Impaired insulin stimulation of muscular ATP production in patients with type 1 diabetes

Authors

  • M. Kacerovsky,

    1. From the Karl-Landsteiner Institute for Endocrinology and Metabolism
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    • Both authors contributed equally to this work.

  • A. Brehm,

    1. 1st Medical Department, Hanusch Hospital
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    • Both authors contributed equally to this work.

  • M. Chmelik,

    1. From the Karl-Landsteiner Institute for Endocrinology and Metabolism
    2. MR Center of Excellence, Medical University of Vienna, Vienna, Austria
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  • A. I. Schmid,

    1. From the Karl-Landsteiner Institute for Endocrinology and Metabolism
    2. MR Center of Excellence, Medical University of Vienna, Vienna, Austria
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  • J. Szendroedi,

    1. From the Karl-Landsteiner Institute for Endocrinology and Metabolism
    2. 1st Medical Department, Hanusch Hospital
    3. Institute for Clinical Diabetology, German Diabetes Center (Leibniz Center for Diabetes Research)
    4. Department of Metabolic Diseases, Heinrich-Heine University Düsseldorf, Düsseldorf, Germany
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  • G. Kacerovsky-Bielesz,

    1. From the Karl-Landsteiner Institute for Endocrinology and Metabolism
    2. 1st Medical Department, Hanusch Hospital
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  • P. Nowotny,

    1. Institute for Clinical Diabetology, German Diabetes Center (Leibniz Center for Diabetes Research)
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  • A. Lettner,

    1. From the Karl-Landsteiner Institute for Endocrinology and Metabolism
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  • M. Wolzt,

    1. Department of Clinical Pharmacology, Medical University of Vienna, Vienna, Austria
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  • J. G. Jones,

    1. Department of Biochemistry and Center for Neurosciences and Cell Biology, University of Coimbra, Coimbra, Portugal
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  • M. Roden

    1. From the Karl-Landsteiner Institute for Endocrinology and Metabolism
    2. 1st Medical Department, Hanusch Hospital
    3. Institute for Clinical Diabetology, German Diabetes Center (Leibniz Center for Diabetes Research)
    4. Department of Metabolic Diseases, Heinrich-Heine University Düsseldorf, Düsseldorf, Germany
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  • The study was registered at ClinicalTrials.gov (NCT00481598).

Prof Michael Roden MD, Institute for Clinical Diabetology, German Diabetes Center (Leibniz Center), Department of Metabolic Diseases, Heinrich-Heine University Düsseldorf, Auf′m Hennekamp 65, Düsseldorf D-40225 Germany.
(fax: +49-211-3382-691; e-mail: michael.roden@ddz.uni-duesseldorf.de).

Abstract

Abstract.  Kacerovsky M, Brehm A, Chmelik M, Schmid AI, Szendroedi J, Kacerovsky-Bielesz G, Nowotny P, Lettner A, Wolzt M, Jones JG, Roden M (Karl-Landsteiner Institute for Endocrinology and Metabolism, Vienna; 1st Medical Department, Hanusch Hospital, Vienna; MR Center of Excellence, Medical University of Vienna, Vienna, Austria; Institute for Clinical Diabetology, German Diabetes Center (Leibniz Center for Diabetes Research), Düsseldorf; Heinrich-Heine University Düsseldorf, Düsseldorf, Germany; Medical University of Vienna, Vienna, Austria; and University of Coimbra, Coimbra, Portugal). Impaired insulin stimulation of muscular ATP production in patients with type 1 diabetes. J Intern Med 2011; 269: 189–199.

Objective.  In type 2 diabetic patients and their first-degree relatives, insulin resistance (IR) is associated with impairment of insulin-stimulated myocellular glucose-6-phosphate (g6p) and unidirectional flux through ATP synthase (fATP), suggesting the presence of inherited abnormal mitochondrial oxidative fitness. We hypothesized that patients with long-standing type 1 diabetes may also exhibit insulin resistance as well as lower fATP.

Design.  This single-centre trial was registered at ClinicalTrials.gov (NCT00481598).

Subjects.  We included eight nonobese type 1 diabetic patients (mean diabetes duration: 17 years) with near-target glycaemic control [haemoglobin A1c (HbA1c): 6.8 ± 0.4%] during treatment with continuous subcutaneous insulin infusion pumps and eight healthy volunteers (HbA1c: 5.4 ± 0.2%) of comparable age, body mass and level of physical activity.

Outcome measures.  Myocellular fATP, g6p and intramyocellular lipid content (IMCL) were measured with 1H/31P magnetic resonance spectroscopy during fasting and hyperinsulinaemic–euglycaemic clamp tests.

Results.  Fasting fATP, g6p and IMCL did not differ between groups. During stimulation by insulin, type 1 diabetic patients exhibited ∼50% (P < 0.001) lower whole-body glucose disposal along with ∼42% (P = 0.003) lower intramyocellular g6p and ∼25% (P = 0.024) lower fATP. Insulin-stimulated fATP correlated positively with whole-body insulin sensitivity (R = 0.706, P = 0.002) and negatively with HbA1c (R = −0.675, P = 0.004).

Conclusions.  Despite documented near-target glycaemic control for 1 year, nonobese patients with long-standing type 1 diabetes can exhibit insulin resistance. This associates with lower insulin-stimulated flux through muscular ATP synthase which could result from glucose toxicity.

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