Impaired Mitochondrial Activity in the Insulin-Resistant Offspring of Patients with Type 2 Diabetes

Petersen, Kitt Falk; Dufour, Sylvie; Befroy, Douglas E.; Garcia, Rina; Shulman, Gerald I.

doi:10.1056/nejmoa031314

Cited by 1,967 publications

(1,693 citation statements)

References 46 publications

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“…While glucose-6-phosphate can observed in the 31 P-MR spectrum, 13 C-MRS gives access to glycogen and glucose, especially in connection with an infusion of 13 C-enriched [1-13 C]glucose. A sequential acquisition of 1 H-and 31 P-MR spectra in muscle and liver allows for an observation of IMCL, intrahepatic lipids (IHCL) and oxidative phosphorylation (135,136). In principle, combinations of such examinations could take place within the same session, i.e.…”

Section: Combination Of 1 H-mrs Of Imcl and Other Mrs Techniquesmentioning

confidence: 99%

Role of proton MR for the study of muscle lipid metabolism

et al. 2006

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1 H-MR spectroscopy (MRS) of intramyocellular lipids (IMCL) became particularly important when it was recognized that IMCL levels are related to insulin sensitivity. While this relation is rather complex and depends on the training status of the subjects, various other influences such as exercise and diet also influence IMCL concentrations. This may open insight into many metabolic interactions; however, it also requires careful planning of studies in order to control all these confounding influences. This review summarizes various historical, methodological, and practical aspects of 1 H-MR spectroscopy (MRS) of muscular lipids. That includes a differentiation of bulk magnetic susceptibility effects and residual dipolar coupling that can both be observed in MRS of skeletal muscle, yet affecting different metabolites in a specific way. Fitting of the intra-(IMCL) and extramyocellular (EMCL) signals with complex line shapes and the transformation into absolute concentrations is discussed. Since the determination of IMCL in muscle groups with oblique fiber orientation or in obese subjects is still difficult, potential improvement with high-resolution spectroscopic imaging or at higher field strength is considered. Fat selective imaging is presented as a possible alternative to MRS and the potential of multinuclear MRS is discussed. 1 H-MRS of muscle lipids allows non-invasive and repeated studies of muscle metabolism that lead to highly relevant findings in clinics and patho-physiology.

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Section: Combination Of 1 H-mrs Of Imcl and Other Mrs Techniquesmentioning

confidence: 99%

Role of proton MR for the study of muscle lipid metabolism

et al. 2006

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“…When mitochondrial activity was determined per muscle weight (i.e. muscle oxidative capacity), studies have either shown no differences [3][4][5] or a lower [6][7][8][9][10][11][12] mitochondrial activity in insulin-resistant participants. Studies that have related mitochondrial activity to markers of mitochondrial volume (intrinsic mitochondrial activity) have either shown a lower [6,12,13] or no difference [9-11, 14, 15] in mitochondrial activity in insulin-resistant participants.…”

Section: Introductionmentioning

confidence: 99%

Effect of physical training on mitochondrial respiration and reactive oxygen species release in skeletal muscle in patients with obesity and type 2 diabetes

et al. 2010

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Aim/hypothesis Studies have suggested a link between insulin resistance and mitochondrial dysfunction in skeletal muscles. Our primary aim was to investigate the effect of aerobic training on mitochondrial respiration and mitochondrial reactive oxygen species (ROS) release in skeletal muscle of obese participants with and without type 2 diabetes. Methods Type 2 diabetic men (n=13) and control (n=14) participants matched for age, BMI and physical activity completed 10 weeks of aerobic training. Pre-and posttraining muscle biopsies were obtained before a euglycaemichyperinsulinaemic clamp and used for measurement of respiratory function and ROS release in isolated mitochondria. Results Training significantly increased insulin sensitivity, maximal oxygen consumption and muscle mitochondrial respiration with no difference between groups. When expressed in relation to a marker of mitochondrial density (intrinsic mitochondrial respiration), training resulted in increased mitochondrial ADP-stimulated respiration (with NADH-generating substrates) and decreased respiration without ADP. Intrinsic mitochondrial respiration was not different between groups despite lower insulin sensitivity in type 2 diabetic participants. Mitochondrial ROS release tended to be higher in participants with type 2 diabetes. Conclusions/interpretation Aerobic training improves muscle respiration and intrinsic mitochondrial respiration in untrained obese participants with and without type 2 diabetes. These adaptations demonstrate an increased metabolic fitness, but do not seem to be directly related to training-induced changes in insulin sensitivity.

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“…6 Indeed, it has been shown that mitochondrial ATP production in skeletal muscle is impaired in insulin-resistant offspring of patients with type 2 diabetes, 7 which raises the possibility that mitochondrial oxidative phosphorylation in skeletal muscle might be impaired in MetS. However, it has not been determined whether lower aerobic capacity is associated with skeletal muscle dysfunction in these patients.…”

Section: Introductionmentioning

confidence: 99%

Lower aerobic capacity was associated with abnormal intramuscular energetics in patients with metabolic syndrome

et al. 2011

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Lower aerobic capacity is a strong and independent predictor of cardiovascular morbidity and mortality in patients with metabolic syndrome (MetS). However, the mechanisms are not fully elucidated. We tested the hypothesis that skeletal muscle dysfunction could contribute to the lower aerobic capacity in MetS patients. The incremental exercise tests with cycle ergometer were performed in 12 male patients with MetS with no habitual exercise and 11 age-, sex-and activity-matched control subjects to assess the aerobic capacity. We performed 31 phosphorus-magnetic resonance spectroscopy (MRS) to assess the high-energy phosphate metabolism in skeletal muscle during aerobic exercise. Proton-MRS was also performed to measure intramyocellular lipid (IMCL) content. Peak oxygen uptake (peak VO 2 ; 34.1±6.2 vs. 41.4±8.4 ml kg À1 min À1 , Po0.05) and anaerobic threshold (AT; 18.0±2.4 vs. 23.1±3.7 ml kg À1 min À1 , Po0.01) adjusted by lean body mass were lower in MetS patients than control subjects. Phosphocreatine (PCr) loss during exercise was 1.5-fold greater in MetS, suggesting reduced intramuscular oxidative capacity. PCr loss was inversely correlated with peak VO 2 (r¼À0.64) and AT (r¼À0.60), respectively. IMCL content was threefold higher in MetS and was inversely correlated with peak VO 2 (r¼À0.47) and AT (r¼À0.52), respectively. Moreover, there was a positive correlation between IMCL content and PCr loss (r¼0.64). These results suggested that lean-body aerobic capacity in MetS patients was lower compared with activity-matched healthy subjects, which might be due to the reduced intramuscular fatty acid oxidative metabolism.

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Impaired Mitochondrial Activity in the Insulin-Resistant Offspring of Patients with Type 2 Diabetes

Abstract: BACKGROUND-Insulin resistance appears to be the best predictor of the development of diabetes in the children of patients with type 2 diabetes, but the mechanism responsible is unknown.

Cited by 1,967 publications

References 46 publications

Role of proton MR for the study of muscle lipid metabolism

Role of proton MR for the study of muscle lipid metabolism

Effect of physical training on mitochondrial respiration and reactive oxygen species release in skeletal muscle in patients with obesity and type 2 diabetes

Lower aerobic capacity was associated with abnormal intramuscular energetics in patients with metabolic syndrome

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