Differential sensitivity to adrenergic stimulation underlies the sexual dimorphism in the development of diabetes caused by Irs-2 deficiency.
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 β-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 α(2)-adrenoceptor (α(2)-AR) agonists to inhibit insulin secretion was attenuated in male Irs2 null mice. Consistent with this, the expression of the α(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.
Department of Physiology and Pharmacology, Faculty of Medicine, University of Salamanca, Salamanca, Spain.
Maria Jose
MJ
Garcia-Barrado
Maria Carmen
MC
Iglesias-Osma
Veronica
V
Moreno-Viedma
Maria Francisca
MF
Pastor Mansilla
Silvia Sanz
SS
Gonzalez
Jose
J
Carretero
Julio
J
Moratinos
Deborah J
DJ
Burks
D000262:Adenylyl Cyclases; D017667:Adipocytes / Q000378:metabolism; D058647:Adrenergic alpha-2 Receptor Agonists / Q000494:pharmacology*; D000818:Animals; D002478:Cells, Cultured; D005576:Colforsin / Q000494:pharmacology; D000242:Cyclic AMP / Q000378:metabolism; D003920:Diabetes Mellitus / Q000235:genetics* / Q000378:metabolism*; D005260:Female; D005786:Gene Expression Regulation / Q000502:physiology; D007328:Insulin / Q000378:metabolism / Q000494:pharmacology; D055504:Insulin Receptor Substrate Proteins / Q000235:genetics* / Q000378:metabolism*; D007515:Islets of Langerhans / Q000502:physiology; D008066:Lipolysis / Q000502:physiology; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D018341:Receptors, Adrenergic, alpha-2 / Q000378:metabolism; D012727:Sex Characteristics; D015398:Signal Transduction; D002787:Sterol Esterase / Q000378:metabolism
D058647:Adrenergic alpha-2 Receptor Agonists; D007328:Insulin; D055504:Insulin Receptor Substrate Proteins; C526298:Irs2 protein, mouse; D018341:Receptors, Adrenergic, alpha-2; D005576:Colforsin; D000242:Cyclic AMP; D002787:Sterol Esterase; D000262:Adenylyl Cyclases