Cardiac substrate uptake and metabolism in obesity and type-2 diabetes: Role of sarcolemmal substrate transporters

Coort, Susan L.; Bonen, Arend; Vusse, Ger J.; Glatz, Jan F. C.; Luiken, Joost J. F. P.

doi:10.1007/s11010-005-9030-5

Cited by 81 publications

(61 citation statements)

References 151 publications

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“…In this study we observed that subjecting rats to a 42% fat (HF) diet for 10 weeks increased cardiac FFA concentration, which can be reduced by in vivo treatment with E 2 . It has previously been shown that obesity, accompained with IR shifts myocardial metabolism towards usage of FFAs affecting contractile function (Coort et al 2007). On a molecular level, increased concentration of FFA also diminishes cardiac glucose metabolism (Coort et al 2004, Rider et al 2013).…”

Section: Discussionmentioning

confidence: 99%

17β-Estradiol protects against the effects of a high fat diet on cardiac glucose, lipid and nitric oxide metabolism in rats

Zafirović

Obradović

Sudar-Milovanović

et al. 2017

Molecular and Cellular Endocrinology

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Please cite this article as: Zafirovic, S., Obradovic, M., Sudar-Milovanovic, E., Jovanovic, A., Stanimirovic, J., Stewart, A.J., Pitt, S.J., Isenovic, E.R., 17β-Estradiol protects against the effects of a high fat diet on cardiac glucose, lipid and nitric oxide metabolism in rats, Molecular and Cellular Endocrinology (2017), doi: 10.1016/j.mce.2017 This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain. AbstractThe aim of this study was to investigate the in vivo effects of estradiol (E 2 ) on myocardial metabolism and inducible nitric oxide synthase (iNOS) expression/activity in obese rats. MaleWistar rats were fed with a normal or a high fat (HF) diet (42% fat) for 10 weeks. Half of the HF fed rats were treated with a single dose of E 2 while the other half were placebo-treated. 24h after treatment animals were sacrificed. E 2 reduced cardiac free fatty acid (FFA Akt, protein kinase B; AS160, Akt substrate of 160 kDa; CD36, fatty acid transporters; E 2 ,

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Section: Discussionmentioning

confidence: 99%

17β-Estradiol protects against the effects of a high fat diet on cardiac glucose, lipid and nitric oxide metabolism in rats

Zafirović

Obradović

Sudar-Milovanović

et al. 2017

Molecular and Cellular Endocrinology

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“…The decrease of the insulin-stimulated glucose uptake in insulinresistant heart is linked, in part, to the impairment of the translocation of the glucose transporter GLUT4 to the plasma membrane (see Ref. 10 for a review). The defect in GLUT4 translocation is, moreover, associated with an alteration of the insulin-induced activation of the protein kinase B (PKB)/Akt signaling pathway (17,26).…”

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confidence: 99%

Inhibition of the mTOR/p70S6K pathway is not involved in the insulin-sensitizing effect of AMPK on cardiac glucose uptake

Ginion

Auquier

Benton

et al. 2011

American Journal of Physiology-Heart and Circulatory Physiology

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The AMP-activated protein kinase (AMPK) is known to increase cardiac insulin sensitivity on glucose uptake. AMPK also inhibits the mammalian target of rapamycin (mTOR)/p70 ribosomal S6 kinase (p70S6K) pathway. Once activated by insulin, mTOR/p70S6K phosphorylates insulin receptor substrate-1 (IRS-1) on serine residues, resulting in its inhibition and reduction of insulin signaling. AMPK was postulated to act on insulin by inhibiting this mTOR/p70S6K-mediated negative feedback loop. We tested this hypothesis in cardiomyocytes. The stimulation of glucose uptake by AMPK activators and insulin correlated with AMPK and protein kinase B (PKB/Akt) activation, respectively. Both treatments induced the phosphorylation of Akt substrate 160 (AS160) known to control glucose uptake. Together, insulin and AMPK activators acted synergistically to induce PKB/Akt overactivation, AS160 overphosphorylation, and glucose uptake overstimulation. This correlated with p70S6K inhibition and with a decrease in serine phosphorylation of IRS-1, indicating the inhibition of the negative feedback loop. We used the mTOR inhibitor rapamycin to confirm these results. Mimicking AMPK activators in the presence of insulin, rapamycin inhibited p70S6K and reduced IRS-1 phosphorylation on serine, resulting in the overphosphorylation of PKB/Akt and AS160. However, rapamycin did not enhance the insulin-induced stimulation of glucose uptake. In conclusion, although the insulin-sensitizing effect of AMPK on PKB/Akt is explained by the inhibition of the insulin-induced negative feedback loop, its effect on glucose uptake is independent of this mechanism. This disconnection revealed that the PKB/Akt/AS160 pathway does not seem to be the rate-limiting step in the control of glucose uptake under insulin treatment.adenosine 5=-monophosphate-activated protein kinase; protein kinase B/Akt; p70 ribosomal S6 kinase; insulin resistance; metformin A COMMON FEATURE OF TYPE 2 diabetes is insulin resistance of peripheral tissues like cardiac muscle. Insulin resistance is a major risk factor for the development of hypertension, cardiac hypertrophy, and heart failure. In addition, this resistance impairs metabolic effects of insulin such as glucose uptake, which is associated, after an ischemic episode, with a poor recovery of cardiac function during reperfusion (see Refs. 7, 8 for reviews). Knowing that ischemic heart disease is responsible for ϳ50% of the deaths in the diabetic population, the treatment of insulin resistance and the increase of glucose uptake in the diabetic heart remains an important issue. The decrease of the insulin-stimulated glucose uptake in insulinresistant heart is linked, in part, to the impairment of the translocation of the glucose transporter GLUT4 to the plasma membrane (see Ref. 10 for a review). The defect in GLUT4 translocation is, moreover, associated with an alteration of the insulin-induced activation of the protein kinase B (PKB)/Akt signaling pathway (17,26).In nondiabetic cardiomyocytes, insulin binding to its receptor induces th...

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“…Because of experimental limitations, we were not able to measure GLUT4 translocation (surface GLUT4). However, several reports have shown that insulin-stimulated glucose transport in the heart appears to be primarily mediated by the Akt/PKB signaling pathway, and that defects in GLUT4 translocation are associated with alterations in this pathway (7,9,20). Furthermore, the Rab GTPase-activating protein AS160 is a substrate for Akt/PKB and serves as a link between insulin activation of Akt/PKB and the subsequent translocation of GLUT4 to the cell surface (41).…”

Section: Discussionmentioning

confidence: 99%

Marine omega-3 fatty acids prevent myocardial insulin resistance and metabolic remodeling as induced experimentally by high insulin exposure

Franekova

Angın

Hoebers

et al. 2015

American Journal of Physiology-Cell Physiology

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Franekova V, Angin Y, Hoebers NT, Coumans WA, Simons PJ, Glatz JF, Luiken JJ, Larsen TS. Marine omega-3 fatty acids prevent myocardial insulin resistance and metabolic remodeling as induced experimentally by high insulin exposure. Am J Physiol Cell Physiol 308: C297-C307, 2015. First published December 4, 2014 doi:10.1152/ajpcell.00073.2014.-Insulin resistance is an important risk factor for the development of several cardiac pathologies, thus advocating strategies for restoring insulin sensitivity of the heart in these conditions. Omega-3 polyunsaturated fatty acids (-3 PUFAs), mainly eicosapentaenoic acid (EPA, C20:5n-3) and docosahexaenoic acid (DHA, C22:6n-3), have been shown to improve insulin sensitivity in insulin-sensitive tissues, but their direct effect on insulin signaling and metabolic parameters in the myocardium has not been reported previously. The aim of this study was therefore to examine the ability of EPA and DHA to prevent insulin resistance in isolated rat cardiomyocytes. Primary rat cardiomyocytes were made insulin resistant by 48 h incubation in high insulin (HI) medium. Parallel incubations were supplemented by 200 M EPA or DHA. Addition of EPA or DHA to the medium prevented the induction of insulin resistance in cardiomyocytes by preserving the phosphorylation state of key proteins in the insulin signaling cascade and by preventing persistent relocation of fatty acid transporter CD36 to the sarcolemma. Only cardiomyocytes incubated in the presence of EPA, however, exhibited improvements in glucose and fatty acid uptake and cell shortening. We conclude that -3 PUFAs protect metabolic and functional properties of cardiomyocytes subjected to insulin resistance-evoking conditions. omega-3 PUFAs; cardiac metabolism; insulin resistance; CD36; adipose triglyceride lipase; sarcomere shortening AN ELEVATED SUPPLY of lipids in obesity and type 2 diabetes leads to alterations of myocardial substrate metabolism, manifested insulin resistance with reduced glucose utilization, and increased long-chain fatty acid (LCFA) utilization (2, 3, 39). Thus isolated cardiomyocytes from various diabetic/obese rodent models show impaired insulin signaling, including reduced activation of protein kinase B (Akt/PKB), reduced glucose transporter 4 (GLUT4) translocation from intracellular compartments to the sarcolemma, as well as impaired insulininduced glucose uptake (10,35,37). Glucose and LCFA are the major substrates for the heart, and GLUT4 and CD36 the major substrate transporters, which are regulated by reversible insulin-induced translocation (48). Notably, increased LCFA supply to cardiomyocytes will evoke persistent relocation of CD36 from intracellular stores to the sarcolemma, followed by chronically elevated LCFA uptake and lipid accumulation, eventually resulting in insulin resistance (5, 36). Additionally, sustained hyperinsulinemia itself has also been shown to chronically stimulate CD36 translocation in cardiomyocytes and, consequently, lead to insulin resistance in a very similar manner to cardiom...

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Cardiac substrate uptake and metabolism in obesity and type-2 diabetes: Role of sarcolemmal substrate transporters

Cited by 81 publications

References 151 publications

17β-Estradiol protects against the effects of a high fat diet on cardiac glucose, lipid and nitric oxide metabolism in rats

17β-Estradiol protects against the effects of a high fat diet on cardiac glucose, lipid and nitric oxide metabolism in rats

Inhibition of the mTOR/p70S6K pathway is not involved in the insulin-sensitizing effect of AMPK on cardiac glucose uptake

Marine omega-3 fatty acids prevent myocardial insulin resistance and metabolic remodeling as induced experimentally by high insulin exposure

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