Effect of Insulin Deprivation on Muscle Mitochondrial ATP Production and Gene Transcript Levels in Type 1 Diabetic Subjects

  1. Helen Karakelides1,
  2. Yan W. Asmann1,
  3. Maureen L. Bigelow1,
  4. Kevin R. Short1,
  5. Ketan Dhatariya1,
  6. Jill Coenen-Schimke1,
  7. Jane Kahl1,
  8. Debabrata Mukhopadhyay2 and
  9. K. Sreekumaran Nair1
  1. 1Division of Endocrinology and Metabolism and Endocrine Research Unit, Mayo Clinic, Rochester, Minnesota
  2. 2Department of Biochemistry and Molecular Biology, Mayo Clinic, Rochester, Minnesota
  1. Address correspondence and reprint requests to K. Sreekumaran Nair, MD, PhD, Mayo Clinic, 200 First St. SW, Joseph 5-194, Rochester, MN 55905. E-mail: nair.sree{at}mayo.edu


OBJECTIVE—Muscle mitochondrial dysfunction occurs in many insulin-resistant states, such as type 2 diabetes, prompting a hypothesis that mitochondrial dysfunction may cause insulin resistance. We determined the impact of insulin deficiency on muscle mitochondrial ATP production by temporarily depriving type 1 diabetic patients of insulin treatment.

RESEARCH DESIGN AND METHODS—We withdrew insulin for 8.6 ± 0.6 h in nine C-peptide–negative type 1 diabetic subjects and measured muscle mitochondrial ATP production and gene transcript levels (gene array and real-time quantitative PCR) and compared with insulin-treated state. We also measured oxygen consumption (indirect calorimetry); plasma levels of glucagon, bicarbonate, and other substrates; and urinary nitrogen.

RESULTS—Withdrawal of insulin resulted in increased plasma glucose, branched chain amino acids, nonesterified fatty acids, β-hydroxybutyrate, and urinary nitrogen but no change in bicarbonate. Insulin deprivation decreased muscle mitochondrial ATP production rate (MAPR) despite an increase in whole-body oxygen consumption and altered expression of many muscle mitochondrial gene transcripts. Transcript levels of genes involved in oxidative phosphorylation were decreased, whereas those involved in vascular endothelial growth factor (VEGF) signaling, inflammation, cytoskeleton signaling, and integrin signaling pathways were increased.

CONCLUSIONS—Insulin deficiency and associated metabolic changes reduce muscle MAPR and expression of oxidative phosphorylation genes in type 1 diabetes despite an increase in whole-body oxygen consumption. Increase in transcript levels of genes involved in VEGF, inflammation, cytoskeleton, and integrin signaling pathways suggest that vascular factors and cell proliferation that may interact with mitochondrial changes occurred.


  • Published ahead of print at http://diabetes.diabetesjournals.org on 27 July 2007. DOI: 10.2337/db07-0378.

    Additional information for this article can be found in an online appendix at http://dx.doi.org/10.2337/db07-0378.

    The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked “advertisement” in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

    • Received March 20, 2007.
    • Accepted July 23, 2007.
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