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Originally published In Press as doi:10.1074/jbc.M010313200 on March 27, 2001

J. Biol. Chem., Vol. 276, Issue 23, 19994-19998, June 8, 2001
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Increased Insulin Sensitivity in Gsalpha Knockout Mice*

Shuhua YuDagger , Arthur Castle§, Min ChenDagger , Randy LeeDagger , Kyoko TakedaDagger , and Lee S. WeinsteinDagger

From the Dagger  Metabolic Diseases Branch and § Diabetes Branch, NIDDK, National Institutes of Health, Bethesda, Maryland 20892

The stimulatory guanine nucleotide-binding protein (Gs) is required for hormone-stimulated cAMP generation. Gnas, the gene encoding the Gs alpha -subunit, is imprinted, and targeted disruption of this gene in mice leads to distinct phenotypes in heterozygotes depending on whether the maternal (m-/+) or paternal (+/p-) allele is mutated. Notably, m-/+ mice become obese, whereas +/p- mice are thinner than normal. In this study we show that despite these opposite changes in energy metabolism, both m-/+ and +/p- mice have greater sensitivity to insulin, with low to normal fasting glucose levels, low fasting insulin levels, improved glucose tolerance, and exaggerated hypoglycemic response to administered insulin. The combination of increased insulin sensitivity with obesity in m-/+ mice is unusual, because obesity is typically associated with insulin resistance. In skeletal muscles isolated from both m-/+ and +/p- mice, the basal rate of 2-deoxyglucose uptake was normal, whereas the rate of 2-deoxyglucose uptake in response to maximal insulin stimulation was significantly increased. The similar changes in muscle sensitivity to insulin in m-/+ and +/p- mice may reflect the fact that muscle Gsalpha expression is reduced by ~50% in both groups of mice. GLUT4 expression is unaffected in muscles from +/p- mice. Increased responsiveness to insulin is therefore the result of altered insulin signaling and/or GLUT4 translocation. This is the first direct demonstration in a genetically altered in vivo model that Gs-coupled pathways negatively regulate insulin signaling.

* The costs of publication of this article were defrayed in part by the payment of page charges. The article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

To whom correspondence should be addressed: Bldg. 10, Rm. 8C101, National Institutes of Health, Bethesda, MD 20892-1752. Tel.: 301-402-2923; Fax: 301-402-0374; E-mail: leew@amb.niddk.nih.gov.

Copyright © 2001 by The American Society for Biochemistry and Molecular Biology, Inc.
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