title: MKR mice are resistant to the metabolic actions of both insulin and adiponectin: discordance between insulin resistance and adiponectin responsiveness.
abstract: Most rodent models of insulin resistance are accompanied by decreased circulating adiponectin levels. Adiponectin treatment improves the metabolic phenotype by increasing fatty acid oxidation in skeletal muscle and suppressing hepatic glucose production. Muscle IGF-I receptor (IGF-IR)-lysine-arginine (MKR) mice expressing dominant-negative mutant IGF-IRs in skeletal muscle are diabetic with insulin resistance in muscle, liver, and adipose tissue. Adiponectin levels are elevated in MKR mice, suggesting an unusual discordance between insulin resistance and adiponectin responsiveness. Therefore, we investigated the metabolic actions of adiponectin in MKR mice. MKR and ob/ob mice were treated both acutely (28 microg/g) and chronically (for 2 wk) with full-length adiponectin. Acute hypoglycemic effects of adiponectin were evident only in ob/ob mice but not in MKR mice. Chronic adiponectin treatment significantly improved both insulin sensitivity and glucose tolerance in ob/ob but not in MKR mice. Adiponectin receptor mRNA levels and adiponectin-stimulated phosphorylation of AMPK in skeletal muscle and liver were similar among MKR, wild-type, and ob/ob mice. Thus MKR mice are adiponectin resistant despite normal expression of adiponectin receptors and normal AMPK phosphorylation in muscle and liver. MKR mice may be a useful model for dissecting relationships between insulin resistance and adiponectin action in regulation of glucose homeostasis.
authors.affiliation: Diabetes Branch, National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Bethesda, Maryland, USA.
authors.forename: Chul-Hee
authors.initials: CH
authors.lastname: Kim
authors.forename: Patricia
authors.initials: P
authors.lastname: Pennisi
authors.forename: Hong
authors.initials: H
authors.lastname: Zhao
authors.forename: Shoshana
authors.initials: S
authors.lastname: Yakar
authors.forename: Jeanne B
authors.initials: JB
authors.lastname: Kaufman
authors.forename: Kenjiro
authors.initials: K
authors.lastname: Iganaki
authors.forename: Joseph
authors.initials: J
authors.lastname: Shiloach
authors.forename: Philipp E
authors.initials: PE
authors.lastname: Scherer
authors.forename: Michael J
authors.initials: MJ
authors.lastname: Quon
authors.forename: Derek
authors.initials: D
authors.lastname: LeRoith
mesh_terms: D052242:Adiponectin / Q000008:administration & dosage* / Q000097:blood; D000818:Animals; D001786:Blood Glucose / Q000378:metabolism*; D004305:Dose-Response Relationship, Drug; D004338:Drug Combinations; D007328:Insulin / Q000008:administration & dosage* / Q000097:blood; D007333:Insulin Resistance; D008099:Liver / Q000187:drug effects / Q000378:metabolism*; D051379:Mice; D018482:Muscle, Skeletal / Q000187:drug effects / Q000378:metabolism*; D017526:Receptor, IGF Type 1 / Q000378:metabolism*
chemical_list: D052242:Adiponectin; D001786:Blood Glucose; D004338:Drug Combinations; D007328:Insulin; D017526:Receptor, IGF Type 1