title: Sex differences in insulin resistance in GABAB1 knockout mice.
abstract: OBJECTIVE
  We have previously demonstrated that the absence of functional GABA B receptors (GABABRs) disturbs glucose homeostasis in GABAB1KO mice. The aim of this work was to extend our studies of these alterations in GABAB1KO mice and investigate the sexual differences therein.
  
  
  METHODS
  Male and female, GABAB1KO and WT mice were used. Glucose and insulin tolerance tests (GTT and ITT), and insulin and glucagon secretion tests (IST and GST) were performed. Blood glucose, serum insulin and hyperglycemic hormones were determined, and HOMA-IR calculated. Skeletal muscle insulin receptor β subunit (IRβ), insulin receptor substrates 1/2 (IRS1, IRS2) and hexokinase-II levels were determined by Western blot. Skeletal muscle insulin sensitivity was assessed by in vivo insulin-induced Akt phosphorylation (Western blot). Food intake and hypothalamic NPY mRNA expression (by qPCR) were also evaluated.
  
  
  RESULTS
  Fasted insulin and HOMA-IR were augmented in GABAB1KO males, with no alterations in females. Areas under the curve (AUC) for GTT and ITT were increased in GABAB1KO mice of both genders, indicating compromised insulin sensitivity. No genotype differences were observed in IST, GST or in IRβ, IRS1, IRS2 and hexokinase-II expression. Akt activation was severely impaired in GABAB1KO males while no alterations were observed in females. GABAB1KO mice showed increased food intake and NPY expression.
  
  
  CONCLUSIONS
  Glucose metabolism and energy balance disruptions were more pronounced in GABAB1KO males, which develop peripheral insulin resistance probably due to augmented insulin secretion. Metabolic alterations in females were milder and possibly due to previously described reproductive disorders, such as persistent estrus.
authors.affiliation: Instituto de Biología y Medicina Experimental-CONICET, Buenos Aires, Argentina.
authors.forename: M M
authors.initials: MM
authors.lastname: Bonaventura
authors.forename: D
authors.initials: D
authors.lastname: Rodriguez
authors.forename: M L
authors.initials: ML
authors.lastname: Ferreira
authors.forename: M
authors.initials: M
authors.lastname: Crivello
authors.forename: E M
authors.initials: EM
authors.lastname: Repetto
authors.forename: B
authors.initials: B
authors.lastname: Bettler
authors.forename: C
authors.initials: C
authors.lastname: Libertun
authors.forename: V A
authors.initials: VA
authors.lastname: Lux-Lantos
mesh_terms: D000818:Animals; D004435:Eating / Q000235:genetics; D005260:Female; D005786:Gene Expression Regulation / Q000235:genetics; D005934:Glucagon / Q000235:genetics / Q000378:metabolism; D007031:Hypothalamus / Q000378:metabolism / Q000473:pathology; D007328:Insulin / Q000235:genetics / Q000378:metabolism; D055504:Insulin Receptor Substrate Proteins / Q000235:genetics / Q000378:metabolism; D007333:Insulin Resistance; D000078790:Insulin Secretion; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D018345:Mice, Knockout; D018482:Muscle, Skeletal / Q000378:metabolism / Q000473:pathology; D009478:Neuropeptide Y / Q000235:genetics / Q000378:metabolism; D010766:Phosphorylation / Q000235:genetics; D051057:Proto-Oncogene Proteins c-akt / Q000235:genetics / Q000378:metabolism; D011972:Receptor, Insulin / Q000235:genetics / Q000378:metabolism; D018080:Receptors, GABA-B; D012727:Sex Characteristics
chemical_list: D007328:Insulin; D055504:Insulin Receptor Substrate Proteins; C526295:Irs1 protein, mouse; C526298:Irs2 protein, mouse; D009478:Neuropeptide Y; D018080:Receptors, GABA-B; D005934:Glucagon; D011972:Receptor, Insulin; D051057:Proto-Oncogene Proteins c-akt