Article Text

PDF
Insulin-like growth factor 1 receptor knockout in mice leads to altered glucose–insulin homeostasis and increased endothelial nitric oxide production
  1. A Abbas,
  2. H Imrie,
  3. A Rajwani,
  4. H Viswambharan,
  5. RM Cubbon,
  6. MB Kahn,
  7. M Gage,
  8. SB Wheatcroft,
  9. PJ Grant,
  10. MT Kearney
  1. University of Leeds, Leeds, UK

Abstract

Introduction Insulin-like growth factor 1 (IGF-1), acting via similar signalling pathways to insulin, enhances glucose uptake and nitric oxide (NO) production. Several studies have demonstrated an inverse relationship between IGF-1 bioactivity and cardiovascular disease. We assessed the hypothesis that a potential mechanism for these findings may be the modulation of endothelial NO bioavailability by IGF-1.

Methods Metabolic tolerance tests were performed on mice, heterozygous for knockout of the IGF-1 receptor (IGF1RKO), and their wild-type littermates (WT). An ex-vivo assessment of vascular function was performed using thoracic aortic rings in an organ bath.

Results IGF1RKO mice had higher random blood glucose measurements than age-matched WT siblings (9.7 mmol/l vs 8.9 mmol/l, respectively, n  =  20, p = 0.03). Glucose tolerance tests revealed impaired glucose handling in IGF1RKO mice compared with WT (mean area under the concentration time curve (AUC) IGF1RKO mice 1086 ± 26.82 (mmol/l) minutes, mean AUC WT mice 950.5 ± 22.5 (mmol/l) minutes, n  =  5, p = 0.005). Insulin tolerance tests revealed that IGF1RKO mice were more insulin sensitive than controls (mean AUC IGF1RKO 552.2 ± 25.18 (mmol/l) minutes, n  =  10; mean AUC for WT 651.4 ± 22.26 (mmol/l) minutes, n  =  11, p = 0.008). Aortic rings from IGF1RKO mice were hypocontractile to phenylepherine compared with those from WT (mean Emax IGF1RKO mice 0.60 ± 0.05 g, n  =  11 vs mean Emax for WT mice 0.79 ± 0.06 g, n  =  10, p = 0.03). Addition of the NO synthase inhibitor, NG-monomethyl-l-arginine (l-NMMA), led to a 65.40 ± 13.40% (n  =  9) increase in mean Emax in IGF1RKO mice compared with an 15.78 ± 12.00% (n  =  9) increase in WT mice (p = 0.01). In addition, IGF1RKO aortic rings were resistant to IGF-1 exposure compared with WT aortic rings (percentage change in mean Emax for IGF1RKO mice of 32.80 ± 11.01%, n  =  9 vs 66.28 ± 10.60% in WT mice, n  =  8, p = 0.05), but maintained sensitivity to insulin.

Conclusion IGF1RKO mice have impaired whole-body glucose handling, enhanced insulin sensitivity and increased basal NO production in the vasculature. These data raise the possibility that reduced IGF-1 receptor action in the endothelium may have a favourable effect on NO bioavailability, possibly by a novel interaction with insulin signalling.

Statistics from Altmetric.com

Request permissions

If you wish to reuse any or all of this article please use the link below which will take you to the Copyright Clearance Center’s RightsLink service. You will be able to get a quick price and instant permission to reuse the content in many different ways.