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Impaired (‘diabetic’) insulin signaling and action occur in fat cells long before glucose intolerance—is insulin resistance initiated in the adipose tissue?

International Journal of Obesity volume 26, pages 897–904 (2002)Cite this article

Abstract

This review postulates and presents recent evidence that insulin resistance is initiated in the adipose tissue and also suggests that the adipose tissue may play a pivotal role in the induction of insulin resistance in the muscles and the liver. Marked impairments in insulin's intracellular signaling cascade are present in fat cells from type 2 diabetic patients, including reduced IRS-1 gene and protein expression, impaired insulin-stimulated PI3-kinase and PKB/Akt activities. In contrast, upstream insulin signaling in skeletal muscle from diabetic subjects only shows modest impairments and PKB/Akt activation in vivo by insulin appears normal. However, insulin-stimulated glucose transport and glycogen synthesis are markedly reduced.

Similar marked impairments in insulin signaling, including reduced IRS-1 expression, impaired insulin-stimulated PI3-kinase and PKB/Akt activities are also seen in some (∼30%) normoglycemic individuals with genetic predisposition for type 2 diabetes. In addition, GLUT4 expression is markedly reduced in these cells, similar to what is seen in diabetic cells. The individuals with reduced cellular expression of IRS-1 and GLUT4 are also markedly insulin resistant and exhibit several characteristics of the Insulin Resistance Syndrome.

Thus, a ‘diabetic’ pattern is seen in the fat cells also in normoglycemic subjects and this is associated with a marked insulin resistance in vivo. It is proposed that insulin resistance and/or its effectors is initiated in fat cells and that this may secondarily encompass other target tissues for insulin, including the impaired glucose transport in the muscles.

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Acknowledgements

The studies performed in the author's laboratory were supported by grants from the Swedish Medical Research Council (project B-3506), the Swedish Diabetes Association, the European Community (QLG1-CT-1999-00674), Gullan and Sven-Erik Karlsson, the Sonya Hedenbratt Memorial Fund and the IngaBritt and Arne Lundberg Foundation.

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  1. Department of Internal Medicine, The Lundberg Laboratory for Diabetes Research, Sahlgrenska Academy at Göteborg University, Göteborg, Sweden

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Smith, U. Impaired (‘diabetic’) insulin signaling and action occur in fat cells long before glucose intolerance—is insulin resistance initiated in the adipose tissue?. Int J Obes 26, 897–904 (2002). https://doi.org/10.1038/sj.ijo.0802028

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