Effect of Insulin Deprivation on Muscle Mitochondrial ATP Production and Gene Transcript Levels in Type 1 Diabetic Subjects
- 1 November 2007
- journal article
- Published by American Diabetes Association in Diabetes
- Vol. 56 (11), 2683-2689
- https://doi.org/10.2337/db07-0378
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.Keywords
This publication has 44 references indexed in Scilit:
- Skeletal Muscle Mitochondrial Functions, Mitochondrial DNA Copy Numbers, and Gene Transcript Profiles in Type 2 Diabetic and Nondiabetic Subjects at Equal Levels of Low or High Insulin and EuglycemiaDiabetes, 2006
- Inhibition of mitochondrial respiration elevates oxygen concentration but leaves regulation of hypoxia-inducible factor (HIF) intactBlood, 2005
- The role of HIF-1α in myeloid cell inflammationTrends in Immunology, 2005
- Decreased Insulin-Stimulated ATP Synthesis and Phosphate Transport in Muscle of Insulin-Resistant Offspring of Type 2 Diabetic ParentsPLoS Medicine, 2005
- PGC-1α-responsive genes involved in oxidative phosphorylation are coordinately downregulated in human diabetesNature Genetics, 2003
- Inborn errors of complex II – Unusual human mitochondrial diseasesBiochimica et Biophysica Acta (BBA) - Bioenergetics, 2002
- Mechanisms Controlling Mitochondrial Biogenesis and Respiration through the Thermogenic Coactivator PGC-1Cell, 1999
- Quantitation of Muscle Glycogen Synthesis in Normal Subjects and Subjects with Non-Insulin-Dependent Diabetes by13C Nuclear Magnetic Resonance SpectroscopyThe New England Journal of Medicine, 1990
- Effect of beta-hydroxybutyrate on whole-body leucine kinetics and fractional mixed skeletal muscle protein synthesis in humans.JCI Insight, 1988
- Abnormal meal carbohydrate disposition in insulin-dependent diabetes. Relative contributions of endogenous glucose production and initial splanchnic uptake and effect of intensive insulin therapy.JCI Insight, 1984