Acute effects of troglitazone on in vivo insulin action in normal rats

Lee, Moon-Kyu; Olefsky, Jerrold M.

doi:10.1016/0026-0495(95)90010-1

Cited by 53 publications

(24 citation statements)

References 11 publications

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“…Both in intact muscle (16) and in vivo (33), TZDs can acutely increase glucose uptake on a scale that suggests that their enhanced transport activity might not be entirely explained by transcriptional events (≤30 min in skeletal muscle, 120 min in vivo). To determine whether mild MPC inhibition can account for this, we measured glucose uptake in L6 myotubes (Fig.…”

Section: Resultsmentioning

confidence: 99%

Thiazolidinediones are acute, specific inhibitors of the mitochondrial pyruvate carrier

Divakaruni¹,

Wiley²,

Rogers³

et al. 2013

Proc. Natl. Acad. Sci. U.S.A.

265

270

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Facilitated pyruvate transport across the mitochondrial inner membrane is a critical step in carbohydrate, amino acid, and lipid metabolism. We report that clinically relevant concentrations of thiazolidinediones (TZDs), a widely used class of insulin sensitizers, acutely and specifically inhibit mitochondrial pyruvate carrier (MPC) activity in a variety of cell types. Respiratory inhibition was overcome with methyl pyruvate, localizing the effect to facilitated pyruvate transport, and knockdown of either paralog, MPC1 or MPC2, decreased the EC 50 for respiratory inhibition by TZDs. Acute MPC inhibition significantly enhanced glucose uptake in human skeletal muscle myocytes after 2 h. These data (i) report that clinically used TZDs inhibit the MPC, (ii) validate that MPC1 and MPC2 are obligatory components of facilitated pyruvate transport in mammalian cells, (iii) indicate that the acute effect of TZDs may be related to insulin sensitization, and (iv) establish mitochondrial pyruvate uptake as a potential therapeutic target for diseases rooted in metabolic dysfunction.AMPK | pioglitazone | rosiglitazone | MSDC-0160 | XF PMP

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Section: Resultsmentioning

confidence: 99%

Thiazolidinediones are acute, specific inhibitors of the mitochondrial pyruvate carrier

Divakaruni¹,

Wiley²,

Rogers³

et al. 2013

Proc. Natl. Acad. Sci. U.S.A.

265

270

View full text Add to dashboard Cite

show abstract

“…It will be critical to determine the specific genes regulated by thiazolidinediones. However, such a mechanism may not account for all of the effects of thiazolidinediones, because troglitazone has been shown to also have acute effects, seen in vivo (32) and in vitro (9,15), on glucose metabolism. Further studies into the mechanisms of action of thiazolidinediones may aid in the development of more specific second generation agents and provide insight into the pathophysiology of insulin resistance, identifying defects that are improved or ameliorated by thiazolidinediones.…”

mentioning

confidence: 99%

Thiazolidinediones and their effects on glucose transporters

Ciaraldi

Henry²

1997

European Journal of Endocrinology

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“…5 However, it is unclear whether thiazolidinediones exert similar effects in normal (nondiabetic) animals. 6,7 Furthermore, effects of thiazolidinediones on myocardial substrate metabolism, mechanical function, and response to ischemia and reperfusion have not been investigated in vivo.…”

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confidence: 99%

Troglitazone Improves Recovery of Left Ventricular Function After Regional Ischemia in Pigs

Zhu

et al. 2000

Circulation

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Background-This study determined whether treatment of normal (nondiabetic) pigs with the insulin-sensitizing agent troglitazone improves recovery of left ventricular (LV) function after acute ischemia and whether such effects are associated with altered myocardial substrate metabolism. Methods and Results-Juvenile pigs (nϭ6) were treated with troglitazone (75 mg ⅐ kg Ϫ1 ⅐ d Ϫ1 PO) for 8 weeks. Untreated pigs (nϭ8) served as controls. Under anesthetized, open-chest conditions, pigs underwent 90 minutes of moderate regional LV ischemia and 90 minutes of reperfusion. Regional LV function was assessed with subendocardial sonomicrometry crystals. Fasting plasma insulin and free fatty acid levels were lower in troglitazone-treated pigs than in untreated pigs, whereas blood glucose did not differ between groups. These findings suggest that treatment enhanced systemic insulin sensitivity. Baseline hemodynamics and regional LV function did not differ between groups. After ischemia and reperfusion, systolic function (external work) of the ischemic region recovered to 44Ϯ6% of baseline in troglitazone-treated pigs versus 18Ϯ6% of baseline in untreated pigs (PϽ0.05). Regional diastolic function (maximum rate of wall expansion) recovered to 78Ϯ7% of baseline in treated pigs versus 52Ϯ7% of baseline in untreated pigs (PϽ0.05). Recovery of global LV systolic and diastolic function was also significantly greater in treated pigs. Myocardial glucose uptake did not differ between groups under any condition; however, net myocardial lactate uptake after reperfusion was 7 times greater in troglitazone-treated pigs than in untreated pigs, suggesting that treatment enhanced myocardial carbohydrate oxidation after reperfusion. Conclusions-In nondiabetic pigs, chronic troglitazone treatment improves recovery of LV systolic and diastolic function after acute ischemia.

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Acute effects of troglitazone on in vivo insulin action in normal rats

Cited by 53 publications

References 11 publications

Thiazolidinediones are acute, specific inhibitors of the mitochondrial pyruvate carrier

Thiazolidinediones are acute, specific inhibitors of the mitochondrial pyruvate carrier

Thiazolidinediones and their effects on glucose transporters

Troglitazone Improves Recovery of Left Ventricular Function After Regional Ischemia in Pigs

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