title: Mechanisms behind insulin resistance in rat skeletal muscle after oophorectomy and additional testosterone treatment.
abstract: The absence of female sex hormones, as well as testosterone treatment of oophorectomized (OVX) female rats has been demonstrated to result in decreased whole-body insulin-mediated glucose uptake. The cellular mechanism behind this insulin resistance and the role of low levels of female sex hormones as a risk factor for development of peripheral insulin resistance are not yet fully clarified. We assessed the protein expression of GLUT4 and glycogen synthase, as well as insulin-induced translocation of GLUT4 to the plasma membrane, in soleus skeletal muscle from control rats, OVX rats, and OVX rats treated for 8 weeks with testosterone (OVX + T). Whole-body insulin-mediated glucose uptake assessed by the hyperinsulinemic-euglycemic clamp procedure was 25% lower in OVX rats (P < 0.001) and addition of testosterone treatment further decreased insulin-mediated glucose uptake in OVX + T rats by 48% (P < 0.001) compared with controls. GLUT4 protein expression in soleus muscles was unaltered in the OVX and OVX + T rats compared with controls. Insulin induced a 3.7-fold increase (P < 0.05) in the plasma membrane content of GLUT4 in soleus muscle from control rats, whereas plasma membrane content of GLUT4 in soleus muscle from OVX or OVX + T rats was unaltered in response to insulin. Glycogen synthase protein expression in muscle homogenates was decreased by 25% in the OVX group (P < 0.05) and by 37% in the OVX + T group (P < 0.05) when compared with the control group. Insulin receptor and tyrosine kinase activities in the basal and insulin-stimulated states did not differ between the OVX and OVX + T rats. In conclusion, the absence of female sex hormones appears to decrease insulin-mediated whole-body glucose uptake via an impaired insulin-stimulated translocation of GLUT4 to the plasma membrane and by decreased protein expression of glycogen synthase. Testosterone treatment further impairs whole-body insulin-mediated glucose uptake, presumably by additional impairment of glycogen synthase expression.
authors.affiliation: Deopartment of Clinical Physiology, Karolinska Hospital, Stockholm, Sweden.
authors.forename: J
authors.initials: J
authors.lastname: Rincon
authors.forename: A
authors.initials: A
authors.lastname: Holmäng
authors.forename: E O
authors.initials: EO
authors.lastname: Wahlström
authors.forename: P
authors.initials: P
authors.lastname: Lönnroth
authors.forename: P
authors.initials: P
authors.lastname: Björntorp
authors.forename: J R
authors.initials: JR
authors.lastname: Zierath
authors.forename: H
authors.initials: H
authors.lastname: Wallberg-Henriksson
mesh_terms: D015720:5'-Nucleotidase / Q000378:metabolism; D000818:Animals; D001786:Blood Glucose / Q000378:metabolism; D015153:Blotting, Western; D002462:Cell Membrane / Q000378:metabolism; D005260:Female; D015309:Glucose Clamp Technique; D051275:Glucose Transporter Type 4; D007328:Insulin / Q000378:metabolism; D007333:Insulin Resistance; D009004:Monosaccharide Transport Proteins / Q000096:biosynthesis; D009124:Muscle Proteins; D018482:Muscle, Skeletal / Q000187:drug effects / Q000502:physiology*; D010052:Ovariectomy; D051381:Rats; D017207:Rats, Sprague-Dawley; D011972:Receptor, Insulin / Q000302:isolation & purification / Q000378:metabolism; D012016:Reference Values; D013739:Testosterone / Q000494:pharmacology*
chemical_list: D001786:Blood Glucose; D051275:Glucose Transporter Type 4; D007328:Insulin; D009004:Monosaccharide Transport Proteins; D009124:Muscle Proteins; C495694:Slc2a4 protein, rat; D013739:Testosterone; D011972:Receptor, Insulin; D015720:5'-Nucleotidase