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: Kristina Hedbacker, Kivanç Birsoy, Robert W Wysocki, Esra Asilmaz, Rexford S Ahima, I Sadaf Farooqi, Jeffrey M Friedman
• Journal: Cell metabolism (Cell Metab) Vol. 11 Issue 1 Pg. 11-22 (Jan 2010) ISSN: 1932-7420 [Electronic] United States
• PMID: 20074524 (Publication Type: Journal Article, Research Support, N.I.H., Extramural)
• Copyright: 2010 Elsevier Inc.

Chemical References

• Blood Glucose
• Hypoglycemic Agents
• Insulin
• Insulin-Like Growth Factor Binding Protein 2
• Leptin
• RNA, Messenger

Topics

• Adenoviridae
• Animals
• Blood Glucose (metabolism)
• Gene Transfer Techniques
• Humans
• Hyperglycemia (metabolism)
• Hyperinsulinism (metabolism)
• Hypoglycemic Agents (metabolism, therapeutic use)
• Insulin (metabolism)
• Insulin-Like Growth Factor Binding Protein 2 (blood, genetics, metabolism)
• Leptin (genetics, metabolism, therapeutic use)
• Liver (metabolism)
• Mice
• Mice, Knockout
• Oligonucleotide Array Sequence Analysis
• RNA, Messenger (metabolism)