Pioglitazone treatment activates AMP-activated protein kinase in rat liver and adipose tissue in vivo

Saha, Asish K.; Avilucea, Paco R; Ye, Ji Ming; Assifi, M. Mura; Kraegen, Edward W.; Ruderman, Neil B.

doi:10.1016/j.bbrc.2003.12.120

Cited by 205 publications

(149 citation statements)

References 29 publications

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“…**p<0.01 and ***p<0.001 vs control. Co Control, Tro troglitazone reports have shown that TZDs affect mitochondrial function and lower ATP production in human hepatocytes and H-2K b muscle cells [11,12,40,41]. Here, we extend these results by demonstrating that troglitazone induces acute mitochondrial membrane depolarisation, activates AMPK and accelerates glucose flux in muscle cells.…”

Section: Discussionsupporting

confidence: 75%

“…By depolarising mitochondria, troglitazone may have provoked a rise in the cellular AMP/ ATP ratio. This is likely, since both rosiglitazone and pioglitazone elevate AMP levels and activate AMPK in H-2K b muscle cells and rat liver [40,41]. Consistent with this possibility, incubation of L6GLUT4myc myotubes with troglitazone for 5 or 10 min significantly increased AMPK activity measured by an in vitro kinase activity assay using SAMS peptide as a substrate (Fig.…”

Section: Troglitazone Acutely Activates Ampk In Muscle Cellssupporting

confidence: 64%

“…Therefore, we entertain the possibility that, like the complex IV inhibitor NaN 3 , troglitazone acutely interacts with components of the respiratory chain upstream of the ATP synthase, decreasing mitochondrial ATP production. This effect of troglitazone may be shared by other clinically relevant thiazolidinediones, since rosiglitazone and pioglitazone inhibit respiratory complex I and reduce oxygen consumption in skeletal muscle [52] and elevate AMP levels in H-2K b muscle cells and rat liver [40,41]. Consequently, AMPK is activated via phosphorylation on T172 by an upstream AMPK kinase, potentially LKB-1, and by allosteric activation by the elevated AMP/ATP ratio and/or the creatine/ phosphocreatine ratio [21][22][23]53].…”

Section: Discussionmentioning

confidence: 99%

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Troglitazone causes acute mitochondrial membrane depolarisation and an AMPK-mediated increase in glucose phosphorylation in muscle cells

et al. 2005

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Aims/hypothesis: Troglitazone was the first thiazolidinedione (TZD) approved for clinical use, exerting hypoglycaemic effects related to its action as a ligand of the peroxisome proliferator-activated receptor γ receptor in adipocytes. However, emerging evidence suggests that mitochondrial function may be affected by troglitazone, and that skeletal muscle cells acutely respond to troglitazone by enhancing glucose uptake. The aim of the present study was to determine the cellular mechanisms by which troglitazone acutely stimulates glucose utilisation in skeletal muscle cells. Methods: L6 cells overexpressing GLUT4myc were incubated with troglitazone. Glucose uptake, transport and phosphorylation as well as AMP-activated protein kinase (AMPK) signalling and insulin signalling were examined. Changes in mitochondrial membrane potential were measured using the J-aggregate-forming dye JC-1. AMPK signalling was interfered with using AMPK α1/α2 siRNA. Results: Troglitazone acutely (in 10 min) reduced the mitochondrial membrane potential in L6GLUT4myc myotubes and robustly stimulated AMPK activity. Following 30 min of incubation with troglitazone or insulin, 2-deoxyglucose uptake was stimulated 1.5-and 2.1-fold respectively, and in cells treated with troglitazone, a 1.8-fold increase in the 2-deoxyglucose-6-phosphate:2-deoxyglucose ratio was observed. Moreover, contrary to insulin, troglitazone did not significantly stimulate 3-O-methylglucose uptake. Unlike insulin, troglitazone did not increase surface GLUT4myc content and did not increase IRS1-associated phosphatidylinositol 3-kinase activity or Akt phosphorylation on T308 and S473. Interestingly, interfering with troglitazone-induced activation of AMPK by decreasing the expression of the enzyme using siRNA inhibited the stimulation of 2-deoxyglucose uptake by the TZD. Conclusions/interpretation: We propose that troglitazone acutely increases glucose flux in muscle via an AMPK-mediated increase in glucose phosphorylation.

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Section: Discussionsupporting

confidence: 75%

Section: Troglitazone Acutely Activates Ampk In Muscle Cellssupporting

confidence: 64%

Section: Discussionmentioning

confidence: 99%

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Troglitazone causes acute mitochondrial membrane depolarisation and an AMPK-mediated increase in glucose phosphorylation in muscle cells

et al. 2005

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“…More interestingly, both first-and second-phase insulin secretion induced by high glucose was potentiated by rosiglitazone in a PI3K-dependent manner [15]. Thiazolidinediones have been shown to activate AMPK in various tissues [28][29][30], and we also found that rosiglitazone acutely stimulates Thr 172 phosphorylation of the α subunit of AMPK, which leads to a two-to fourfold increase in enzyme activity of AMPK in pancreatic beta cells. These effects were abolished by LY294002 and wortmannin, suggesting that PI3K is an upstream regulator of AMPK activation.…”

Section: Discussionmentioning

confidence: 50%

Serine-385 phosphorylation of inwardly rectifying K+ channel subunit (Kir6.2) by AMP-dependent protein kinase plays a key role in rosiglitazone-induced closure of the KATP channel and insulin secretion in rats

et al. 2009

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Aims/hypothesis Rosiglitazone, an insulin sensitiser, not only improves insulin sensitivity but also enhances insulin secretory capacity by ameliorating gluco-and lipotoxicity in beta cells. Rosiglitazone can stimulate insulin secretion at basal and high glucose levels via a phosphatidylinositol 3-kinase (PI3K)-dependent pathway. We hypothesised that regulation of phosphorylation of the ATP-sensitive potassium (K ATP ) channel might serve as a key step in the regulation of insulin secretion. Methods Insulin secretory responses were studied in an isolated pancreas perfusion system, cultured rat islets and MIN6 and RINm5F beta cells. Signal transduction pathways downstream of PI3K were explored to link rosiglitazone to K ATP channel conductance with patch clamp techniques and insulin secretion measured by ELISA. Results Rosiglitazone stimulated AMP-activated protein kinase (AMPK) activity and induced inhibition of the K ATP channel conductance in islet beta cells; both effects were blocked by the PI3K inhibitor LY294002. Following stimulation of AMPK by 5-aminoimidazole-4-carboxamide ribonucleoside (AICAR), a pharmacological activator, both AICAR-stimulated insulin secretion and inhibition of K ATP channel conductance were unaffected by LY294002, indicating that AMPK activation occurs at a site downstream of PI3K activity. The serine residue at amino acid position 385 of Kir6.2 was found to be the substrate phosphorylation site of AMPK when activated by rosiglitazone or AICAR. Conclusions/interpretation Our data indicate that PI3K-dependent activation of AMPK is required for rosiglitazonestimulated insulin secretion in pancreatic beta cells. Phosphorylation of the Ser 385 residue of the Kir6.2 subunit of the K ATP channel by AMPK may play a role in insulin secretion.

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“…Another class of drugs that is currently widely used to treat type 2 diabetes is the thiazolidinediones, such as rosiglitazone and pioglitazone, both of which were reported to activate AMPK in intact cells [66,67]. Like the biguanides, the thiazolidinediones do not activate AMPK directly, and both classes of drug may achieve this indirectly by inhibiting complex I of the respiratory chain (explaining the side effect of lactic acidosis produced by phenformin) and thus increasing the cellular AMP:ATP ratio [68][69][70].…”

Section: Pharmacological Activators Of Ampk As Treatments For Diabetementioning

confidence: 99%

Role of AMP‐activated protein kinase in the metabolic syndrome and in heart disease

2007

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Obesity, type 2 diabetes and the metabolic syndrome are disorders of energy balance, which the AMP-activated protein kinase (AMPK) regulates both at the cellular and whole body levels. AMPK switches cells from an anabolic state where nutrients are taken up and stored, to a catabolic state where they are oxidized. Drugs that activate AMPK indirectly (metformin and thiazolidinediones) are now the mainstay of treatment for type 2 diabetes, but more direct AMPK activators may have fewer side effects. However, activating mutations in AMPK can cause heart disease, and it will be important to look for adverse effects in the heart.

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Pioglitazone treatment activates AMP-activated protein kinase in rat liver and adipose tissue in vivo

Cited by 205 publications

References 29 publications

Troglitazone causes acute mitochondrial membrane depolarisation and an AMPK-mediated increase in glucose phosphorylation in muscle cells

Troglitazone causes acute mitochondrial membrane depolarisation and an AMPK-mediated increase in glucose phosphorylation in muscle cells

Serine-385 phosphorylation of inwardly rectifying K+ channel subunit (Kir6.2) by AMP-dependent protein kinase plays a key role in rosiglitazone-induced closure of the KATP channel and insulin secretion in rats

Role of AMP‐activated protein kinase in the metabolic syndrome and in heart disease

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