Impaired Insulin Signaling in Endothelial Cells Reduces Insulin-Induced Glucose Uptake by Skeletal Muscle

Department of Diabetes and Metabolic Diseases, Graduate School of Medicine, University of Tokyo, Tokyo 113-8655, Japan.
Cell metabolism (Impact Factor: 17.57). 03/2011; 13(3):294-307. DOI: 10.1016/j.cmet.2011.01.018
Source: PubMed

ABSTRACT In obese patients with type 2 diabetes, insulin delivery to and insulin-dependent glucose uptake by skeletal muscle are delayed and impaired. The mechanisms underlying the delay and impairment are unclear. We demonstrate that impaired insulin signaling in endothelial cells, due to reduced Irs2 expression and insulin-induced eNOS phosphorylation, causes attenuation of insulin-induced capillary recruitment and insulin delivery, which in turn reduces glucose uptake by skeletal muscle. Moreover, restoration of insulin-induced eNOS phosphorylation in endothelial cells completely reverses the reduction in capillary recruitment and insulin delivery in tissue-specific knockout mice lacking Irs2 in endothelial cells and fed a high-fat diet. As a result, glucose uptake by skeletal muscle is restored in these mice. Taken together, our results show that insulin signaling in endothelial cells plays a pivotal role in the regulation of glucose uptake by skeletal muscle. Furthermore, improving endothelial insulin signaling may serve as a therapeutic strategy for ameliorating skeletal muscle insulin resistance.

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    • "The reciprocal has also been demonstrated in humans; that is, enhancement of insulin-stimulated blood flow via ET-1 antagonism increases skeletal muscle glucose uptake, and this observation has been shown in both the human leg (Lteif et al. 2007) and forearm (Shemyakin et al. 2010). A recent mouse study by Kubota et al. (2011) has further highlighted the role of vascular insulin signalling in regulating skeletal muscle glucose uptake. The authors found that impaired insulin signalling in endothelial cells, as a result of endothelium-specific ablation of IRS-2, reduced insulin-induced phosphorylation of endothelial nitric oxide synthase (eNOS) and capillary recruitment, which in turn led to reduced glucose uptake by skeletal muscle. "
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    ABSTRACT: What is the topic of this review? This review highlights the importance of increased vascular insulin sensitivity for maintaining glycaemic control and cardiovascular health. What advances does it highlight? We discuss the role of habitual physical activity in modulating vascular actions of insulin. Type 2 diabetes and cardiovascular disease commonly coexist. Current evidence suggests that impaired insulin signalling in the vasculature may be a common link between metabolic and cardiovascular diseases, including glycaemic dysregulation and atherosclerosis. Herein, we highlight the importance of the actions of insulin on the vasculature for glycaemic control and arterial health. In addition, we summarize and discuss findings from our group and others demonstrating that increased physical activity may be an effective approach to enhancing vascular insulin sensitivity. Furthermore, in light of the existing literature, we formulate the hypothesis that increased shear stress may be a prime mechanism through which habitual physical activity improves insulin signalling in the vasculature. Ultimately, we propose that targeting vascular insulin resistance may represent a viable strategy for improving glycaemic control and reducing cardiovascular risk in patients with type 2 diabetes. © 2015 The Authors. Experimental Physiology © 2015 The Physiological Society.
    Experimental physiology 07/2015; 100(7):759-71. DOI:10.1113/EP085107 · 2.67 Impact Factor
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    • "Studies have shown that axon guidance is involved in reinnervation of skeletal muscle (Sanes & Covault 1985; Engle 2010), and its related genes appear to be expressed during muscle nerve formation (Phelan & Hollyday 1990). Significantly altered biological pathway insulin signaling and mannose metabolism are also known to be involved in sepsis and related skeletal muscle dysfunction (Xu et al. 2013), and improving endothelial insulin signaling may serve as a therapeutic strategy for ameliorating skeletal muscle insulin resistance (Kubota et al. 2011). Overall, our study offers insights into the molecular mechanisms of skeletal muscle development. "
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    ABSTRACT: Age-dependent decline in skeletal muscle function leads to several inherited and acquired muscular disorders in elderly individuals. The levels of microRNAs (miRNAs) could be altered during muscle maintenance and repair. We therefore performed a comprehensive investigation for miRNAs from five different periods of bovine skeletal muscle development using next-generation small RNA sequencing. In total, 511 miRNAs, including one putatively novel miRNA, were identified. Thirty-six miRNAs were differentially expressed between prenatal and postnatal stages of muscle development including several myomiRs (miR-1, miR-206 and let-7 families). Compared with miRNA expression between different muscle tissues, 14 miRNAs were up-regulated and 22 miRNAs were down-regulated in the muscle of postnatal stage. In addition, a novel miRNA was predicted and submitted to the miRBase database as bta-mir-10020. A dual luciferase reporter assay was used to demonstrate that bta-mir-10020 directly targeted the 3'-UTR of the bovine ANGPT1 gene. The overexpression of bta-mir-10020 significantly decreased the DsRed fluorescence in the wild-type expression cassette compared to the mutant type. Using three computational approaches - miranda, pita and rnahybrid - these differentially expressed miRNAs were also predicted to target 3609 bovine genes. Disease and biological function analyses and the KEGG pathway analysis revealed that these targets were statistically enriched in functionality for muscle growth and disease. Our miRNA expression analysis findings from different states of muscle development and aging significantly expand the repertoire of bovine miRNAs now shown to be expressed in muscle and could contribute to further studies on growth and developmental disorders in this tissue type. © 2015 Stichting International Foundation for Animal Genetics.
    Animal Genetics 02/2015; 46(3). DOI:10.1111/age.12272 · 2.21 Impact Factor
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    • "In individuals with insulin resistance , the influence of insulin on microvascular perfusion is markedly impaired (Czernichow et al., 2010; Muris et al., 2012), suggesting that insulin regulates glucose uptake and insulin sensitivity via a feedforward mechanism. Consistent with this notion, capillary recruitment and glucose tolerance are impaired in mice with endothelial deletion of Irs-2 (Kubota et al., 2011). In contrast, mice with endothelial cell-specific insulin receptor knockout do not exhibit glucose intolerance (Vicent et al., 2003). "
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    ABSTRACT: Accumulating evidence has suggested a role for p53 activation in various age-associated conditions. Here, we identified a crucial role of endothelial p53 activation in the regulation of glucose homeostasis. Endothelial expression of p53 was markedly upregulated when mice were fed a high-calorie diet. Disruption of endothelial p53 activation improved dietary inactivation of endothelial nitric oxide synthase that upregulated the expression of peroxisome proliferator-activated receptor-γ coactivator-1α in skeletal muscle, thereby increasing mitochondrial biogenesis and oxygen consumption. Mice with endothelial cell-specific p53 deficiency fed a high-calorie diet showed improvement of insulin sensitivity and less fat accumulation, compared with control littermates. Conversely, upregulation of endothelial p53 caused metabolic abnormalities. These results indicate that inhibition of endothelial p53 could be a novel therapeutic target to block the vicious cycle of cardiovascular and metabolic abnormalities associated with obesity.
    Cell Reports 05/2014; 7(5). DOI:10.1016/j.celrep.2014.04.046 · 8.36 Impact Factor
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