Human microvascular endothelial cells are sensitive to IGF-I but resistant to insulin at the receptor level

Johansson, Git; Chisalita, S.I.; Arnqvist, Hans J.

doi:10.1016/j.mce.2008.07.012

Cited by 22 publications

(18 citation statements)

References 26 publications

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“…This suggests that the available insulin holoreceptors in the aortic VSMCs are too few to generate a signal that is propagated. The insulin resistance of vascular smooth muscle therefore seems to be located at the receptor level as we recently described in human microvascular endothelial cells ( Johansson et al 2008). In accordance with our proposed mechanism for insulin resistance in human VSMCs (Fig.…”

supporting

confidence: 90%

Human aortic smooth muscle cells are insulin resistant at the receptor level but sensitive to IGF1 and IGF2

Chisalita¹,

Johansson²,

Liefvendahl³

et al. 2009

Journal of Molecular Endocrinology

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Whether insulin, at physiological concentrations, has direct effects on vascular smooth muscle cells (VSMCs) remains controversial. Our aim was to characterize the mechanism for insulin resistance in VSMCs. For comparison, the effects of IGF1 and IGF2 were also studied. Cultured human aortic smooth muscle cells (HASMC) were used. Receptor mRNA was analyzed by quantitative reverse transcription PCR and receptor protein by ELISA and western blot. Biological effects were studied by thymidine incorporation and glucose accumulation. In HASMC, both mRNA and protein expression of IGF1 receptors (IGF1R) were fivefold higher compared to insulin receptor (IR). IR isoform A mRNA was 13-fold more expressed than IR isoform B. IR and IGF1R co-precipitated, indicating the presence of hybrid IR/IGF1R. Phosphorylation of the IGF1R b-subunit was obtained by IGF1 10 K9

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supporting

confidence: 90%

Human aortic smooth muscle cells are insulin resistant at the receptor level but sensitive to IGF1 and IGF2

Chisalita¹,

Johansson²,

Liefvendahl³

et al. 2009

Journal of Molecular Endocrinology

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“…Hybrid receptors are more common in insulin-resistant individuals with type 2 diabetes and correlate with insulin sensitivity (14). In endothelial cells (ECs), IGF-1Rs substantially outnumber IRs (15), raising the possibility that IGF-1R may be a negative regulator of insulin signaling in the endothelium.…”

mentioning

confidence: 99%

The Insulin-Like Growth Factor-1 Receptor Is a Negative Regulator of Nitric Oxide Bioavailability and Insulin Sensitivity in the Endothelium

et al. 2011

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OBJECTIVEIn mice, haploinsufficiency of the IGF-1 receptor (IGF-1R+/−), at a whole-body level, increases resistance to inflammation and oxidative stress, but the underlying mechanisms are unclear. We hypothesized that by forming insulin-resistant heterodimers composed of one IGF-1Rαβ and one insulin receptor (IR), IRαβ complex in endothelial cells (ECs), IGF-1R reduces free IR, which reduces EC insulin sensitivity and generation of the antioxidant/anti-inflammatory signaling radical nitric oxide (NO).RESEARCH DESIGN AND METHODSUsing a number of complementary gene-modified mice with reduced IGF-1R at a whole-body level and specifically in EC, and complementary studies in EC in vitro, we examined the effect of changing IGF-1R/IR stoichiometry on EC insulin sensitivity and NO bioavailability.RESULTSIGF-1R+/− mice had enhanced insulin-mediated glucose lowering. Aortas from these mice were hypocontractile to phenylephrine (PE) and had increased basal NO generation and augmented insulin-mediated NO release from EC. To dissect EC from whole-body effects we generated mice with EC-specific knockdown of IGF-1R. Aortas from these mice were also hypocontractile to PE and had increased basal NO generation. Whole-body and EC deletion of IGF-1R reduced hybrid receptor formation. By reducing IGF-1R in IR-haploinsufficient mice we reduced hybrid formation, restored insulin-mediated vasorelaxation in aorta, and insulin stimulated NO release in EC. Complementary studies in human umbilical vein EC in which IGF-1R was reduced using siRNA confirmed that reducing IGF-1R has favorable effects on NO bioavailability and EC insulin sensitivity.CONCLUSIONSThese data demonstrate that IGF-1R is a critical negative regulator of insulin sensitivity and NO bioavailability in the endothelium.

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“…Vascular endothelial and smooth muscle cells abundantly express IGF1R and are more sensitive to IGF-1 than to insulin (Chisalita and Arnqvist 2004;Chisalita et al 2009;Johansson et al 2008). Several lines of evidence suggest that normal developmental IGF-1 levels promote vascular health later in life ).…”

Section: Discussionmentioning

confidence: 99%

“…The cardiovascular system is an especially important target organ for IGF-1 (Chisalita and Arnqvist 2004;Chisalita et al 2009;Johansson et al 2008;Li et al 2007;Toth et al 2014Toth et al , 2015, and there is increasing evidence suggesting that early-life IGF-1 levels may determine cardiovascular health in later life (Sonntag et al 2005a. Accordingly, previous studies demonstrate that rodent models with developmental IGF-1 deficiency exhibit a cardiac and/or vascular phenotype in adulthood Helms et al 2010;Reddy et al 2014).…”

Section: Introductionmentioning

confidence: 99%

IGF-1 deficiency in a critical period early in life influences the vascular aging phenotype in mice by altering miRNA-mediated post-transcriptional gene regulation: implications for the developmental origins of health and disease hypothesis

Tarantini

Giles

Wren

et al. 2016

AGE

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Epidemiological findings support the concept of Developmental Origins of Health and Disease, suggesting that early-life hormonal influences during a sensitive period of development have a fundamental impact on vascular health later in life. The endocrine changes that occur during development are highly conserved across mammalian species and include dramatic increases in circulating IGF-1 levels during adolescence. The present study was designed to characterize the effect of developmental IGF-1 deficiency on the vascular aging phenotype. To achieve that goal, early-onset endocrine IGF-1 deficiency was induced in mice by knockdown of IGF-1 in the liver using Cre-lox technology (Igf1 f/f mice crossed with mice expressing albumindriven Cre recombinase). This model exhibits lowcirculating IGF-1 levels during the peripubertal phase of development, which is critical for the biology of aging. Due to the emergence of miRNAs as important regulators of the vascular aging phenotype, the effect of early-life IGF-1 deficiency on miRNA expression profile in the aorta was examined in animals at 27 months of age. We found that developmental IGF-1 deficiency elicits persisting late-life changes in miRNA expression in the vasculature, which significantly differed from AGE (2016) 38:239-258

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Human microvascular endothelial cells are sensitive to IGF-I but resistant to insulin at the receptor level

Cited by 22 publications

References 26 publications

Human aortic smooth muscle cells are insulin resistant at the receptor level but sensitive to IGF1 and IGF2

Human aortic smooth muscle cells are insulin resistant at the receptor level but sensitive to IGF1 and IGF2

The Insulin-Like Growth Factor-1 Receptor Is a Negative Regulator of Nitric Oxide Bioavailability and Insulin Sensitivity in the Endothelium

IGF-1 deficiency in a critical period early in life influences the vascular aging phenotype in mice by altering miRNA-mediated post-transcriptional gene regulation: implications for the developmental origins of health and disease hypothesis

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