An early hallmark in the development of type 2 diabetes is the resistance to the effect of insulin in skeletal muscle and in the heart. Since mitochondrial function was found to be diminished in ...patients with type 2 diabetes, it was suggested that this defect might be involved in the etiology of insulin resistance. Although several hypotheses were suggested, yet unclear is the mechanistic link between these two phenomena.
Herein, we review the evidence for disturbances in mitochondrial function in skeletal muscle and the heart in the diabetic state. Also the mechanisms involved in improving mitochondrial function are considered and, whenever possible, human data is cited.
Reported evidence shows that interventions that improve skeletal muscle mitochondrial function also improve insulin sensitivity in humans. In the heart, available data from animal studies suggests that enhancement of mitochondrial function can reverse aging-induced changes in heart function, and can be protective against cardiomyopathy and heart failure.
Mitochondria and their functions can be targeted with the aim of improving skeletal muscle insulin sensitivity and cardiac function. However, human clinical intervention studies are needed to fully substantiate the potential of mitochondria as a target to prevent cardiometabolic disease.
Lower Intrinsic ADP-Stimulated Mitochondrial Respiration Underlies In Vivo Mitochondrial Dysfunction in Muscle of Male Type
2 Diabetic Patients
Esther Phielix 1 ,
Vera B. Schrauwen-Hinderling 1 2 ,
...Marco Mensink 1 ,
Ellen Lenaers 3 ,
Ruth Meex 3 ,
Joris Hoeks 1 ,
Marianne Eline Kooi 2 ,
Esther Moonen-Kornips 1 3 ,
Jean-Pierre Sels 4 ,
Matthijs K.C. Hesselink 3 and
Patrick Schrauwen 1
1 Department of Human Biology, Maastricht University, Maastricht, the Netherlands
2 Department of Radiology, Maastricht University Hospital, Maastricht, the Netherlands
3 Department of Human Movement Sciences, Maastricht University, Maastricht, the Netherlands
4 Department of Internal Medicine, Maastricht University Hospital, Maastricht, the Netherlands
Corresponding author: Dr. Patrick Schrauwen, p.schrauwen{at}hb.unimaas.nl
Abstract
OBJECTIVE— A lower in vivo mitochondrial function has been reported in both type 2 diabetic patients and first-degree relatives of type
2 diabetic patients. The nature of this reduction is unknown. Here, we tested the hypothesis that a lower intrinsic mitochondrial
respiratory capacity may underlie lower in vivo mitochondrial function observed in diabetic patients.
RESEARCH DESIGN AND METHODS— Ten overweight diabetic patients, 12 first-degree relatives, and 16 control subjects, all men, matched for age and BMI, participated
in this study. Insulin sensitivity was measured with a hyperinsulinemic-euglycemic clamp. Ex vivo intrinsic mitochondrial
respiratory capacity was determined in permeabilized skinned muscle fibers using high-resolution respirometry and normalized
for mitochondrial content. In vivo mitochondrial function was determined by measuring phosphocreatine recovery half-time after
exercise using 31 P-magnetic resonance spectroscopy.
RESULTS— Insulin-stimulated glucose disposal was lower in diabetic patients compared with control subjects (11.2 ± 2.8 vs. 28.9 ± 3.7
μmol · kg −1 fat-free mass · min −1 , respectively; P = 0.003), with intermediate values for first-degree relatives (22.1 ± 3.4 μmol · kg −1 fat-free mass · min −1 ). In vivo mitochondrial function was 25% lower in diabetic patients ( P = 0.034) and 23% lower in first-degree relatives, but the latter did not reach statistical significance ( P = 0.08). Interestingly, ADP-stimulated basal respiration was 35% lower in diabetic patients ( P = 0.031), and fluoro-carbonyl cyanide phenylhydrazone–driven maximal mitochondrial respiratory capacity was 31% lower in
diabetic patients ( P = 0.05) compared with control subjects with intermediate values for first-degree relatives.
CONCLUSIONS— A reduced basal ADP-stimulated and maximal mitochondrial respiratory capacity underlies the reduction in in vivo mitochondrial
function, independent of mitochondrial content. A reduced capacity at both the level of the electron transport chain and phosphorylation
system underlies this impaired mitochondrial capacity.
Footnotes
Published ahead of print at http://diabetes.diabetesjournals.org on 4 August 2008.
Readers may use this article as long as the work is properly cited, the use is educational and not for profit, and the work
is not altered. See http://creativecommons.org/licenses/by-nc-nd/3.0/ for details.
The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore
be hereby marked “advertisement” in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.
Accepted March 19, 2008.
Received February 27, 2008.
DIABETES
Background and purpose
Dolichoarteriopathies of the extracranial part of the internal carotid artery (ICA) are associated with cerebrovascular events, yet information on their prevalence and risk ...factors remains limited. The aim of the present study therefore was to study the prevalence and risk factors of dolichoarteriopathies in a sample of patients with cerebrovascular symptoms from the Plaque At RISK (PARISK) study.
Methods
In a random sample of 100 patients from the PARISK study, multidetector computed tomography angiography (MDCTA) was performed as part of clinical workup. On MDCTA, we evaluated the extracranial trajectory of the ICA by measuring the length (in millimeters), the tortuosity index (TI; defined as the ICA length divided by the shortest possible distance from bifurcation to skull base), and dolichoarteriopathy type (tortuosity, coiling or kinking). Next, we investigated the association between cardiovascular risk factors and these measurements using linear and logistic regression analyses.
Results
The mean (standard deviation) length of the ICA was 93 (± 14) mm, with a median (interquartile range) TI of 1.2 (1.1–1.3). The overall prevalence of dolichoarteriopathies was 69%, with tortuosity being the most common (72%), followed by coiling (20%), and kinking (8%). We found that age and obesity were associated with a higher TI: difference per 10‐year increase in age: 0.05 (95% confidence interval CI 0.02–0.08) and 0.16 (95% CI 0.07–0.25) for obesity. Obesity and hypercholesterolemia were associated with a more severe type of dolichoarteriopathy (odds ratio OR 2.07 95% CI 1.04–4.12 and OR 2.17 95% CI 1.02–4.63, respectively).
Conclusion
Dolichoarteriopathies in the extracranial ICA are common in patients with cerebrovascular symptoms, and age, obesity and hypercholesterolemia may play an important role in the pathophysiology of these abnormalities.
We investigated the prevalence of internal carotid artery dolichoarteriopathies using quantitative measurements and traditional visual rating in a random sample of patients with cerebrovascular symptoms who underwent multidetector computed tomography angiography. Tortuosity was the most common type of dolichoarteriopathy (72%), followed by coiling (20%), and kinking (8%). Age, obesity, and hypercholesterolemia were significantly associated with a more severe type of dolichoarteriopathy and/or tortuosity index. Therefore, these cardiovascular risk factors may play an important role in the pathophysiology of these abnormalities.
Fat can be stored not only in adipose tissue but also in other tissues such as skeletal muscle. Fat droplets accumulated in skeletal muscle intramyocellular lipids (IMCLs) can be quantified by ...different methods, all with advantages and drawbacks. Here, we briefly review IMCL quantification methods that use biopsy specimens (biochemical quantification, electron microscopy, and histochemistry) and non‐invasive alternatives (magnetic resonance spectroscopy, magnetic resonance imaging, and computed tomography).
Increasing evidence suggests that inflammation inside the vessel wall has a prominent role in atherosclerosis. In carotid atherosclerosis in particular, vulnerable plaque characteristics are strongly ...linked to an increased stroke risk. An association between leukocytes and plaque characteristics has not been investigated before and could help with gaining knowledge on the role of inflammation in plaque vulnerability, which could contribute to a new target for intervention. In this study, we investigated the association of the leukocyte count with carotid vulnerable plaque characteristics.
All patients from the Plaque At RISK (PARISK) study whom had complete data on their leukocyte count and CTA- and MRI-based plaque characteristics were included. Univariable logistic regression was used to detect associations of the leukocyte count with the separate plaque characteristics (intra-plaque haemorrhage (IPH), lipid-rich-necrotic core (LRNC), thin or ruptured fibrous cap (TRFC), plaque ulceration and plaque calcifications). Subsequently, other known risk factors for stroke were included as covariates in a multivariable logistic regression model.
161 patients were eligible for inclusion in this study. Forty-six (28.6%) of these patients were female with a mean age of 70 IQR 64-74. An association was found between a higher leukocyte count and lower prevalence of LRNC (OR 0.818 (95% CI 0.687-0.975)) while adjusting for covariates. No associations were found between the leucocyte count and the presence of IPH, TRFC, plaque ulceration or calcifications.
The leukocyte count is inversely associated with the presence of LRNC in the atherosclerotic carotid plaque in patients with a recently symptomatic carotid stenosis. The exact role of leukocytes and inflammation in plaque vulnerability deserves further attention.
Carotid radiofrequency coils inside a PET/MRI system can result in PET quantification errors. We compared the performance of a dedicated PET/MRI carotid coil against a coil for MRI-only use. An ...18F-fluorodeoxyglucose (18F-FDG) phantom was scanned without and with an MRI-only coil and with the PET/MRI coil. The decay-corrected normalized activity was compared for the different coil configurations. Eighteen patients were scanned with the three coil configurations. The maximal standardized uptake values (SUVmax) and signal-to-noise ratios (SNR) were calculated. Repeated measures ANOVA was performed to assess the differences in SUVmax and SNR between the coil configurations. In the phantom study, the PET/MRI coil demonstrated a slight decrease (<5%), while the MRI-only coil showed a substantial decrease (up to 10%) in normalized activity at the position of coil elements compared to no dedicated coil configuration. In the patient study, the SUVmax values for both no surface coil (3.59 ± 0.15) and PET/MRI coil (3.54 ± 0.15) were significantly higher (p = 0.03 and p = 0.04, respectively) as compared to the MRI-only coil (3.28 ± 0.16). No significant difference was observed between PET/MRI and no surface coil (p = 1.0). The SNR values for both PET/MRI (7.31 ± 0.44) and MRI-only (7.62 ± 0.42) configurations demonstrated significantly higher (p < 0.001) SNR values as compared to the no surface coil (3.78 ± 0.22), while no significant difference was observed in SNR between the PET/MRI and MRI-only coil (p = 1.0). This study demonstrated that the PET/MRI coil can be used for PET imaging without requiring attenuation correction while acquiring high-resolution MR images.
Stroke represents a major cause of morbidity and mortality worldwide with carotid atherosclerosis responsible for a large proportion of ischemic strokes. Given the high burden of the disease , early ...diagnosis and optimal secondary prevention are essential elements in clinical practice. For a long time, the degree of stenosis had been considered the parameter to judge the severity of carotid atherosclerosis. Over the last 30 years, literature has shifted attention from stenosis to structural characteristics of atherosclerotic lesion, eventually leading to the "vulnerable plaque" model. These "vulnerable plaques" frequently demonstrate high-risk imaging features that can be assessed by various non-invasive imaging modalities.
Objectives We aimed to investigate whether early thrombus formation can be visualized with in vivo magnetic resonance imaging (MRI) by the use of a novel bimodal α2 -antiplasmin–based contrast agent ...(CA). Background Thrombus formation plays a central role in several vascular diseases. During the early phases of thrombus formation, activated factor XIII (FXIIIa) covalently cross-links α2 -antiplasmin to fibrin, indicating the potential of α2 -antiplasmin–based CAs in the detection of early thrombus formation. Methods A bimodal CA was synthesized by coupling gadolinium-diethylene triamine pentaacetic acid and rhodamine to an α2 -antiplasmin–based peptide. For the control CA, a glutamine residue essential for cross-linking was replaced by alanine. In vitro-generated thrombi were exposed to both CAs and imaged by MRI and 2-photon laser-scanning microscopy. Immunohistochemistry was performed on human pulmonary thromboemboli sections to determine the presence of α2 -antiplasmin and FXIII in different thrombus remodeling phases. In vivo feasibility of the CA in detecting early thrombus formation specifically was investigated with MRI. Results In vitro–generated thrombi exposed to the α2 -antiplasmin–based CA showed hyperintense magnetic resonance signal intensities at the thrombus edge. No hyperintense signal was observed when we used the α2 -antiplasmin–based CA in the presence of FXIII inhibitor dansylcadaverine nor when we used the control CA. Two-photon laser-scanning microscopy demonstrated that the α2 -antiplasmin–based CA bound to fibrin. Immunohistochemistry demonstrated substantial α2 -antiplasmin staining in fresh compared with lytic and organized thrombi. The administration of CA in vivo within seconds after inducing thrombus formation increased contrast-to-noise ratios (CNRs 2.28 ± 0.39, n=6) at the site of thrombus formation compared with the control CA (CNRs −0.14 ± 0.55, p = 0.003, n = 6) and α2 -antiplasmin–based CA administration 24 to 48 h after thrombus formation (CNRs 0.11 ± 0.23, p = 0.006, n = 6). Conclusions A bimodal CA was developed, characterized, and validated. Our results showed that this bimodal CA enabled noninvasive in vivo magnetic resonance visualization of early thrombus formation.
OBJECTIVE: To investigate molecular adaptations that accompany the elevation of intramyocellular lipid (IMCL) content on a high-fat (HF) diet for 1 week. RESEARCH METHODS AND PROCEDURES: Ten subjects ...consumed a normal-fat (NF) diet for 1 week, followed by an HF diet for another week. After both dietary periods, we determined the IMCL content by proton magnetic resonance spectroscopy in the vastus lateralis muscle and quantified changes in gene expression, protein content, and activity in biopsy samples. We investigated genes involved in carbohydrate and fatty acid handling lipoprotein lipase, acetyl-coenzyme A carboxylase (ACC) 2, hormone-sensitive lipase, hexokinase II, and glucose transporter 4 and measured protein levels of CD36 and phosphorylated and unphosphorylated ACC2 and the activity of adenosine monophosphate-activated kinase. RESULTS: IMCL content was increased by 54% after the HF period. Lipoprotein lipase mRNA concentration was increased by 33%, whereas ACC2 mRNA concentration tended to be increased after the HF diet. Hexokinase II, glucose transporter 4, and hormone-sensitive lipase mRNA were unchanged after the HF diet. ACC2 and CD36 protein levels, phosphorylation status of ACC2, and adenosine monophosphate-activated kinase activity did not change in response to the HF diet. DISCUSSION: We found that IMCL content in skeletal muscle increased after 1 week of HF feeding, accompanied by molecular adaptations that favor fat storage in muscle rather than oxidation.
PDF
