| First Author | Garcia-Barrado MJ | Year | 2011 |
| Journal | Biochem Pharmacol | Volume | 81 |
| Issue | 2 | Pages | 279-88 |
| PubMed ID | 20959116 | Mgi Jnum | J:167776 |
| Mgi Id | MGI:4880595 | Doi | 10.1016/j.bcp.2010.10.008 |
| Citation | Garcia-Barrado MJ, et al. (2011) Differential sensitivity to adrenergic stimulation underlies the sexual dimorphism in the development of diabetes caused by Irs-2 deficiency. Biochem Pharmacol 81(2):279-88 |
| abstractText | The diabetic phenotype caused by the deletion of insulin receptor substrate-2 (Irs-2) in mice displays a sexual dimorphism. Whereas the majority of male Irs-2(-/-) mice are overtly diabetic by 12 weeks of age, female Irs-2(-/-) animals develop mild obesity and progress less rapidly to diabetes. Here we investigated beta-cell function and lipolysis as potential explanations for the gender-related differences in this model. Glucose-stimulated insulin secretion was enhanced in islets from male null mice as compared to male WT whereas this response in female Irs-2(-/-) islets was identical to that of female controls. The ability of alpha(2)-adrenoceptor (alpha(2)-AR) agonists to inhibit insulin secretion was attenuated in male Irs2 null mice. Consistent with this, the expression of the alpha(2A)-AR was reduced in male Irs-2(-/-) islets. The response of male Irs-2(-/-) islets to forskolin was enhanced, owing to increased production of cAMP. Basal lipolysis was increased in male Irs-2(-/-) but decreased in female Irs-2(-/-) mice, concordant with the observation that adipose tissue is sparse in males whereas female Irs2 null mice are mildly obese. Adipocytes from both male and female Irs-2(-/-) were resistant to the anti-lipolytic effects of insulin but female Irs-2(-/-) fat cells were additionally resistant to the catabolic effects of beta-adrenergic agonists. This catecholamine resistance was associated with impaired generation of cAMP. Consequently, targets of cAMP-dependent protein kinase (PKA) which mediate lipolysis were not phosphorylated in adipose tissue of female Irs-2(-/-) mice. Our findings suggest that IRS-2 deficiency in mice alters the expression and/or sensitivity of components of adrenergic signaling. |
