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Pathophysiology

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

  1. Afroze Abbas1,
  2. Helen Imrie1,
  3. Hema Viswambharan1,
  4. Piruthivi Sukumar1,
  5. Adil Rajwani1,
  6. Richard M. Cubbon1,
  7. Matthew Gage1,
  8. Jessica Smith1,
  9. Stacey Galloway1,
  10. Nadira Yuldeshava1,
  11. Matthew Kahn1,
  12. Shouhong Xuan2,
  13. Peter J. Grant1,
  14. Keith M. Channon3,
  15. David J. Beech1,
  16. Stephen B. Wheatcroft1 and
  17. Mark T. Kearney1⇓
  1. 1Division of Cardiovascular and Diabetes Research, Leeds Multidisciplinary Cardiovascular Research Centre, University of Leeds, Leeds, U.K.
  2. 2Department of Genetics and Development, Columbia University, New York, New York
  3. 3British Heart Foundation Centre of Research Excellence, University of Oxford, Oxford, U.K.
  1. Corresponding author: Mark T. Kearney, m.t.kearney{at}leeds.ac.uk.
  1. A.A., H.I., and H.V. contributed equally to this study.

Diabetes 2011 Aug; 60(8): 2169-2178. https://doi.org/10.2337/db11-0197
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    FIG. 1.

    Haploinsufficiency of IGF-1R at a whole-body level leads to resistance to IGF-1–mediated glucose lowering and glucose intolerance but enhanced insulin sensitivity. A: Intraperitoneal glucose tolerance test. B: Intraperitoneal insulin tolerance test. C: Intraperitoneal IGF-1 tolerance test. Fasting plasma insulin (D) and fasting plasma IGF-1 (E) in mice with haploinsufficiency of IGF-1R and wild-type littermates. *P < 0.05; at least n = 10 per group for all experiments. Data shown as mean ± SEM.

  • FIG. 2.
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    FIG. 2.

    Haploinsufficiency of IGF-1R at a whole-body level leads to resistance to IGF-1–mediated aortic relaxation, blunted constriction to PE, and enhanced basal aortic NO production. Endothelial function in aortic rings from mice with haploinsufficiency of IGF-1R and wild-type littermates. A: Vasorelaxation in response to IGF-1 in wild type. B: IGF-1 relaxation is blunted in IGF-1R–deficient mice. C: eNOS activity in response to IGF-1 is blunted in IGF-1R haploinsufficient mice. D and E: Constriction in response to l-NMMA in wild-type mice (D) and IGF-1R haploinsufficient mice (E). F: Maximal constriction (Emax) in response to l-NMMA indicative of NO bioavailability is significantly higher in IGF-1R haploinsufficient mice. G: Constriction dose–response curve to PE in wild-type and IGF-1R haploinsufficient mice. H: Maximal constriction in response to PE is reduced in mice with haploinsufficiency of IGF-1R. I: IGF-1R expression in isolated pulmonary ECs in mice with haploinsufficiency of IGF-1R and wild-type littermates. *P < 0.05; at least n = 10 per group for all experiments.

  • FIG. 3.
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    FIG. 3.

    Haploinsufficiency of IGF-1R at a whole-body level leads to increased levels of tyrosine-phosphorylated IR, increased insulin-mediated NO production, and serine phosphorylation of eNOS in ECs. A: Enhanced basal tyrosine phosphorylation of IR in isolated ECs from IGF-1R haploinsufficient mice. B: Increased insulin-mediated NO production in ECs from IGF-1R haploinsufficient mice (bottom panel shows representative time series graph for change of DAF-FM fluorescence in pulmonary ECs in response to insulin [100 nmol/L]). C: Serine phosphorylation of eNOS is enhanced in response to insulin in ECs from IGF-1R haploinsufficient mice. D: No difference in IR levels in ECs from IGF-1R haploinsufficient mice. E: Reduced IGF-1R levels in ECs from IGF-1R haploinsufficient mice. F: Reduced hybrid receptors in ECs from IGF-1R haploinsufficient mice. *P < 0.05; n = 5–10 mice per experiment. AU, arbitrary unit; IB, immunoblotted; WT, wild type. (A high-quality color representation of this figure is available in the online issue.)

  • FIG. 4.
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    FIG. 4.

    Metabolic profiles of mice with haploinsufficiency and holoinsufficiency of IGF-1R in the endothelium. A and B: Glucose tolerance tests (A) and insulin tolerance tests (B) are similar in wild type and mice with haploinsufficiency of IGF-1R in the endothelium. C and D: Glucose tolerance tests (C) and insulin tolerance tests (D) are similar in wild type and mice with holoinsufficiency of IGF-1R in the endothelium. E and F: Fasting blood glucose (E) and fasting insulin levels (F) are similar in wild-type mice and mice with haploinsufficiency and holoinsufficiency of IGF-1R in the endothelium. At least n = 4 mice per group for all experiments. (A high-quality color representation of this figure is available in the online issue.)

  • FIG. 5.
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    FIG. 5.

    Vascular responses in aortic rings of mice with haploinsufficiency and holoinsufficiency of IGF-1R in the endothelium. A: Constrictor responses to PE in rings preincubated with l-NMMA in wild-type mice. B: Enhanced constrictor responses to PE in mice with EC-specific haploinsufficiency of IGF-1R. C: Constrictor responses to PE in rings preincubated with l-NMMA in wild-type mice. D: Enhanced constrictor responses (indicative of increased NO bioavailability) in rings in mice with EC-specific holoinsufficiency of IGF-1R. E: Blunted constrictor responses to PE in mice with EC-specific haploinsufficiency of IGF-1R. F: Blunted constrictor responses to PE in mice with EC-specific holoinsufficiency of IGF-1R. G: Maximal change in tension in response to l-NMMA in wild-type mice, mice with EC-specific haploinsufficiency of IGF-1R, and mice with EC-specific holoinsufficiency of IGF-1R, demonstrating gene dose effect of IGF-1R on NO bioavailability. H: Maximal change in tension in response to PE in wild-type mice, mice with EC-specific haploinsufficiency of IGF-1R, and mice with EC-specific holoinsufficiency of IGF-1R, demonstrating gene dose effect of IGF-1R on constrictor responses to PE. I: Quantification of hybrid receptors in wild-type mice, mice with EC-specific haploinsufficiency of IGF-1R, and mice with EC-specific holoinsufficiency of IGF-1R. All experiments had at least n = 5 mice. *P < 0.05. (A high-quality color representation of this figure is available in the online issue.)

  • FIG. 6.
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    FIG. 6.

    Deletion of IGF-1R in mice with haploinsufficiency of IR (IR+/−) restores insulin-stimulated NO production. A: Glucose tolerance tests in IR+/− and IR+/−/IGF-1R+/− mice. B: Insulin tolerance tests in IR+/− and IR+/−/IGF-1R+/− mice. C: Deletion of IGF-1R in IR+/− mice restores insulin-mediated eNOS activation. D: Insulin-mediated aortic relaxation is blunted in IR+/− mice. E and F: Deletion of IGF-1R in IR+/− mice restores insulin-mediated relaxation in aortic rings (E) and maximal relaxation to insulin in IR+/− and IR+/−/IGF-1R+/− mice (F). G: Insulin-mediated NO release in response to insulin in isolated ECs of IR+/− mice is restored by deletion of IGF-1R. H: Representative time series graph for change of DAF-FM fluorescence in pulmonary ECs in response to insulin. I: Hybrid receptor expression (100 nmol/L). All experiments had at least n = 6 animals. *P < 0.05. AU, arbitrary unit; IB, immunoblotted; IP, immunoprecipitation. (A high-quality color representation of this figure is available in the online issue.)

  • FIG. 7.
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    FIG. 7.

    siRNA-mediated knockdown of IGF-1R in HUVECs reproduces the in vivo scenario, increasing EC insulin-mediated eNOS activation. A: Relative levels of IGF-1R measured using quantitative PCR in siRNA and scrambled peptide–treated HUVECs. B: No difference in IR RNA. C: PCR gel showing specific effect of siRNA on IR and IGF-1R in HUVEC. D: Reduced hybrid receptors in siRNA-treated HUVECs. E: Increased basal and insulin-mediated eNOS serine phosphorylation in siRNA-treated cells. F: Increased basal and insulin-mediated eNOS activation in siRNA-treated cells. All data are mean of at least three experiments. *P < 0.05; #P < 0.05 vs. control. AU, arbitrary unit; Con, Ctrl, control; Scr, Scram, scrambled.

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The Insulin-Like Growth Factor-1 Receptor Is a Negative Regulator of Nitric Oxide Bioavailability and Insulin Sensitivity in the Endothelium
Afroze Abbas, Helen Imrie, Hema Viswambharan, Piruthivi Sukumar, Adil Rajwani, Richard M. Cubbon, Matthew Gage, Jessica Smith, Stacey Galloway, Nadira Yuldeshava, Matthew Kahn, Shouhong Xuan, Peter J. Grant, Keith M. Channon, David J. Beech, Stephen B. Wheatcroft, Mark T. Kearney
Diabetes Aug 2011, 60 (8) 2169-2178; DOI: 10.2337/db11-0197

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The Insulin-Like Growth Factor-1 Receptor Is a Negative Regulator of Nitric Oxide Bioavailability and Insulin Sensitivity in the Endothelium
Afroze Abbas, Helen Imrie, Hema Viswambharan, Piruthivi Sukumar, Adil Rajwani, Richard M. Cubbon, Matthew Gage, Jessica Smith, Stacey Galloway, Nadira Yuldeshava, Matthew Kahn, Shouhong Xuan, Peter J. Grant, Keith M. Channon, David J. Beech, Stephen B. Wheatcroft, Mark T. Kearney
Diabetes Aug 2011, 60 (8) 2169-2178; DOI: 10.2337/db11-0197
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