GLUT4 content decreases along with insulin resistance and high levels of inflammatory markers in rats with metabolic syndrome

Leguisamo, Natalia Motta; Lehnen, Alexandre Machado; Machado, Ubiratan Fabres; Okamoto, Maristela Mitiko; Markoski, Melissa Medeiros; Pinto, Graziela Hünning; Schaan, Beatriz D.

doi:10.1186/1475-2840-11-100

Cited by 109 publications

(91 citation statements)

References 64 publications

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“…A decrease in the gene and/or protein expression of IRS-1 with concomitant insulin resistance was observed in muscle biopsies of insulin-resistant Pima Indians (36), muscle of T2D subjects (33), and muscle biopsies from women with gestational diabetes (15). Similar concordance of mRNA gene expression of GLUT4 in the skeletal muscle of rats (41) and humans (15,33) and for GYS mRNA expression in the muscle of T2D subjects (72) and insulin resistance has been reported. The decline observed in GLUT4 and GYS1 gene expression in the diabetic animals during insulin deprivation (D Ϫ I) indicates decreased muscle insulin sensitivity, which was confirmed by the status of Akt-related signaling under acute insulin stimulation.…”

Section: Discussionmentioning

confidence: 59%

Impact of insulin deprivation and treatment on sphingolipid distribution in different muscle subcellular compartments of streptozotocin-diabetic C57Bl/6 mice

Zabielski

Błachnio-Zabielska

Lanza

et al. 2014

American Journal of Physiology-Endocrinology and Metabolism

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Insulin deprivation in type 1 diabetes (T1D) individuals increases lipolysis and plasma free fatty acids (FFA) concentration, which can stimulate synthesis of intramyocellular bioactive lipids such as ceramides (Cer) and longchain fatty acid-CoAs (LCFa-CoAs). Ceramide was shown to decrease muscle insulin sensitivity, and at mitochondrial levels it stimulates reactive oxygen species production. Here, we show that insulin deprivation in streptozotocin diabetic C57BL/6 mice increases quadriceps muscle Cer content, which was correlated with a concomitant decrease in the body fat and increased plasma FFA, glycosylated hemoglobin level (%Hb A 1c), and muscular LCFa-CoA content. The alternations were accompanied by an increase in protein expression in LCFa-CoA and Cer synthesis (FATP1/ACSVL5, CerS1, CerS5), a decrease in the expression of genes implicated in muscle insulin sensitivity (GLUT4, GYS1), and inhibition of insulin signaling cascade by Akt␣ and GYS3␤ phosphorylation under acute insulin stimulation. Both the content and composition of sarcoplasmic fraction sphingolipids were most affected by insulin deprivation, whereas mitochondrial fraction sphingolipids remained stable. The observed effects of insulin deprivation were reversed, except for content and composition of LCFa-CoA, CerS protein expression, GYS1 gene expression, and phosphorylation status of Akt and GYS3␤ when exogenous insulin was provided by subcutaneous insulin implants. Principal component analysis and Pearson's correlation analysis revealed close relationships between the features of the diabetic phenotype, the content of LCFa-CoAs and Cers containing C18-fatty acids in sarcoplasm, but not in mitochondria. Insulin replacement did not completely rescue the phenotype, especially regarding the content of LCFa-CoA, or proteins implicated in Cer synthesis and muscle insulin sensitivity. These persistent changes might contribute to muscle insulin resistance observed in T1D individuals. type 1 diabetes; skeletal muscle; mitochondria; ceramide; long-chain fatty acid-coenzyme A METICULOUS GLYCEMIC CONTROL in type 1 diabetic (T1D) individuals can be achieved by administration of prandial, shortacting, and long-acting insulin to mimic ␤-cell secretion in response to varying nutrient levels. Metabolic control in these individuals and stringent adherence to guidelines normalize the plasma glucose and glycosylated hemoglobin levels (%Hb A 1c ) and allow for relatively normal life in T1D. Yet T1D individuals are at greater risk of developing cardiovascular disorders and also known to develop insulin resistance (12, 17). The molecular mechanisms responsible for insulin resistance in T1D subjects are unclear, but variable glucose concentrations (28, 70), advanced glycation end products (62, 73), or desensitization of target tissues by insulin (61) have been proposed. Subcutaneous insulin delivery using an insulin pump partially mimics ␤-cell insulin secretion. However, unlike in nondiabetic individuals with twofold higher hepatic insulin concentration than in ...

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Section: Discussionmentioning

confidence: 59%

Impact of insulin deprivation and treatment on sphingolipid distribution in different muscle subcellular compartments of streptozotocin-diabetic C57Bl/6 mice

Zabielski

Błachnio-Zabielska

Lanza

et al. 2014

American Journal of Physiology-Endocrinology and Metabolism

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“…Reduced GLUT4 expression is characteristic of insulin resistance in the heart (24,47) as well as in other insulinsensitive organs (16). It is detectable early after the onset of high-fat feeding in hearts from WT mice and is associated with reduced glucose uptake, even in the absence of impaired insulin signaling (47).…”

Section: Discussionmentioning

confidence: 99%

Partial deletion of ROCK2 protects mice from high-fat diet-induced cardiac insulin resistance and contractile dysfunction

Soliman

Nyamandi

Garcia-Patino

et al. 2015

American Journal of Physiology-Heart and Circulatory Physiology

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KM. Partial deletion of ROCK2 protects mice from high-fat diet-induced cardiac insulin resistance and contractile dysfunction. Am J Physiol Heart Circ Physiol 309: H70 -H81, 2015. First published April 24, 2015 doi:10.1152/ajpheart.00664.2014.-Obesity is associated with cardiac insulin resistance and contractile dysfunction, which contribute to the development of heart failure. The RhoA-Rho kinase (ROCK) pathway has been reported to modulate insulin resistance, but whether it is implicated in obesity-induced cardiac dysfunction is not known. To test this, wild-type (WT) and ROCK2 ϩ/Ϫ mice were fed normal chow or a high-fat diet (HFD) for 17 wk. Whole body insulin resistance, determined by an insulin tolerance test, was observed in HFD-WT, but not HFD-ROCK2 ϩ/Ϫ , mice. The echocardiographically determined myocardial performance index, a measure of global systolic and diastolic function, was significantly increased in HFD-WT mice, indicating a deterioration of cardiac function. However, no change in myocardial performance index was found in hearts from HFD-ROCK2 ϩ/Ϫ mice. Speckle-tracking-based strain echocardiography also revealed regional impairment in left ventricular wall motion in hearts from HFD-WT, but not HFD-ROCK2 ϩ/Ϫ , mice. Activity of ROCK1 and ROCK2 was significantly increased in hearts from HFD-WT mice, and GLUT4 expression was significantly reduced. Insulin-induced phosphorylation of insulin receptor substrate (IRS) Tyr 612 , Akt, and AS160 was also impaired in these hearts, while Ser 307 phosphorylation of IRS was increased. In contrast, the increase in ROCK2, but not ROCK1, activity was prevented in hearts from HFD-ROCK2 ϩ/Ϫ mice, and cardiac levels of TNF␣ were reduced. This was associated with normalization of IRS phosphorylation, downstream insulin signaling, and GLUT4 expression. These data suggest that increased activation of ROCK2 contributes to obesityinduced cardiac dysfunction and insulin resistance and that inhibition of ROCK2 may constitute a novel approach to treat this condition. ROCK2; insulin signaling; heart; insulin receptor substrate phosphorylation

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“…These data may suggest that insulin sensitivity is improved in HFD-fed Phd2 f/f /aP2-Cre mice compared with HFD-fed control mice. It is reported that Glut4 expression in skeletal muscle is suppressed in a rat model of insulin resistance, 31 suggesting that Glut4 upregulation in Phd2 f/f /aP2-Cre mice may be due to an improvement in insulin sensitivity. However, it is not clear how PHD2 deficiency in adipocytes affects the skeletal muscle insulin signaling pathway; further study is needed.…”

Section: Discussionmentioning

confidence: 99%

Prolyl Hydroxylase Domain Protein 2 Plays a Critical Role in Diet-Induced Obesity and Glucose Intolerance

et al. 2013

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Matsuura et al Role of PHD2 in Adipocytes 2079Several cell culture studies have revealed that hypoxia and HIF convert cell metabolism that is dependent on aerobic glucose oxidation and fatty acid synthesis into that which is dependent on anaerobic glycolysis. HIF not only upregulates a series of glycolytic enzymes 15,16 but also actively inhibits oxidative phosphorylation in mitochondria by inducing pyruvate dehydrogenase kinase 1 (PDK1).17,18 PDK1 inhibits pyruvate dehydrogenase activity and consequently reduces the conversion of pyruvate to acetyl CoA, an essential substrate for oxidative phosphorylation. 17,18 In addition, HIF inhibits adipogenesis by inducing DEC1/Stra13. 13 These HIF-induced metabolic alterations such as increased glucose consumption and less fatty acid synthesis might be beneficial for nutrient excess in obese or diabetic subjects. Although HIF could be a potential therapeutic target, direct manipulation of HIF is often difficult in vivo. In contrast, PHD is an ideal target to manipulate HIF levels, and several chemical inhibitors of PHD have been developed. 19 However, the role of adipocyte PHD in the development of obesity-induced glucose intolerance has not been determined. In the present study, we generated mice lacking PHD2, also known as Egl 9 homolog1 (EglN1) in adipocytes, because PHD2 is the most crucial isoform to regulate HIF level in vitro 20 and in vivo 21 among 3 PHD isoforms (PHD1, PHD2, and PHD3). We found that PHD2 deletion in adipocyte attenuates weight gain and alleviates glucose intolerance induced by a high-fat diet (HFD). MethodsAdditional details of the experimental procedures are included in the online-only Data Supplement.All animal procedures were approved by the Animal Care and Use Committee of Kyushu University and conducted in accordance with the institutional guidelines. Previously generated Phd2-floxed mice f/f mice. Phd2 f/f mice served as controls. These mice were fed an HFD containing 60% kcal fat (High Fat Diet 32, Clea Japan, Inc) from 12 to 18 weeks of age. Mice 12 and 18 weeks of age were analyzed. Preparation of cell lysate and total RNA, Western blot analysis, quantitative reverse transcription-polymerase chain reaction, luciferase assay, and histological/immunohistochemical analysis were performed using conventional methods. The primer sequences for quantitative reverse transcription-polymerase chain reaction are shown in Table I Figure 1A and Figure IA in the online-only Data Supplement). Expression of PHD2 in heart and bone marrowderived macrophages was slightly reduced. We did not find any apparent abnormalities in the appearance in Phd2 Figure 2B and 2D). However, the extent of HFD-induced adipocyte hypertrophy was significantly reduced in Phd2 f/f /aP2-Cre mice compared with control mice (Figure 2C and 2D). A detailed analysis of the size distribution of the adipocytes revealed that WAT from controls contained a greater number of larger adipocytes (>10 000 μm 2 ) than that Enhanced Angiogenesis in WAT From HFD-Fed Phd2f/f /aP2-Cre Mice B...

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GLUT4 content decreases along with insulin resistance and high levels of inflammatory markers in rats with metabolic syndrome

Cited by 109 publications

References 64 publications

Impact of insulin deprivation and treatment on sphingolipid distribution in different muscle subcellular compartments of streptozotocin-diabetic C57Bl/6 mice

Impact of insulin deprivation and treatment on sphingolipid distribution in different muscle subcellular compartments of streptozotocin-diabetic C57Bl/6 mice

Partial deletion of ROCK2 protects mice from high-fat diet-induced cardiac insulin resistance and contractile dysfunction

Prolyl Hydroxylase Domain Protein 2 Plays a Critical Role in Diet-Induced Obesity and Glucose Intolerance

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