Effect of insulin deprivation on muscle mitochondrial ATP production and gene transcript levels in type 1 diabetic subjects

Helen Karakelides, Yan Asmann, Maureen L. Bigelow, Kevin R. Short, Ketan Dhatariya, Jill Coenen-Schimke, Jane Kahl, Debabrata Mukhopadhyay, K Sreekumaran Nair

Research output: Contribution to journalArticle

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Abstract

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.

Original languageEnglish (US)
Pages (from-to)2683-2689
Number of pages7
JournalDiabetes
Volume56
Issue number11
DOIs
StatePublished - Nov 2007

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Adenosine Triphosphate
Insulin
Muscles
Genes
Oxygen Consumption
Oxidative Phosphorylation
Bicarbonates
Cytoskeleton
Integrins
Vascular Endothelial Growth Factor A
Nitrogen
Hydroxybutyrates
Inflammation
Branched Chain Amino Acids
Indirect Calorimetry
Mitochondrial Genes
C-Peptide
Glucagon
Type 1 Diabetes Mellitus
Nonesterified Fatty Acids

ASJC Scopus subject areas

  • Internal Medicine
  • Endocrinology, Diabetes and Metabolism

Cite this

Effect of insulin deprivation on muscle mitochondrial ATP production and gene transcript levels in type 1 diabetic subjects. / Karakelides, Helen; Asmann, Yan; Bigelow, Maureen L.; Short, Kevin R.; Dhatariya, Ketan; Coenen-Schimke, Jill; Kahl, Jane; Mukhopadhyay, Debabrata; Nair, K Sreekumaran.

In: Diabetes, Vol. 56, No. 11, 11.2007, p. 2683-2689.

Research output: Contribution to journalArticle

Karakelides, Helen ; Asmann, Yan ; Bigelow, Maureen L. ; Short, Kevin R. ; Dhatariya, Ketan ; Coenen-Schimke, Jill ; Kahl, Jane ; Mukhopadhyay, Debabrata ; Nair, K Sreekumaran. / Effect of insulin deprivation on muscle mitochondrial ATP production and gene transcript levels in type 1 diabetic subjects. In: Diabetes. 2007 ; Vol. 56, No. 11. pp. 2683-2689.
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AU - Dhatariya, Ketan

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