucose transport were enhanced by T-174 (EC 50 ; 6 and 4 mM, respectively). Combination of insulin with T-174 was additive to stimulate glucose disposal. 7 These results suggest that the antihyperglycaemic e ect 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.

Regulation of Glucose Transport and Insulin Signaling by Troglitazone or Metformin in Adipose Tissue of Type 2 Diabetic Subjects

“…None of these defects were influenced by metformin treatment. There are reports of thiazolidinediones improving adipocyte glucose uptake and GLUT4 expression in various animal models of insulin resistance (38,39), results that mirror the current findings in human adipocytes and suggest that the effects are general to the class of thiazolidinediones and not specific for troglitazone.…”

Direct Thiazolidinedione Action on Isolated Rat Skeletal Muscle Fuel Handling Is Independent of Peroxisome Proliferator–Activated Receptor-γ−Mediated Changes in Gene Expression

“…Rapid stimulation of lactate release by 20 I nsulin resistance is a common metabolic abnormality associated with obesity, hypertension, and type 2 diabetes (1). Thiazolidinediones (TZDs) are a class of oral antidiabetic agents that improve insulin sensitivity and glucose homeostasis in type 2 diabetic patients (2-4) as well as in various animal models of diabetes and obesity (2)(3)(4)(5)(6)(7)(8)(9). The TZDs troglitazone, rosiglitazone, and pioglitazone have already been used in clinical practice, but the mechanisms by which TZDs improve insulin sensitivity as well as deranged glucose and lipid metabolism are not yet fully understood (2)(3)(4)10).…”

Thiazolidinediones: metabolic actions in vitro

“…In many studies, TZDs were found to stimulate glucose transport into skeletal muscle in vitro [16,70,111,112,113,114,115,116,117,118,119,120] but the accompanying changes in intracellular glucose fluxes were rather inconsistent, ranging from stimulation to inhibition of both glucose oxidation and glycogen synthesis [16,70,111,112,113,114,121]. The heterogeneity of effects on intracellular glucose routing is obviously related to the diversity in experimental settings.…”

“…The most important observation supporting a causal interdependence between TZD-induced PPARγ activation and the improvement of glucose homeostasis is the association of PPARγ agonistic activity in vitro with antidiabetic action in vivo, which characterizes numerous TZDs [16,37,69,70,71,72], and also non-TZD PPARγ agonists belonging to the classes of isoxazolidinediones [73,74], tyrosine derivatives [75,76,77], and phenylacetic or phenoxyacetic acid derivatives [37]. Although the maximal antihyperglycaemic potentials of many TZDs and other PPARγ agonists are similar, oral dose requirements for half-maximal glucose lowering in diabetic mice differ considerably and correlate strongly with PPARγ binding activities and transactivating potentials of the respective compound in vitro [37, 69,71].…”

“…The heterogeneity of effects on intracellular glucose routing is obviously related to the diversity in experimental settings. Studies varied with regard to the structure and concentration of the TZD used, the period of exposure, and the muscle preparations which included perfused rat hindlimb [120], freshly isolated rat soleus muscle [16,111,112,113,121], pre-cultured human muscle biopsies [114,115,116], and permanently cultured muscle cell lines [70,117,118,119]. Comparing different studies is further complicated by the lipophilic character of TZDs that strongly bind to protein [122], which implies a modulation of the bioavailable TZD concentration in vitro by the quantity and quality of protein and detergent added to the incubation or perfusion medium.…”