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

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.

Transcriptional profiling of myotubes from patients with type 2 diabetes: no evidence for a primary defect in oxidative phosphorylation genes

“…There were no significant differences between control and diabetic participants transcriptional alterations in diabetic myotubes in our study, however, suggests that the downregulation of mitochondrial OXPHOS genes observed in insulin-resistant skeletal muscle in vivo is caused by differences in the magnitude of or response to factors outside the muscle cell, such as neuronal regulation, blood flow and circulating levels of substrates, cytokines and hormones. This idea is supported by several recent studies, which have indicated that both absolute and relative insulinopenia (insulin resistance), hyperglycaemia and circulating levels of NEFA are possible factors contributing to impaired mitochondrial biogenesis in vivo [14,17,18,[32][33][34]. Accordingly, none of the present human studies have been able to prove a cause-and-effect relationship between mitochondrial dysfunction and insulin resistance in vivo [13][14][15][16][17][18][19][20][21][22][23][24].…”

Mitochondrial superoxide and coenzyme Q in insulin-deficient rats: increased electron leak

“…5). There is evidence that ROS production may limit respiratory coupling (9) and, thus, efficiency of ATP synthesis; so we speculate that this process may, in part, explain the reduction in ATP production rates reported in insulin-deficient diabetes (18).…”

Mitochondrial Metabolism and Insulin Action

“…This response is attenuated in insulin-resistant T2D individuals, supporting a direct role for insulin resistance leading to mitochondrial dysfunction [143]. Further evidence for this notion comes from a study by Karakelides et al, who showed that acute insulin removal from subjects with type 1 diabetes, caused reductions in mitochondrial ATP production and in mitochondrial gene expression in skeletal muscle [145]. Additionally a recent study in patients with congenital defects in insulin signal transduction, reported that mitochondrial function (assessed by phosphocreatine recovery rates) in muscle was reduced in this population [146].…”