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This version published online on June 9, 2005
Endocrinology, doi:10.1210/en.2005-0087
A more recent version of this article appeared on September 1, 2005
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Submitted on January 21, 2005
Accepted on May 25, 2005

Leptin improves insulin resistance and hyperglycemia in a mouse model of type 2 diabetes

Yuka Toyoshima, Oksana Gavrilova, Shoshana Yakar, William Jou, Stephanie Pack, Zeenat Asghar, Michael Wheeler, and Derek LeRoith*

Diabetes Branch, Mouse Metabolic Core Facility, NIDDK, National Institutes of Health, Bethesda, Maryland 20892, USA; Department of Physiology, University of Toronto, Toronto, Canada

* To whom correspondence should be addressed. E-mail: derek{at}helix.nih.gov.

Leptin has metabolic effects on peripheral tissues including muscle, liver, and pancreas, and it has been successfully used to treat lipodystrophic diabetes, a leptin-deficient state. To study whether leptin therapy can be used for treatment of more common cases of type 2 diabetes, we used a mouse model of type 2 diabetes (MKR mice) that show normal leptin levels and are diabetic due to a primary defect in both IGF-I and insulin receptors signaling in skeletal muscle. Here we show that leptin administration to the MKR mice resulted in improvement of diabetes, an effect that was independent of the reduced food intake. The main effect of leptin therapy was enhanced hepatic insulin responsiveness possibly through decreasing gluconeogenesis. In addition, the reduction of lipid stores in liver and muscle induced by enhancing fatty acid oxidation and by inhibiting lipogenesis, led to an improvement of the lipotoxic condition. Our data suggest that leptin could be a potent anti-diabetic drug in cases of type 2 diabetes that are not leptin deficient.
Key words: Leptin • Type 2 diabetes • lipotoxicity




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