Article Text

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


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.

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