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Effect of Hyperglycemia on Mitochondrial Respiration in Type 2 Diabetes

Copenhagen Muscle Research Centre (R.R., R.B., F.D.), Department of Biomedical Sciences, Faculty of Health Sciences, University of Copenhagen, DK-2200 Copenhagen, Denmark; Department of Internal Medicine (R.R.), Yale University School of Medicine, New Haven, Connecticut 06510; and Department of Endocrinology (R.R., P.M.V.H., T.A., S.M.) and Clinical Research Centre (S.B.H.), Hvidovre University Hospital, 2650 Hvidovre, Denmark

Address all correspondence and requests for reprints to: Rasmus Rabøl, M.D., Postdoctoral Fellow, Department of Internal Medicine, Section of Endocrinology, Yale University School of Medicine, The Anlyan Center, Room S260, P.O. Box 208020, New Haven, Connecticut 06520-0820. E-mail: rasmus.rabol{at}yale.edu.

Aim: Skeletal muscle mitochondrial content is reduced in type 2 diabetes mellitus (T2DM). Whether hyperglycemia inhibits mitochondrial biogenesis and/or function is unknown. This study examined the effect of different levels of glycemia on skeletal muscle mitochondrial function in patients with T2DM.

Patients and Methods: Eleven patients with T2DM [9 males, 2 females; age, 52.8 ± 2.5 yr (mean ± SE); body mass index, 30.2 ± 1.1 kg/m²] in poor glycemic control were treated with insulin aspart and NPH insulin for a median period of 46 d (range, 31–59). Mitochondrial respiration and citrate synthase activity (a marker of mitochondrial content) were measured before and after treatment. Eleven healthy subjects (age, 53.3 ± 2.7 yr; body mass index, 30.6 ± 1.1 kg/m²) were included as controls.

Results: Hemoglobin A1c (9.1 ± 0.5 to 7.5 ± 0.3%; P < 0.001) and fasting plasma glucose (12.7 ± 1.1 to 6.5 ± 0.3 mmol/liter; P < 0.001) were reduced after treatment. Mitochondrial respiration per milligram muscle was lower in T2DM compared to controls [substrates for complex I, 24% lower (P < 0.05); substrates for complex I+II, 17% lower (P < 0.05)]. Mitochondrial respiration and citrate synthase activity did not differ before and after improvements in glycemic control, but mitochondrial respiration correlated with fasting plasma glucose before (r² = 0.53; P < 0.05) but not after treatment [r² = 0.0024; not significant (NS)]. Mitochondrial respiration normalized to mitochondrial content did not differ between control subjects and patients with T2DM.

Discussion: Mitochondrial respiration and content was not improved after significant improvements in glycemic control. However, severe hyperglycemia inhibited respiration reversibly, but moderate hyperglycemia and mitochondrial function were not correlated.