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Am J Physiol Endocrinol Metab 290: E746-E749, 2006. First published November 8, 2005; doi:10.1152/ajpendo.00298.2005
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Overexpression of the insulin receptor inhibitor PC-1/ENPP1 induces insulin resistance and hyperglycemia

Betty A. Maddux,1 Yow-Ning Chang,1 Domenico Accili,2 Owen P. McGuinness,3 Jack F. Youngren,1 and Ira D. Goldfine1

1Department of Medicine and Diabetes Center, University of California, San Francisco, California 2Diabetes Center, Columbia University, New York, New York 3Department of Molecular Physiology and Biophysics, Vanderbilt University School of Medicine, Nashville, Tennessee

Submitted 1 July 2005 ; accepted in final form 27 October 2005

The ectoenzyme PC-1 is an insulin receptor inhibitor that is elevated in cells and tissues of humans with type 2 diabetes (T2D). We have recently shown that acute PC-1 overexpression in liver causes insulin resistance and glucose intolerance in mice (3), but the chronic effects of PC-1 overexpression on these functions are unknown. Herein we produced transgenic mice overexpressing the potent q allele of human PC-1 in muscle and liver. Compared with controls, these mice had 2- to 3-fold elevations of PC-1 content in liver and 5- to 10-fold elevations in muscle. In the fed state, the PC-1 animals had 100 mg/dl higher glucose levels and sixfold higher insulin levels compared with controls. During glucose tolerance tests, these PC-1 animals had peak glucose levels that were >150 mg/dl higher than controls. In vivo uptake of 2-deoxy-D-glucose in muscle during insulin infusion was decreased in the PC-1 animals. These in vivo data support the concept, therefore, that PC-1 plays a role in insulin resistance and hyperglycemia and suggest that animals with overexpression of human PC-1 in insulin-sensitive tissues may be important models to investigate insulin resistance.

diabetes mellitus; insulin


Address for reprint requests and other correspondence: I. D. Goldfine, Dept. of Medicine and Diabetes Center, Univ. of California, San Francisco, 1600 Divisadero, C415, San Francisco, CA 94143-1616 (e-mail: iragoldfine43{at}gmail.com)




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J. B. McAteer, S. Prudente, S. Bacci, H. N. Lyon, J. N. Hirschhorn, V. Trischitta, J. C. Florez, and for the ENPP1 Consortium
The ENPP1 K121Q Polymorphism Is Associated With Type 2 Diabetes in European Populations: Evidence From an Updated Meta-Analysis in 42,042 Subjects
Diabetes, April 1, 2008; 57(4): 1125 - 1130.
[Abstract] [Full Text] [PDF]


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