Insulin Signaling and Action in Fat Cells: Associations with Insulin Resistance and Type 2 Diabetes

Authors

  • ULF SMITH,

    Corresponding author
    1. The Lundberg Laboratory for Diabetes Research, Department of Internal Medicine, Sahlgrenska University Hospital, Gothenburg, Sweden
      Address correspondence to Dr. Ulf Smith, Dept. of Internal Medicine, Sahlgrenska University Hospital, S-413 45 Gothenburg, Sweden. Tel: 46 31 342 1104; fax: 46 31 82 91 38; e-mail: ulf.smith@medicine.gu.se
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  • METTE AXELSEN,

    1. The Lundberg Laboratory for Diabetes Research, Department of Internal Medicine, Sahlgrenska University Hospital, Gothenburg, Sweden
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  • EUGENIA CARVALHO,

    1. The Lundberg Laboratory for Diabetes Research, Department of Internal Medicine, Sahlgrenska University Hospital, Gothenburg, Sweden
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  • BJÖRN ELIASSON,

    1. The Lundberg Laboratory for Diabetes Research, Department of Internal Medicine, Sahlgrenska University Hospital, Gothenburg, Sweden
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  • PER-ANDERS JANSSON,

    1. The Lundberg Laboratory for Diabetes Research, Department of Internal Medicine, Sahlgrenska University Hospital, Gothenburg, Sweden
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  • CHRISTIAN WESSLAU

    1. The Lundberg Laboratory for Diabetes Research, Department of Internal Medicine, Sahlgrenska University Hospital, Gothenburg, Sweden
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Address correspondence to Dr. Ulf Smith, Dept. of Internal Medicine, Sahlgrenska University Hospital, S-413 45 Gothenburg, Sweden. Tel: 46 31 342 1104; fax: 46 31 82 91 38; e-mail: ulf.smith@medicine.gu.se

Abstract

ABSTRACT: Adipose tissue only accounts for a relatively small proportion (<10%) of the peripheral glucose utilization in response to insulin. However, the fat cells may still play an important role in insulin resistance and Syndrome X through, for instance, its endocrine functions (production of leptin, TNFα, PAI-1, etc.) and involvement in lipid metabolism (FFA release and hydrolysis of triglycerides). The fat cells are also highly sensitive to insulin and may thus be used to elucidate molecular mechanisms for insulin resistance in man. Examinations of the intracellular signaling mechanisms for insulin in fat cells from individuals with Type 2 diabetes revealed markedly lower insulin-stimulated PI3-kinase activity. This was due to a pronounced reduction in the cellular expression of the docking protein, IRS 1, whereas expression of IRS 2 was normal. However, IRS 2-associated PI3-kinase activity was only approximately one-third of that found to be associated with IRS 1 in normal cells.

Downstream activation and serine phosphorylation of PKB/Akt by insulin were also markedly reduced in Type 2 diabetes. Furthermore, the dose-response curve for this effect of insulin was similar to that for glucose transport in both normal and Type 2 diabetic cells. Thus, these data show that both PI3-kinase and PKB activation by insulin are markedly reduced in Type 2 diabetes. We also examined whether an attenuated activation of PI3-kinase by insulin can be seen in non-diabetic insulin-resistant states. Approximately 30% of healthy subjects with at least two first-degree relatives with Type 2 diabetes exhibited perturbations in IRS-1 expression and signaling. These individuals were characterized by insulin resistance as well as other markers of Syndrome X. Thus, impaired IRS-1 expression and downstream signaling events in fat cells in response to insulin are associated with insulin resistance and Syndrome X.

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