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Insulin resistance in type 1 diabetes mellitus

  • Author Footnotes
    1 Both authors equally contributed to this work.
    Kirti Kaul
    Footnotes
    1 Both authors equally contributed to this work.
    Affiliations
    Institute for Clinical Diabetology, German Diabetes Center, Leibniz Center for Diabetes Research at Heinrich-Heine University Düsseldorf, Germany

    German Center of Diabetes Research Partner, Düsseldorf, Germany
    Search for articles by this author
  • Author Footnotes
    1 Both authors equally contributed to this work.
    Maria Apostolopoulou
    Footnotes
    1 Both authors equally contributed to this work.
    Affiliations
    Institute for Clinical Diabetology, German Diabetes Center, Leibniz Center for Diabetes Research at Heinrich-Heine University Düsseldorf, Germany

    German Center of Diabetes Research Partner, Düsseldorf, Germany
    Search for articles by this author
  • Michael Roden
    Correspondence
    Corresponding author at: Department of Endocrinology and Diabetology, Medical Faculty, Heinrich-Heine University, Institute for Clinical Diabetology, German Diabetes Center, c/o Auf`m Hennekamp 65, D-40225 Düsseldorf, Germany. Tel.: +49 211 3382 201; fax: +49 211 3382 691.
    Affiliations
    Institute for Clinical Diabetology, German Diabetes Center, Leibniz Center for Diabetes Research at Heinrich-Heine University Düsseldorf, Germany

    German Center of Diabetes Research Partner, Düsseldorf, Germany

    Department of Endocrinology and Diabetology, Medical Faculty, Heinrich-Heine University, Düsseldorf, Germany
    Search for articles by this author
  • Author Footnotes
    1 Both authors equally contributed to this work.
Published:September 11, 2015DOI:https://doi.org/10.1016/j.metabol.2015.09.002

      Abstract

      For long the presence of insulin resistance in type 1 diabetes has been questioned. Detailed metabolic analyses revealed 12%–61% and up to 20% lower whole-body (skeletal muscle) and hepatic insulin sensitivity in type 1 diabetes, depending on the population studied. Type 1 diabetes patients feature impaired muscle adenosine triphosphate (ATP) synthesis and enhanced oxidative stress, predominantly relating to hyperglycemia. They may also exhibit abnormal fasting and postprandial glycogen metabolism in liver, while the role of hepatic energy metabolism for insulin resistance remains uncertain. Recent rodent studies point to tissue-specific differences in the mechanisms underlying insulin resistance. In non-obese diabetic mice, increased lipid availability contributes to muscle insulin resistance via diacylglycerol/protein kinase C isoforms. Furthermore, humans with type 1 diabetes respond to lifestyle modifications or metformin by 20%–60% increased whole-body insulin sensitivity, likely through improvement in both glycemic control and oxidative phosphorylation. Intensive insulin treatment and islet transplantation also increase but fail to completely restore whole-body and hepatic insulin sensitivity. In conclusion, insulin resistance is a feature of type 1 diabetes, but more controlled trials are needed to address its contribution to disease progression, which might help to optimize treatment and reduce comorbidities.

      Abbreviations:

      MRS (magnetic resonance spectroscopy), AMPK (5´AMP activated protein kinase), AGE (advanced glycation end product), ATP (adenosine triphosphate), bEGP (basal endogenous glucose production), DAG (diacylglycerol), FDR (first degree relative), FFA (free fatty acids), GIR (glucose infusion rate), HEC (hyperinsulinemic–euglycemic clamp), iEGP (insulin mediated suppression of EGP), IMCL (intramyocellular lipids), IRS (insulin receptor substrate), MCR (metabolic clearance rate), JNK (c-Jun-N terminal kinase pathway), MAPK (mitogen activated protein kinase), NF-κB (nuclear factor kappa-light-chain-enhancer of activated B-cells), PI3K-AKT (phosphatidylinositol-4,5-bisphosphate 3-kinase-protein kinase B), PKC (protein kinase C), Ra (glucose appearance rate), RAGE (receptor for advanced glycation end product), Rd (glucose disposal rate), ROS (reactive oxygen species), SREBP (sterol regulatory element binding protein), STZ (streptozocin), T1D (type 1 diabetes), T2D (type 2 diabetes)

      Keywords

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