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* The Lundberg Laboratory for Diabetes Research,
Department of Clinical Nutrition,
Department of Clinical Physiology, and
The Wallenberg Laboratory for Cardiovascular Research, Sahlgrenska Academy at Göteborg University, Sweden,
# Department of Internal Medicine and Molecular Science, Osaka University, Japan; and
¶ Department of Medicine, University of Helsinki, Finland
1Correspondence: The Lundberg Laboratory for Diabetes Research, Department of Internal Medicine, Sahlgrenska Academy at Göteborg University, Sahlgrenska University Hospital, SE-413 45 Göteborg, Sweden. E-mail: ulf.smith{at}medic.gu.se
The epidemic increase in type 2 diabetes can be prevented only if markers of risk can be identified and used for early intervention. We examined the clinical phenotype of individuals characterized by normal or low IRS-1 protein expression in fat cells as well as the potential molecular mechanisms related to the adipose tissue. Twenty-five non-obese individuals with low or normal IRS-1 expression in subcutaneous abdominal fat cells were extensively characterized and the results compared with 71 carefully matched subjects with or without a known genetic predisposition for type 2 diabetes. In contrast to the commonly used risk marker, known heredity for diabetes, low cellular IRS-1 identified individuals who were markedly insulin resistant, had high proinsulin and insulin levels, and exhibited evidence of early atherosclerosis measured as increased intima media thickness in the carotid artery bulb. Circulating levels of adiponectin were also significantly reduced. Gene analyses of fat cells in a parallel study showed attenuated expression of several genes related to fat cell differentiation (adiponectin, aP2, PPAR
, and lipoprotein lipase) in the group of individuals characterized by a low IRS-1 expression and insulin resistance. A low IRS-1 expression in fat cells is a marker of insulin resistance and risk for type 2 diabetes and is associated with evidence of early vascular complications. Impaired adipocyte differentiation, including low gene expression and circulating levels of adiponectin, can provide a link between the cellular marker and the in vivo phenotype.—Jansson, P.-A., Pellmé, F., Hammarstedt, A., Sandqvist, M., Brekke, H., Caidahl, K., Forsberg, M., Volkmann, R., Carvalho, E., Funahashi, T., Matsuzawa, Y., Wiklund, O., Yang, X., Taskinen, M.-R., Smith, U. A novel cellular marker of insulin resistance and early atherosclerosis in humans is related to impaired fat cell differentiation and low adiponectin.
Key Words: type 2 diabetes • insulin signaling • adipose tissue • macroangiopathy • insulin.
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