title: Antidiabetic effects of IGFBP2, a leptin-regulated gene.
abstract: We tested whether leptin can ameliorate diabetes independent of weight loss by defining the lowest dose at which leptin treatment of ob/ob mice reduces plasma glucose and insulin concentration. We found that a leptin dose of 12.5 ng/hr significantly lowers blood glucose and that 25 ng/hr of leptin normalizes plasma glucose and insulin without significantly reducing body weight, establishing that leptin exerts its most potent effects on glucose metabolism. To find possible mediators of this effect, we profiled liver mRNA using microarrays and identified IGF Binding Protein 2 (IGFBP2) as being regulated by leptin with a similarly high potency. Overexpression of IGFBP2 by an adenovirus reversed diabetes in insulin-resistant ob/ob, Ay/a, and diet-induced obese mice, as well as insulin-deficient streptozotocin-treated mice. Hyperinsulinemic clamp studies showed a 3-fold improvement in hepatic insulin sensitivity following IGFBP2 treatment of ob/ob mice. These results show that IGFBP2 can regulate glucose metabolism, a finding with potential implications for the pathogenesis and treatment of diabetes.
authors.affiliation: Rockefeller University, New York, NY 10065, USA.
authors.forename: Kristina
authors.initials: K
authors.lastname: Hedbacker
authors.forename: Kivanç
authors.initials: K
authors.lastname: Birsoy
authors.forename: Robert W
authors.initials: RW
authors.lastname: Wysocki
authors.forename: Esra
authors.initials: E
authors.lastname: Asilmaz
authors.forename: Rexford S
authors.initials: RS
authors.lastname: Ahima
authors.forename: I Sadaf
authors.initials: IS
authors.lastname: Farooqi
authors.forename: Jeffrey M
authors.initials: JM
authors.lastname: Friedman
mesh_terms: D000256:Adenoviridae; D000818:Animals; D001786:Blood Glucose / Q000378:metabolism; D018014:Gene Transfer Techniques; D006801:Humans; D006943:Hyperglycemia / Q000378:metabolism; D006946:Hyperinsulinism / Q000378:metabolism; D007004:Hypoglycemic Agents / Q000378:metabolism / Q000627:therapeutic use*; D007328:Insulin / Q000378:metabolism; D018971:Insulin-Like Growth Factor Binding Protein 2 / Q000097:blood / Q000235:genetics / Q000378:metabolism*; D020738:Leptin / Q000235:genetics / Q000378:metabolism / Q000627:therapeutic use*; D008099:Liver / Q000378:metabolism; D051379:Mice; D018345:Mice, Knockout; D020411:Oligonucleotide Array Sequence Analysis; D012333:RNA, Messenger / Q000378:metabolism
chemical_list: D001786:Blood Glucose; D007004:Hypoglycemic Agents; D007328:Insulin; D018971:Insulin-Like Growth Factor Binding Protein 2; D020738:Leptin; D012333:RNA, Messenger