Effects of a New Oral Hypoglycaemic Agent (CS‐045) on Metabolic Abnormalities and Insulin Resistance in Type 2 Diabetes

Mimura, Kazuo; Umeda, Fumio; Hiramatsu, Shinsuke; Taniguchi, Setsuo; Ono, Yasuhiro; Nakashima, Naoki; Kobayashi, Kazuo; Masakado, Mitsunori; Sako, Yasuhiro; Nawata, Hajime

doi:10.1111/j.1464-5491.1994.tb00333.x

Cited by 83 publications

(47 citation statements)

References 23 publications

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“…One of the thiazolidinedione derivatives, troglitazone (TGZ), was recently applied to the treatment of type 2 diabetic patients with insulin resistance. Evidence from both in vivo and in vitro studies indicates that TGZ alters glucose, protein, and lipid metabolism (2)(3)(4)(5). The thiazolidinediones are high-affinity ligands for the adipocyte-specific peroxisome proliferatoractivated receptor (PPAR)-␥ form (6).…”

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Troglitazone Induces GLUT4 Translocation in L6 Myotubes

et al. 2001

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A number of studies have demonstrated that insulin resistance in the skeletal muscle plays a pivotal role in the insulin resistance associated with obesity and type 2 diabetes. A decrease in GLUT4 translocation from the intracellular pool to the plasma membranes in skeletal muscles has been implicated as a possible cause of insulin resistance. Herein, we examined the effects of an insulin-sensitizing drug, troglitazone (TGZ), on glucose uptake and the translocation of GLUT4 in L6 myotubes. The prolonged exposure (24 h) of L6 myotubes to TGZ (10 ؊5 mol/l) caused a substantial increase in the 2-deoxy-[ 3 H]D-glucose (2-DG) uptake without changing the total amount of the glucose transporters GLUT4, GLUT1, and GLUT3. The TGZ-induced 2-DG uptake was completely abolished by cytochalasin-B (10 mol/l). The ability of TGZ to translocate GLUT4 from light microsomes to the crude plasma membranes was greater than that of insulin. Both cycloheximide treatment (3.5 ؋ 10 ؊6 mol/l) and the removal of TGZ by washing reversed the 2-DG uptake to the basal level. Moreover, insulin did not enhance the TGZ-induced 2-DG uptake additively. The TGZ-induced 2-DG uptake was only partially reversed by wortmannin to 80%, and TGZ did not change the expression and the phosphorylation of protein kinase B; the expression of protein kinase C (PKC)-, PKC-␤2, and PKC-; or 5AMP-activated protein kinase activity. ␣-Tocopherol, which has a molecular structure similar to that of TGZ, did not increase 2-DG uptake. We conclude that the glucose transport in L6 myotubes exposed to TGZ for 24 h is the result of an increased translocation of GLUT4. The present results imply that the effects of troglitazone on GLUT4 translocation may include a new mechanism for improving glucose transport in skeletal muscle.

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Troglitazone Induces GLUT4 Translocation in L6 Myotubes

et al. 2001

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“…T hiazolidinediones, insulin-sensitizing agents, improve hyperglycemia and hyperinsulinemia by increasing insulin responsiveness and/or sensitivity in obese, type 2 diabetic, and glucoseintolerant patients (1,2). These compounds increase peripheral glucose uptake, while decreasing the serum insulin level and gluconeogenesis in rodent models of type 2 diabetes (3)(4)(5).…”

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Troglitazone Not Only Increases GLUT4 but Also Induces Its Translocation in Rat Adipocytes

et al. 2001

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Thiazolidinediones, insulin-sensitizing agents, have been reported to increase glucose uptake along with the expression of glucose transporters in adipocytes and cardiomyocytes. Recently, we have further suggested that the translocation of GLUT4 is stimulated by thiazolidinediones in L6 myocytes. However, the direct effects of thiazolidinediones on translocation of glucose transporters have not yet been determined. In this study, using hemagglutinin epitope-tagged GLUT4 (GLUT4-HA), we provide direct evidence of the effect of troglitazone on the translocation of GLUT4 in rat epididymal adipocytes. Primary cultures of rat adipocytes were transiently transfected with GLUT4-HA and overexpressed eightfold compared with endogenous GLUT4 in transfected cells. A total of 24 h of treatment with troglitazone (10 ؊4 mol/l) increased the cell surface level of GLUT4-HA by 1.5 ؎ 0.03-fold (P < 0.01) without changing the total amount of GLUT4-HA, whereas it increased the protein level of endogenous GLUT4 (1.4-fold) without changing that of GLUT1. Thus, the direct effect on the translocation can be detected apart from the increase in endogenous GLUT4 content using GLUT4-HA. Troglitazone not only increased the translocation of GLUT4-HA on the cell surface in the basal state but also caused a leftward shift in the doseresponse relations between GLUT4-HA translocation and insulin concentration in the medium (ED 50 : from ϳ0.1 to 0.03 nmol/l). These effects may partly contribute to the antidiabetic activity of troglitazone in patients with obesity and type 2 diabetes.

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“…Troglitazone is a new oral antidiabetic agent reported to enhance insulin sensitivity [22], increase the conversion of glucose to glycogen in rat HepG2 cells [22], reduce hepatic gluconeogenic enzyme activity in rats and mice [23] and to improve metabolic control in non-insulin-dependent diabetic patients [24][25][26]. Troglitazone has also been demonstrated to reduce lipid peroxidation [27].…”

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Effects of troglitazone on in vitro oxidation of LDL and HDL induced by copper ions and endothelial cells

Cominacini

Garbin

Pastorino³

et al. 1997

Diabetologia

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Low density lipoprotein (LDL) oxidation is believed to play an important role in the development of atherosclerotic plaques [1][2][3][4][5]. This view is supported by LDL with characteristics similar to those of oxidatively modified LDL being present in atheromatous lesions [6]. Studies in cultured cells have demonstrated that oxidized LDL is chemotactic for monocytes and stimulates monocyte endothelial cell interaction [7,8]. It can also cause initial endothelial cell damage and increase uptake by scavenger receptors on macrophages, leading to cholesterol accumulation and foam cell formation [7,9].Oxidative modification of LDL is not likely to occur in circulation [3]. In view of the difficulties in identifying oxidized lipoprotein in plasma, many workers have attempted to analyse the oxidation susceptibility of isolated LDL particles in vitro [10,11]. If LDL can penetrate macrophages only after its modification [3], the ability of LDL to resist oxidation could be an Diabetologia (1997) Summary Troglitazone is a new oral antidiabetic agent able to reduce lipid peroxidation. In this study we evaluated its effect on the susceptibility of LDL and HDL to in vitro oxidation induced by copper ions and endothelial cells. In Cu ++ -induced LDL modification, different amounts of troglitazone were added to aliquots of the same pool of plasma with subsequent ultracentrifuge separation of LDL and HDL. Differences in LDL and HDL susceptibility to in vitro oxidation with Cu ++ were studied by measuring the changes in fluorescence intensity (expressed as lag phase). LDL derived from plasma incubated with different amounts of troglitazone were also incubated with umbilical vein endothelial cells (HU-VEC), the modification being monitored by LDL relative electrophoretic mobility and fluorescence. During Cu ++ -and HUVEC-induced LDL oxidation, the decay rate of vitamin E, and the potency of troglitazone as a radical scavenger in comparison with vitamin E were also studied. Troglitazone determined a significant, dose-dependent decrease in Cu ++ -induced LDL and HDL oxidation. Incubation with HUVEC was also followed by a progressive, significant decrease of LDL relative electrophoretic mobility and fluorescence intensity. During Cu ++ -and HU-VEC-induced-LDL modification, troglitazone significantly reduced the rate of vitamin E decay. In this study we also demonstrated that under the same oxidative stress, troglitazone was much more potent as a radical scavenger than vitamin E. In conclusion, the results demonstrate that troglitazone can reduce LDL and HDL in vitro oxidation and that, during this process, it can protect vitamin E. In addition to ensuring blood glucose control, the drug may therefore be useful in inhibiting lipoprotein peroxidation. [Diabetologia (1997)

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Effects of a New Oral Hypoglycaemic Agent (CS‐045) on Metabolic Abnormalities and Insulin Resistance in Type 2 Diabetes

Cited by 83 publications

References 23 publications

Troglitazone Induces GLUT4 Translocation in L6 Myotubes

Troglitazone Induces GLUT4 Translocation in L6 Myotubes

Troglitazone Not Only Increases GLUT4 but Also Induces Its Translocation in Rat Adipocytes

Effects of troglitazone on in vitro oxidation of LDL and HDL induced by copper ions and endothelial cells

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