ABSTRACT: South Asians are more insulin resistant than Europeans, which cannot be fully explained by differences in adiposity. We investigated whether differences in oxidative capacity and capacity for fatty acid utilisation in South Asians might contribute, using a range of whole-body and skeletal muscle measures.
Twenty men of South Asian ethnic origin and 20 age and BMI-matched men of white European descent underwent exercise and metabolic testing and provided a muscle biopsy to determine expression of oxidative and lipid metabolism genes and of insulin signalling proteins. In analyses adjusted for age, BMI, fat mass and physical activity, South Asians, compared to Europeans, exhibited; reduced insulin sensitivity by 26% (p = 0.010); lower VO2max (40.6±6.6 vs 52.4±5.7 ml x kg(-1) x min(-1), p = 0.001); and reduced fat oxidation during submaximal exercise at the same relative (3.77±2.02 vs 6.55±2.60 mg x kg(-1) x min(-1) at 55% VO2max, p = 0.013), and absolute (3.46±2.20 vs 6.00±1.93 mg x kg(-1) x min(-1) at 25 ml O(2) x kg(-1) x min(-1), p = 0.021), exercise intensities. South Asians exhibited significantly higher skeletal muscle gene expression of CPT1A and FASN and significantly lower skeletal muscle protein expression of PI3K and PKB Ser473 phosphorylation. Fat oxidation during submaximal exercise and VO2max both correlated significantly with insulin sensitivity index and PKB Ser473 phosphorylation, with VO2max or fat oxidation during exercise explaining 10-13% of the variance in insulin sensitivity index, independent of age, body composition and physical activity.
These data indicate that reduced oxidative capacity and capacity for fatty acid utilisation at the whole body level are key features of the insulin resistant phenotype observed in South Asians, but that this is not the consequence of reduced skeletal muscle expression of oxidative and lipid metabolism genes.
PLoS ONE 01/2010; 5(12):e14197. · 4.09 Impact Factor
ABSTRACT: Adiponectin is a fat-derived hormone involved in the regulation of metabolism. Adiponectin concentration is inversely related to body weight and, in animals, causes weight loss. We, therefore, measured adiponectin concentration in patients with heart failure (HF) and cachexia.
Serum adiponectin concentrations were measured in three groups of patients with coronary artery disease (CAD): (i) HF, reduced left ventricular systolic function, and cachexia (n = 10); (ii) HF, reduced systolic function but no cachexia (n = 20); (iii) HF-controls-patients with CAD, no HF, and preserved systolic function (n = 10); and in a healthy control group (n = 7). Patients with HF and cachexia had higher concentrations of adiponectin [23.8 (10.2-37.2) microg/mL] than all other groups: HF-no cachexia 8.1 (0.5-16.6) microg/mL; CAD-controls 7.1 (0.4-13.5) microg/mL; and healthy controls 8.7 (2.5-16.8) microg/mL) (P < 0.05 for each comparison). Adiponectin correlated negatively with body mass index, percentage of body fat, waist circumference and insulin resistance, and positively with B-type natriuretic peptide (BNP) and tumour necrosis factor-alpha.
Cachexia in HF is associated with an increase in adiponectin concentration. This may represent preservation of the physiological response to change in body fat but might also suggest that adiponectin plays a role in the pathogenesis of cachexia. The correlation between BNP and adiponectin also raises the possibility that the former might increase the secretion of the latter.
European Heart Journal 04/2007; 28(7):829-35. · 10.48 Impact Factor
ABSTRACT: While tobacco smoking is the main risk factor for chronic obstructive pulmonary disease (COPD) only a fraction of smokers go on to develop the disease. We investigated the relationship between the insertion (I)--deletion (D) polymorphisms in the Angiotensin converting enzyme (ACE) gene and the risk of developing COPD in smokers by determining the distribution of the ACE genotypes (DD, ID and II) in 151 life-long male smokers. 74 of the smokers had developed COPD (62 +/- 2 years; FEV1 44 +/- 6% reference) whereas the rest retained normal lung function (56 +/- 2 yrs; FEV1 95 +/- 3% reference). In addition, we genotyped 159 males recruited randomly from the general population. The prevalence of the DD genotype was highest (p = 0.01) in the smokers that developed COPD and its presence was associated with a 2-fold increase in the risk for COPD (OR 2.2; IC95% 1.1 to 5.5). Surprisingly, the 151 individuals in the smoking population did not demonstrate Hardy-Weinberg equilibrium unlike the 159 recruited from the general population. Our results suggest that ACE polymorphisms are associated with both the smoking history of an individual and their risk of developing COPD.
International Journal of COPD 02/2007; 2(3):329-34.
ABSTRACT: Whole-body plethysmography is a common method of measuring pulmonary function. Although this technique provides a sensitive measure of pulmonary function, it can be problematic and unsuitable in some patients. The development of more accessible techniques would be beneficial.
A prospective study was performed to validate diaphragm ultrasonography as an alternative to whole-body plethysmography in patients referred for pulmonary function testing. Diaphragm movement and position were assessed by ultrasonography after standard pulmonary function testing using whole-body plethysmography.
A wide range of lung function was observed. Standard lung volumes were as follows: total lung capacity, 5.57 +/- 1.31 L, residual volume, 2.27 +/- 0.56 L; and vital capacity, 3.30 +/- 0.98 L (mean +/- SD). The ratio of forced expiratory volume in 1 second to forced vital capacity was calculated as 0.69 +/- 0.08. Ultrasonography showed that mean diaphragm excursion values were 11.1 +/- 3.8 mm (2-dimensional), 14.7 +/- 4.1 mm during quiet breathing (M-mode), and 14.8 +/- 3.9 mm during a maximal sniff (M-mode). The velocity of diaphragm movement rose sharply during the sniff maneuver from 15.2 +/- 5.8 mm/s during quiet breathing to 104.0 +/- 33.4 mm/s. Static 2-dimensional measures of diaphragm position at the end of quiet inspiration or expiration correlated with standard measures of lung volume on plethysmography (eg, a correlation coefficient of 0.83 was obtained with end inspiration and vital capacity). All measures of diaphragm movement (whether by 2-dimensional or M-mode techniques) were poorly correlated with any lung volumes measured.
These data suggest that dynamic measurements using diaphragm ultrasonography provide a relatively poor measure of pulmonary function in relation to whole-body plethysmography.
Journal of ultrasound in medicine: official journal of the American Institute of Ultrasound in Medicine 03/2006; 25(2):225-32. · 1.25 Impact Factor
ABSTRACT: Understanding the changed ability of cardiac myofilaments to produce pump work requires knowledge of kinetics of crossbridge function as well as more widely studied parameters such as Ca-sensitivity and isometric force development. We tested the hypothesis that altered crossbridge kinetics contribute to reduced myofilament work in early-stage heart failure (left ventricular dysfunction, LVD).
The sinusoidal oscillation technique can yield insights into crossbridge function. Dynamic stiffness, oscillatory work and power were assessed in chemically skinned, Ca-activated trabeculae from rabbit ventricles in early-stage failure, 8 weeks after infarction induced by coronary artery ligation (LIG). Results were compared with sham-operated controls (SH). LVD was assessed by echocardiography.
Ca-activated force and myofilament Ca-sensitivity were not significantly altered at this early stage of LVD. In maximally Ca-activated preparations, the frequency of minimal dynamic stiffness (f(min)) was 23% lower in LIG. f(min) increases by >80% between pCa 5.8 and 4 in SH but not in LIG. Maximal phase lead and lag angles (between length and tension) were lower in LIG at frequencies near f(min), lowering oscillatory work and power. The Lissajous figures (oscillatory work loops) of imposed length vs. tension are often asymmetric near f(min). The degree of asymmetry was greater in LIG.
Reduced capacity for mechanical power, consistent with depressed haemodynamic performance in LVD hearts, is only partially attributable to crossbridge slowing; changes in the phase relationship will also contribute. These changes are not readily attributable to known alterations in contractile protein isoforms. Some deductions are drawn about which steps in the crossbridge cycle are modified in this model of LVD. Altered cardiac myocyte Ca-transients, reported to be associated with LVD, will be translated into pump work by a contractile machinery that is functionally altered, even though isometric force and myofilament Ca-sensitivity might remain near-normal at this stage.
Cardiovascular Research 01/2004; 61(1):94-104. · 6.06 Impact Factor
ABSTRACT: This study aimed to determine structural alterations occurring in cardiac myofilaments after exogenous application of oxidants
and the effects of oxidants on contractile protein function in a rabbit coronary artery ligation model of heart failure. Myocardial
”stiffness” was higher in the ligated animals (Lig) than sham-operated controls (Sh, 4.9±1.5 versus 1.6±0.8 mN.mm–1). Superoxide anion (O2
–) exposure decreased active stiffness in both groups, whereas hypochlorous acid (HOCl) had no effect in Lig but increased
stiffness in Sh. Resting stiffness was higher in Lig than Sh (0.6±0.2 versus 0.2±0.1 mN.mm–1), remaining unchanged after O2
– exposure but increasing after HOCl in both groups. The frequency at minimum stiffness was lower in Lig than Sh (0.9±0.2 versus
1.7±0.6 Hz) and was reduced in both groups after oxidant exposure. Myofilament calcium sensitivity (pCa50) was not altered by O2
– in Sh but increased in Lig (pCa50 increased from 5.41±0.05 to 5.56±0.06). Protease contamination in the xanthine oxidase used to generate O2
– did not affect myofilament ultrastructure at the concentrations used here. These data demonstrate that contractile proteins
from ”failed” myocardium have a similar response to exogenously applied oxidants as controls and that application of protease-contaminated
xanthine oxidase system does not degrade the contractile protein structure.
Pflügers Archiv - European Journal of Physiology 01/1999; 438(3):289-298. · 4.46 Impact Factor