Wortmannin inhibits insulin‐stimulated but not contraction‐stimulated glucose transport activity in skeletal muscle

Lee, Abraham D.; Hansen, Polly A.; Holloszy, John O.

doi:10.1016/0014-5793(95)00147-2

Cited by 204 publications

(164 citation statements)

References 25 publications

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“…R ϭ 0.801, P Ͻ 0.01, n ϭ 10. during and after electrically stimulated contractile activity was reduced in mouse muscle overexpressing the 4P AS160 mutant compared with control muscles undergoing an identical contraction protocol. However, a low dose of wortmannin that was sufficient to completely prevent the contraction-induced increase in AS160 phosphorylation in isolated rat epitrochlearis muscle (6) has no effect on contraction-stimulated glucose transport (25,47). In addition, although contraction-stimulated glucose transport was normal for AMPK␣2 knockout (17) and only partially reduced for AMPK␣2 kinase-dead (29) animals, the in vitro contraction-stimulated increase in AS160 phosphorylation observed in wild-type controls was absent from each of these genetically modified models (40).…”

Section: Discussionmentioning

confidence: 99%

Prior exercise increases phosphorylation of Akt substrate of 160 kDa (AS160) in rat skeletal muscle

Arias¹,

Kim²,

Funai³

et al. 2007

American Journal of Physiology-Endocrinology and Metabolism

104

116

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Arias EB, Kim J, Funai K, Cartee GD. Prior exercise increases phosphorylation of Akt substrate of 160 kDa (AS160) in rat skeletal muscle. Am J Physiol Endocrinol Metab 292: E1191-E1200, 2007. First published December 19, 2006; doi:10.1152/ajpendo.00602.2006.-The main purpose of this study was to determine whether the increased glucose transport (GT) found immediately postexercise (IPEX) or 4 h postexercise (4hPEX) is accompanied by increased phosphorylation of Akt substrate of 160 kDa (AS160, a protein regulator of GLUT4 translocation). Paired epitrochlearis muscles were dissected from rats (sedentary or IPEX, 2-h swim) and used to measure protein phosphorylation and insulin-independent GT. IPEX values exceeded sedentary values for GT and phosphorylations of AS160, AMP-activated protein kinase (pAMPK) and acetyl-CoA carboxylase (pACC) but not for AS160 abundance or phosphorylation of Akt serine (pSerAkt), Akt threonine (pThrAkt), or glycogen synthase kinase-3 (pGSK3). AS160 phosphorylation was significantly correlated with GT (R ϭ 0.801, P Ͻ 0.01) and pAMPK (R ϭ 0.655, P Ͻ 0.05). Muscles from other rats were studied 4hPEX along with sedentary controls. One muscle per rat was incubated without insulin, and the contralateral muscle was incubated with insulin. 4hPEX values exceeded sedentary values for insulinstimulated GT. The elevated pAMPK and pACC found IPEX had reversed by 4hPEX. Insulin caused a significant increase in pSerAkt, pThrAkt, pGSK3, and AS160 phosphorylation with or without exercise. Exercise significantly increased AS160 phosphorylation, regardless of insulin, with unchanged AS160 abundance. Among the signaling proteins studied, insulin-stimulated GT was significantly correlated only with insulin-stimulated pThrAkt (R ϭ 0.720, P Ͻ 0.0005). The results are consistent with a role for increased AS160 phosphorylation in the increased insulin-independent GT IPEX, and the exercise effects on AS160 phosphorylation and/or pThrAkt at 4hPEX are potentially relevant to the increased insulin-stimulated glucose transport at this time.

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Section: Discussionmentioning

confidence: 99%

Prior exercise increases phosphorylation of Akt substrate of 160 kDa (AS160) in rat skeletal muscle

Arias¹,

Kim²,

Funai³

et al. 2007

American Journal of Physiology-Endocrinology and Metabolism

104

116

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“…The signalling pathways through which these distinct mechanisms operate differ [5]. While the insulin pathway involves insulin binding to its receptor inducing tyrosine kinase activity, phosphorylation of insulin receptor substrate proteins with subsequent activation of phosphatidylinositol-3-kinase [6], the contraction pathway, is independent of these steps [7][8][9]. A number of molecules including calcium [5,10], protein kinase C [5], AMP-activated protein kinase (AMPK) [11], bradykinin [12] and NO [13] have been implicated in contractionmediated glucose uptake.…”

Section: Introductionmentioning

confidence: 99%

Effects of the nitric oxide donor, sodium nitroprusside, on resting leg glucose uptake in patients with type 2 diabetes

et al. 2005

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Aims/hypothesis: Nitric oxide (NO) has been implicated as an important signalling molecule in the contraction-mediated glucose uptake pathway and may represent a novel strategy for blood glucose control. The current study sought to determine whether acute infusion of the NO donor, sodium nitroprusside (SNP), increases leg glucose uptake at rest in patients with type 2 diabetes. Methods: Fifteen male patients with type 2 diabetes (aged 54±4 years, mean±SD) were entered into a randomised, cross-over design study, examining the effect of a 30-min intra-femoral infusion of SNP on leg glucose uptake. Comparison was made with a 30-min infusion of verapamil, titrated to elicit similar leg blood flow responses to SNP. Leg blood flow was measured by thermodilution in the femoral vein, and leg glucose uptake was calculated as the product of leg blood flow and the femoral arterio-venous (A-V) glucose concentration gradient. Results: The two drugs increased leg blood flow to a similar extent (p= 0.50). Both leg A-V glucose concentration gradient (SNP 0.12±0.05, verapamil −0.06±0.04 mmol/l; mean±SEM, p=0.03) and leg glucose uptake (SNP 0.17±0.09, verapamil −0.09±0.06 mmol/min; p=0.03) were higher with the SNP treatment than with verapamil. These results occurred independently of any significant difference in plasma insulin concentration between drugs (p=0.56). Conclusions/interpretation: Acute infusion of SNP resulted in greater glucose uptake relative to verapamil. NO may therefore be an important mediator of peripheral glucose disposal and a potential therapeutic target in patients with type 2 diabetes.

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“…Two distinct signalling cascades operate in skeletal muscle to stimulate glucose utilization, namely the insulin-and contractionmediated pathways [1,2]. Neither cascade has been fully characterized at the molecular level.…”

Section: Introductionmentioning

confidence: 99%

“…Indeed, a nitric oxide donor, sodium nitroprusside (SNP), stimulates the genAbbreviations used : EDL, extensor digitorum longus ; NOS, nitric oxide synthase ; SNP, sodium nitroprusside. 1 To whom correspondence should be addressed.…”

Section: Introductionmentioning

confidence: 99%

Evidence for altered sensitivity of the nitric oxide/cGMP signalling cascade in insulin-resistant skeletal muscle

Young

Leighton

1998

Biochemical Journal

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Nitric oxide activates guanylate cyclase to form cGMP, comprising a signalling system that is believed to be a distinct mechanism for increasing glucose transport and metabolism in skeletal muscle. The effects of a selective cGMP phosphodiesterase inhibitor, zaprinast, on basal glucose utilization was investigated in incubated rat soleus muscle preparations isolated from both insulin-sensitive (lean Zucker; Fa/?) and insulin-resistant (obese Zucker; fa/fa) rats. Zaprinast at 27 μM significantly increased cGMP levels in incubated soleus muscle isolated from lean, but not obese, Zucker rats. Muscles were incubated with 14C-labelled glucose and various concentrations of zaprinast (3, 27 and 243 μM). Zaprinast (at 27 and 243 μM) significantly increased rates of net and 14C-labelled lactate release and of glycogen synthesis in lean Zucker rat soleus muscle; glucose oxidation was also increased by 27 μM zaprinast. In addition, regardless of concentration, the phosphodiesterase inhibitor failed to increase any aspect of 14C-labelled glucose utilization in soleus muscles isolated from obese Zucker rats. The maximal activity of nitric oxide synthase (NOS) was significantly decreased in insulin-resistant obese Zucker muscles. Thus the lack of effect of zaprinast in insulin-resistant skeletal muscle is consistent with decreased NOS activity. To test whether there is a defect in insulin-resistant skeletal muscle for endogenous activation of guanylate cyclase, soleus muscles were isolated from both insulin-sensitive and insulin-resistant Zucker rats and incubated with various concentrations of the NO donor sodium nitroprusside (SNP; 0.1, 1, 5 and 15 mM). SNP significantly increased rates of net and 14C-labelled lactate release, as well as glucose oxidation in muscles isolated from both insulin-sensitive and insulin-resistant rats. A decreased response to SNP was observed in the dose-dependent generation of cGMP within isolated soleus muscles from insulin-resistant rats. A possible link between impaired NO/cGMP signalling and abnormal glucose utilization by skeletal muscle is discussed.

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Wortmannin inhibits insulin‐stimulated but not contraction‐stimulated glucose transport activity in skeletal muscle

Cited by 204 publications

References 25 publications

Prior exercise increases phosphorylation of Akt substrate of 160 kDa (AS160) in rat skeletal muscle

Prior exercise increases phosphorylation of Akt substrate of 160 kDa (AS160) in rat skeletal muscle

Effects of the nitric oxide donor, sodium nitroprusside, on resting leg glucose uptake in patients with type 2 diabetes

Evidence for altered sensitivity of the nitric oxide/cGMP signalling cascade in insulin-resistant skeletal muscle

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