Impaired insulin signaling in endothelial cells reduces insulin-induced glucose uptake by skeletal muscle
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.
- SourceAvailable from: Cong-jun Li
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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. "
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). "
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 · 7.21 Impact Factor
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- "Our findings are also consistent with and expand the conclusions reached in studies of Irs2 EC-specific knockouts (Kubota et al., 2011). These workers proposed that reduced insulininduced eNOS phosphorylation in EC-specific Irs2 −/− mice causes insulin resistance via impaired capillary recruitment in skeletal muscle. "
ABSTRACT: Atherosclerotic cardiovascular disease is the leading cause of death in insulin-resistant (type 2) diabetes. Vascular endothelial dysfunction paves the way for atherosclerosis through impaired nitric oxide availability, inflammation, and generation of superoxide. Surprisingly, we show that ablation of the three genes encoding isoforms of transcription factor FoxO in endothelial cells prevents atherosclerosis in low-density lipoprotein receptor knockout mice by reversing these subphenotypes. Paradoxically, the atheroprotective effect of FoxO deletion is associated with a marked decrease of insulin-dependent Akt phosphorylation in endothelial cells, owing to reduced FoxO-dependent expression of the insulin receptor adaptor proteins Irs1 and Irs2. These findings support a model in which FoxO is the shared effector of multiple atherogenic pathways in endothelial cells. FoxO ablation lowers the threshold of Akt activity required for protection from atherosclerosis. The data demonstrate that FoxO inhibition in endothelial cells has the potential to mediate wide-ranging therapeutic benefits for diabetes-associated cardiovascular disease.Cell metabolism 03/2012; 15(3):372-81. DOI:10.1016/j.cmet.2012.01.018 · 16.75 Impact Factor