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1.
ACE Inhibition and Endothelial Function: Main Findings of PERFECT,a Sub-Study of the EUROPA Trial 总被引:1,自引:0,他引:1
Bots ML Remme WJ Lüscher TF Fox KM Bertrand M Ferrari R Simoons ML Grobbee DE;EUROPA-PERFECT Investigators 《Cardiovascular drugs and therapy / sponsored by the International Society of Cardiovascular Pharmacotherapy》2007,21(4):269-279
Background ACE inhibition results in secondary prevention of coronary artery disease (CAD) through different mechanisms including improvement
of endothelial dysfunction. The Perindopril-Function of the Endothelium in Coronary artery disease Trial (PERFECT) evaluated
whether long-term administration of perindopril improves endothelial dysfunction.
Methods PERFECT is a 3-year double blind randomised placebo controlled trial to determine the effect of perindopril 8 mg once daily
on brachial artery endothelial function in patients with stable CAD without clinical heart failure. Endothelial function in
response to ischaemia was assessed using ultrasound. Primary endpoint was difference in flow-mediated vasodilatation (FMD)
assessed at 36 months.
Results In 20 centers, 333 patients randomly received perindopril or matching placebo. Ischemia-induced FMD was 2.7% (SD 2.6). In
the perindopril group FMD went from 2.6% at baseline to 3.3% at 36 months and in the placebo group from 2.8 to 3.0%. Change
in FMD after 36 month treatment was 0.55% (95% confidence interval −0.36, 1.47; p = 0.23) higher in perindopril than in placebo group. The rate of change in FMD per 6 months was 0.14% (SE 0.05, p = 0.02) in perindopril and 0.02% (SE 0.05, p = 0.74) in placebo group (0.12% difference in rate of change p = 0.07).
Conclusion Perindopril resulted in a modest, albeit not statistically significant, improvement in FMD.
The EUROPA-PERFECT investigators are listed at the end of the article. 相似文献
2.
A common variant in PNPLA3, which encodes adiponutrin, is associated with liver fat content in humans 总被引:1,自引:1,他引:0
A. Kotronen L. E. Johansson L. M. Johansson C. Roos J. Westerbacka A. Hamsten R. Bergholm P. Arkkila J. Arola T. Kiviluoto R. M. Fisher E. Ehrenborg M. Orho-Melander M. Ridderstråle L. Groop H. Yki-Järvinen 《Diabetologia》2009,52(6):1056-1060
Aims/hypothesis It has recently been suggested that the rs738409 G allele in PNPLA3, which encodes adiponutrin, is strongly associated with increased liver fat content in three different ethnic groups. The
aims of the present study were as follows: (1) to try to replicate these findings in European individuals with quantitative
measures of hepatic fat content; (2) to study whether the polymorphism influences hepatic and adipose tissue insulin sensitivity;
and (3) to investigate whether PNPLA3 expression is altered in the human fatty liver.
Methods We genotyped 291 Finnish individuals in whom liver fat had been measured using proton magnetic resonance spectroscopy. Hepatic
PNPLA3 expression was measured in 32 participants. Hepatic and adipose tissue insulin sensitivities were measured using a euglycaemic–hyperinsulinaemic
(insulin infusion 0.3 mU kg−1 min−1) clamp technique combined with infusion of [3-3H]glucose in 109 participants.
Results The rs738409 G allele in PNPLA3 was associated with increased quantitative measures of liver fat content (p = 0.011) and serum aspartate aminotransferase concentrations (p = 0.002) independently of age, sex and BMI. Fasting serum insulin and hepatic and adipose tissue insulin sensitivity were
related to liver fat content independently of genotype status. PNPLA3 mRNA expression in the liver was positively related to obesity (r = 0.62, p < 0.0001) and to liver fat content (r = 0.58, p = 0.025) in participants who were not morbidly obese (BMI < 40 kg/m2).
Conclusions/interpretation A common variant in PNPLA3 increases the risk of hepatic steatosis in humans.
A. Kotronen and L. E. Johansson contributed equally to this study. 相似文献
3.
L. Sibal A. Aldibbiat S. C. Agarwal G. Mitchell C. Oates S. Razvi J. U. Weaver J. A. Shaw P. D. Home 《Diabetologia》2009,52(8):1464-1473
Aims/hypothesis Type 1 diabetes is associated with premature arterial disease. Bone-marrow derived, circulating endothelial progenitor cells
(EPCs) are believed to contribute to endothelial repair. The hypothesis tested was that circulating EPCs are reduced in young
people with type 1 diabetes without vascular injury and that this is associated with impaired endothelial function and increased
carotid intima–media thickness (CIMT).
Methods We compared 74 people with type 1 diabetes with 80 healthy controls. CD34, CD133, vascular endothelial (VE) growth factor
receptor-2 (VEGFR-2) and VE-cadherin antibodies were used to quantify EPCs and progenitor cell subtypes using flow-cytometry.
Ultrasound assessment of endothelial function by brachial artery flow-mediated dilatation (FMD) and CIMT was made. Circulating
endothelial markers, inflammatory markers and plasma plasminogen activator inhibitor-1 (PAI-1) levels were measured.
Results CD34+VE-cadherin+, CD133+VE-cadherin+ and CD133+VEGFR-2+ EPC counts were significantly lower in people with diabetes (46–69%;
p = 0.004–0.043). In people with type 1 diabetes, FMD was reduced by 45% (p < 0.001) and CIMT increased by 25% (p < 0.001), these being correlated (r = −0.25, p = 0.033). There was a significant relationship between FMD and CD34+VE-cadherin+ (r = 0.39, p = 0.001), CD133+VEGFR-2+ (r = 0.25, p = 0.037) and CD34+ (r = 0.34, p = 0.003) counts. Circulating high-sensitivity C-reactive protein, PAI-1, interleukin-6 and E-selectin were significantly
higher in the diabetes group (p < 0.001 to p = 0.049), the last two of these correlating with FMD (r = −0.27, p = 0.028 and r = −0.24, p = 0.048, respectively).
Conclusions/interpretation These findings suggest that abnormalities of endothelial function in addition to pro-inflammatory and pro-thrombotic states
are already common in people with type 1 diabetes before development of clinically evident arterial damage. Low EPC counts
confirm risk of macrovascular complications and may account for impaired endothelial function and predict future cardiovascular
events.
Electronic supplementary material The online version of this article (doi:) contains supplementary material, which is available to authorised users. 相似文献
4.
Mazzoccoli G Fontana A Grilli M Dagostino MP Copetti M Pellegrini F Vendemiale G 《Age (Dordrecht, Netherlands)》2012,34(3):751-760
Arterial and venous thrombosis have always been regarded as different pathologies and epidemiological studies have examined
the association between venous thrombosis and indicators of atherosclerosis and/or arterial thromboembolic events. We measured
the flow-mediated dilation (FMD), a well-known marker of arterial endothelial dysfunction, in young–middle-aged and old-aged
patients with and without unprovoked deep venous thrombosis (DVT). The aim of this study was to investigate whether DVT was
a significant predictor for impaired FMD, considering all the patients and young–middle-aged (age < 65 years) and old-aged
(age ≥ 65 years) patients separately. FMD was measured in the brachial artery on a population of 120 subjects with the same
atherosclerosis risk factors, 68 male and 52 female, 70 young–middle-aged subjects (mean age ± SD 49.5 ± 10.5 years) and 50
old-aged subjects (76.2 ± 7.7 years). Patients with DVT showed a significant decrease of FMD compared to patients without
DVT (6.8 ± 5.5% vs. 10.9 ± 3.5%, p < 0.001). Moreover, old-aged patients showed a significant decrease of FMD compared to the young–middle-aged subjects (7.4 ± 4.1%
vs. 9.8 ± 5.3%, p = 0.005). In the whole study population, DVT was strongly associated with FMD (risk factors adjusted β = −4.14, p < 0.001). A significant interaction between age and the presence of DVT on predicting FMD was found (p = 0.003) suggesting a differential behavior of DVT as predictor of FMD. In young–middle-aged group, multivariate model confirmed
that DVT was the most significant predictor of continuous FMD (β = −6.06, p < 0.001). On the contrary, DVT was no more a predictor of FMD in the old age group (β = −0.73, p=0.556). Furthermore, old-aged patients without DVT showed a statistically significant decrease of FMD compared to the young–middle-aged
subjects without DVT (8.2±2.1% vs. 12.6±2.7%, p<0.001) and old-aged patients with DVT showed a not statistically significant decrease of the FMD compared to the young–middle-aged
patients with DVT (6.7±5.3% vs. 6.8±5.7%, p = 0.932). In conclusion, young–middle-aged patients with spontaneous DVT show an impaired FMD, whereas this impairment in
old-aged subjects is evident independently from the presence or absence of DVT. Aging per se may be associated with physiologic
abnormalities in the systemic arteries and with endothelial dysfunction. 相似文献
5.
Holt HB Wild SH Wareham N Ekelund U Umpleby M Shojaee-Moradie F Holt RI Phillips DI Byrne CD 《Diabetologia》2007,50(8):1698-1706
Aims/hypothesis The relative contributions of fitness (maximal oxygen uptake), physical activity energy expenditure (PAEE) and fatness to
whole-body, liver and fat insulin sensitivity is uncertain. The aim of this study was to determine whether fitness and PAEE
are associated with whole-body, liver and fat insulin sensitivity independently of body fat.
Materials and methods We recruited 25 men (mean [SD] age 53 [6] years). Whole-body (M value) and liver (percentage suppression of endogenous glucose output) insulin sensitivity were estimated using a hyperinsulinaemic–euglycaemic
clamp. Insulin sensitivity in fat (insulin sensitivity index for NEFA) was estimated during an OGTT. Total and truncal fat
were measured by dual-energy X-ray absorptiometry, fitness by treadmill, and PAEE (n = 21) by 3 day heart rate monitoring and Baecke questionnaire.
Results In univariate analyses, fatness was strongly associated with insulin sensitivity (whole-body, liver and fat). Fitness was
associated with whole-body (r = 0.53, p < 0.007) and liver (0.42, p = 0.04) insulin sensitivity, while PAEE was associated with liver insulin sensitivity (r = 0.55, p = 0.01). Regression models were established to describe associations between fatness, fitness and physical activity and measures
of insulin sensitivity (whole-body, fat and liver) as outcomes. Only fatness was independently associated with whole-body
insulin sensitivity (B coefficient −0.01, p = 0.001). Fitness was not associated with any outcome. Only PAEE was independently associated with liver insulin sensitivity
(B coefficient 13.5, p = 0.02).
Conclusions/interpretation Fatness explains most of the variance in whole-body insulin sensitivity. In contrast, PAEE explains most of the variance in
liver insulin sensitivity. 相似文献
6.
Pál Soltész Henriett Dér György Kerekes Péter Szodoray Gabriella Szücs Katalin Dankó Yehuda Shoenfeld Gyula Szegedi Zoltán Szekanecz 《Clinical rheumatology》2009,28(6):655-662
Patients with autoimmune diseases may have increased vascular risk leading to higher mortality rates. Novel imaging techniques
are necessary for the early assessment and management of these patients. In this study, we compared augmentation index (AIx)
and pulse wave velocity (PWV), indicators of arterial stiffness, to brachial arterial flow-mediated vasodilation (FMD) and
common carotid artery intima–media thickness (ccIMT), standard indicators of endothelial dysfunction and atherosclerosis,
respectively. We wished to assess the vascular status of autoimmune patients by using a novel, cheap, and reproducible technique,
the arteriograph. Altogether, 101 patients with systemic autoimmune diseases including primary antiphospholipid syndrome,
systemic sclerosis, rheumatoid arthritis, and polymyositis, all having various types of vasculopathies, as well as 36 healthy
individuals were investigated. Arterial stiffness was assessed by a TensioClinic arteriograph, a recently validated technique.
Brachial arterial FMD and ccIMT were determined using high-resolution ultrasonography. Autoimmune patients exerted impaired
FMD (3.7 ± 3.8%), increased ccIMT (0.7 ± 0.2 mm), AIx (1.2 ± 32.2%), and PWV (9.7 ± 2.4 m/s) in comparison to control subjects
(FMD = 8.4 ± 4.0%; ccIMT = 0.6 ± 0.1 mm; Aix = −41.1 ± 22.5%; PWV = 8.0 ± 1.5 m/s; p < 0.05). We found a significant negative correlation of FMD with AIx (R = −0.64; p < 0.0001) and PWV (R = −0.37; p = 0.00014). There were significant positive correlations between ccIMT and AIx (R = 0.34; p = 0.0009), ccIMT and PWV (R = 0.44; p < 0.0001), as well as AIx and PWV (R = 0.47; p < 0.0001). AIx, PWV, and ccIMT positively correlated and FMD negatively correlated with the age of the autoimmune patients.
Arterial stiffness indicated by increased AIx and PWV may be strongly associated with endothelial dysfunction and overt atherosclerosis
in patients with autoimmune diseases. Assessment of arterial stiffness, FMD, and ccIMT are reproducible and reliable noninvasive
techniques for the complex assessment of vascular abnormalities in patients at high risk. 相似文献
7.
Aims/hypothesis This study was designed to investigate the effect of short-term ACE inhibitor treatment on insulin sensitivity and to examine possible underlying metabolic and haemodynamic effects in obese insulin-resistant subjects.Methods A randomised, double-blind placebo-controlled trial was performed in 18 obese insulin-resistant men (age, 53 ± 2 years; BMI, 32.6 ± 0.8 kg/m2; homeostasis model assessment of insulin resistance, 5.6 ± 0.5; systolic blood pressure [SBP], 140.8 ± 3.2; diastolic blood pressure [DBP], 88.8 ± 1.6 mmHg), who were free of any medication. The aim was to examine the effects of 2 weeks of ACE inhibitor treatment (ramipril, 5 mg/day) on insulin sensitivity, forearm blood flow, substrate fluxes across the forearm, whole-body substrate oxidation and intramuscular triacylglycerol (IMTG) content.Results Ramipril treatment decreased ACE activity compared with placebo (−22.0 ± 1.7 vs 0.2 ± 1.1 U/l, respectively, p < 0.001), resulting in a significantly reduced blood pressure (SBP, −10.8 ± 2.1 vs −2.7 ± 2.0 mmHg, respectively, p = 0.01; DBP, −10.1 ± 1.3 vs −4.2 ± 2.1 mmHg, respectively, p = 0.03). Ramipril treatment had no effect on whole-body insulin-mediated glucose disposal (before: 17.9 ± 2.0, after: 19.1 ± 2.4 μmol kg body weight−1 min−1, p = 0.44), insulin-mediated glucose uptake across the forearm (before: 1.82 ± 0.39, after: 1.92 ± 0.29 μmol 100 ml forearm tissue−1 min−1, p = 0.81) and IMTG content (before: 45.4 ± 18.8, after: 48.8 ± 27.5 μmol/mg dry muscle, p = 0.92). Furthermore, the increase in carbohydrate oxidation (p < 0.001) and forearm blood flow (p < 0.01), and the decrease in fat oxidation (p < 0.001) during insulin stimulation were not significantly different between treatments.Conclusions/interpretation Short-term ramipril treatment adequately reduced ACE activity and blood pressure, but had no significant effects on insulin sensitivity, forearm blood flow, substrate fluxes across the forearm, whole-body substrate oxidation and IMTG content in obese insulin-resistant subjects. 相似文献
8.
C. Langenberg L. Pascoe A. Mari A. Tura M. Laakso T. M. Frayling I. Barroso R. J. F. Loos N. J. Wareham M. Walker 《Diabetologia》2009,52(8):1537-1542
Aims/hypothesis We investigated whether variation in MTNR1B, which was recently identified as a common genetic determinant of fasting glucose levels in healthy, diabetes-free individuals,
is associated with measures of beta cell function and whole-body insulin sensitivity.
Methods We studied 1,276 healthy individuals of European ancestry at 19 centres of the Relationship between Insulin Sensitivity and
Cardiovascular disease (RISC) study. Whole-body insulin sensitivity was assessed by euglycaemic–hyperinsulinaemic clamp and
indices of beta cell function were derived from a 75 g oral glucose tolerance test (including 30 min insulin response and
glucose sensitivity). We studied rs10830963 in MTNR1B using additive genetic models, adjusting for age, sex and recruitment centre.
Results The minor (G) allele of rs10830963 in MTNR1B (frequency 0.30 in HapMap Centre d’Etude du Polymorphisme [Utah residents with northern and western European ancestry] [CEU];
0.29 in RISC participants) was associated with higher levels of fasting plasma glucose (standardised beta [95% CI] 0.17 [0.085,
0.25] per G allele, p = 5.8 × 10−5), consistent with recent observations. In addition, the G-allele was significantly associated with lower early insulin response
(−0.19 [−0.28, −0.10], p = 1.7 × 10−5), as well as with decreased beta cell glucose sensitivity (−0.11 [−0.20, −0.027], p = 0.010). No associations were observed with clamp-assessed insulin sensitivity (p = 0.15) or different measures of body size (p > 0.7 for all).
Conclusions/interpretation Genetic variation in MTNR1B is associated with defective early insulin response and decreased beta cell glucose sensitivity, which may contribute to
the higher glucose levels of non-diabetic individuals carrying the minor G allele of rs10830963 in MTNR1B.
Electronic supplementary material The online version of this article (doi:) contains a list of the members of the RISC Consortium, which is available to authorised users. 相似文献
9.
Parasar Ghosh Amresh Kumar Sudeep Kumar Amita Aggarwal Nakul Sinha Ramnath Misra 《Clinical rheumatology》2009,28(11):1259-1265
Patients with systemic lupus erythematosus (SLE), especially Asian Indians, are at increased risk of developing premature
atherosclerosis. To find out the prevalence and predictors of carotid intima-medial thickness (IMT) and brachial artery flow-mediated
dilatation (FMD). Endothelial dysfunction was assessed by FMD in brachial artery and IMT was measured in common carotid artery
in SLE patients and healthy controls. Sixty SLE patients (mean age 31 ± 9 years) and 38 healthy controls (mean age 34 ± 6 years)
were included. The IMT was higher in SLE patients as compared to controls (0.49 ± 0.08 mm vs. 0.39 ± 0.05 mm, p < 0.0001). SLE and damage were independent predictors of abnormal IMT. FMD was impaired in SLE patients compared to controls
(9.97% vs. 18.97%, p < 0.00001). None of the classical cardiovascular risk factors were predictors of FMD or abnormal IMT. Indian patients with
SLE have higher prevalence of subclinical atherosclerosis and endothelial dysfunction. Presence of damage was associated with
abnormal IMT in SLE patients. 相似文献
10.
Stefan N Peter A Cegan A Staiger H Machann J Schick F Claussen CD Fritsche A Häring HU Schleicher E 《Diabetologia》2008,51(4):648-656
Aims/hypothesis Stearoyl-CoA desaturase 1 (SCD1) is the rate-limiting enzyme in monounsaturated fatty acid synthesis. It is imperative for
the assembly of VLDL particles, which transport triacylglycerol (TG) from liver to adipose tissue and other sites. We aimed
to determine the role of hepatic SCD1 activity in human glucose and lipid metabolism.
Methods We studied 54 people participating in a lifestyle intervention programme with diet modification and increased physical activity.
Insulin sensitivity was determined during a euglycaemic–hyperinsulinaemic clamp and estimated from an OGTT. Liver fat was
quantified by 1H-magnetic resonance spectroscopy at baseline and after 9 months of intervention. The pattern of fatty acids in serum VLDL-TGs
was determined by ultracentrifugation followed by thin layer and gas chromatography, with the 18:1 n-9: 18:0 ratio providing an index of hepatic SCD1 activity.
Results The hepatic SCD1 activity index correlated negatively with liver fat (r = −0.29, p = 0.04) and positively with insulin sensitivity, both OGTT-derived (r = 0.42, p = 0.003) and clamp-derived (r = 0.27, p = 0.07). These correlations depended on overall adiposity. They were absent in leaner participants (n = 27, liver fat: p = 0.34, insulin sensitivity [OGTT]: p = 0.75, insulin sensitivity [clamp]: p = 0.24), but were strong in obese individuals (n = 27, p = 0.004, p = 0.0002 and p = 0.006, respectively). Furthermore, during intervention a high SCD1 activity index at baseline predicted a decrease in liver
fat only in obese participants (r = −0.46, p = 0.02).
Conclusions/interpretation Our data suggest that high hepatic SCD1 activity may regulate fat accumulation in the liver and possibly protects from insulin
resistance in obesity.
N. Stefan and A. Peter contributed equally to this work. 相似文献
11.
Aims/hypothesis The physiological increase in muscle protein anabolism induced by insulin is blunted in healthy, glucose-tolerant older adults.
We hypothesised that the age-related defect in muscle protein anabolism is a true insulin resistance state and can be overridden
by supraphysiological hyperinsulinaemia.
Methods We used dye dilution, stable isotopic and immunoblotting techniques to measure leg blood flow, muscle protein synthesis, protein
kinase B/mammalian target of rapamycin (Akt/mTOR) signalling, and amino acid kinetics in 14 healthy, glucose-tolerant older
volunteers at baseline, and during an insulin infusion at postprandial (PD, 0.15 mU min−1 100 ml−1) or supraphysiologically high (HD, 0.30 mU min−1 100 ml−1) doses.
Results Leg blood flow, muscle protein synthesis, and Akt/mTOR signalling were not different at baseline. During hyperinsulinaemia,
leg blood flow (p < 0.01) and muscle protein synthesis increased in the HD group only (PD [%/h]: from 0.063 ± 0.006 to 0.060 ± 0.005; HD [%/h]:
from 0.061 ± 0.007 to 0.098 ± 0.007; p < 0.01). Muscle Akt phosphorylation increased in both groups, but the increase tended to be greater in the HD group (p = 0.07). The level of p70 ribosomal S6 kinase 1 (S6K1) phosphorylation increased in the HD group only (p < 0.05). Net amino acid balance across the leg improved in both groups, but a net anabolic effect was observed only in the
HD group (p < 0.05).
Conclusions/interpretation We conclude that supraphysiological hyperinsulinaemia is necessary to stimulate muscle protein synthesis and anabolic signalling
in healthy older individuals, suggesting the existence of a true age-related insulin resistance of muscle protein metabolism. 相似文献
12.
Frederiksen L Højlund K Hougaard DM Brixen K Andersen M 《Age (Dordrecht, Netherlands)》2012,34(1):145-156
The indication for testosterone therapy in aging hypogonadal men without hypothalamic, pituitary, or testicular disease remains
to be elucidated. The aim of this study was to investigate the effect of testosterone therapy on insulin sensitivity, substrate
metabolism, body composition, and lipids in aging men with low normal bioavailable testosterone levels using a predefined
cutoff level for bioavailable testosterone. A randomized, double-blinded, placebo-controlled study of testosterone treatment
(gel) was done on 38 men, aged 60–78 years, with bioavailable testosterone <7.3 nmol/l and a waist circumference >94 cm. Insulin-stimulated
glucose disposal (Rd) and substrate oxidation were assessed by euglycemic hyperinsulinemic clamps combined with indirect calorimetry.
Lean body mass (LBM) and total fat mass (TFM) were measured by dual x-ray absorptiometry, and serum total testosterone was
measured by tandem mass spectrometry. Bioavailable testosterone was calculated. Coefficients (b) represent the placebo-controlled mean effect of intervention. LBM (b = 1.9 kg, p = 0.003) increased while HDL–cholesterol (b = −0.12 mmol/l, p = 0.043) and TFM decreased (b = −1.2 kg, p = 0.038) in the testosterone group compared to placebo. Basal lipid oxidation (b = 5.65 mg/min/m2, p = 0.045) increased and basal glucose oxidation (b = −9.71 mg/min/m2, p = 0.046) decreased in response to testosterone therapy even when corrected for changes in LBM. No significant changes in
insulin-stimulated Rd was observed (b = −0.01mg/min/m2, p = 0.92). Testosterone therapy increased muscle mass and lipid oxidation in aging men with low normal bioavailable testosterone
levels; however, our data did not support an effect of testosterone on whole-body insulin sensitivity using the euglycemic
hyperinsulinemic clamp technique. 相似文献
13.
Seockhoon Chung In-Young Yoon Yoon-Kyung Shin Chul Hee Lee Jeong-Whun Kim Hee Jeong Ahn 《Sleep & breathing》2009,13(1):11-17
Introduction Obstructive sleep apnea syndrome (OSAS) is considered to be associated with cardiovascular complications, and atherosclerosis
could mediate this relationship. Cardiovascular risk factors of OSAS still need to be elucidated in elderly patients, since
studies about the association between OSAS and cardiovascular diseases have been done mainly in middle-aged adults. To investigate
whether endothelial dysfunction, as an early marker of atherosclerosis, and inflammatory responses in OSAS were affected by
age, we studied flow-mediated dilatation (FMD) and C-reactive protein (CRP) in elderly and middle-aged patients with OSAS.
Materials and methods This study enrolled 161 male subjects of 117 middle-aged (35–59 years old) and 44 elderly (≥60 years old) patients with OSAS.
After they finished nocturnal polysomnography (NPSG), FMD was measured on the brachial artery and blood samples were obtained
to determine serum CRP levels.
Results and discussion FMD was significantly lower in the elderly patients (p = 0.04), but no difference was observed between two age groups in body mass index (BMI), neck circumference, waist-to-hip
ratio, apnea hypopnea index (AHI), serum CRP level, or NPSG findings related with nocturnal hypoxemia such as average O2 saturation, percentage of time below 90% O2 saturation, and oxygen desaturation index (ODI). From the results of stepwise multiple linear regression analysis, the lowest
oxygen saturation was a significant determinant of FMD (β = 0.25, p < 0.01, adjusted R
2 = 6%), and BMI (β = 0.22, p < 0.05) and waist-to-hip ratio (β = 0.21, p < 0.05) were significant variables to explain CRP (adjusted R
2 = 11%, p < 0.01) in the middle aged patients. In the elderly patients, no variable was significant for predicting FMD, but AHI was
significant determinant of CRP (β = 0.46, p < 0.01, adjusted R
2 = 19%, p < 0.01). In predicting cardiovascular risks of OSAS, both hypoxia and obesity should be considered in the middle-aged group,
whereas nocturnal respiratory disturbances are important in the elderly group. 相似文献
14.
Holt HB Wild SH Postle AD Zhang J Koster G Umpleby M Shojaee-Moradie F Dewbury K Wood PJ Phillips DI Byrne CD 《Diabetologia》2007,50(5):1024-1032
Aims/hypothesis The regulation of cortisol metabolism in vivo is not well understood. We evaluated the relationship between cortisol metabolism
and insulin sensitivity, adjusting for total and regional fat content and for non-alcoholic fatty liver disease.
Materials and methods Twenty-nine middle-aged healthy men with a wide range of BMI were recruited. We measured fat content by dual-energy X-ray
absorptiometry and magnetic resonance imaging (MRI), liver fat by ultrasound and MRI, the hypothalamic-pituitary-adrenal axis
by adrenal response to ACTH1-24, unconjugated urinary cortisol excretion, corticosteroid-binding globulin, and cortisol clearance by MS. We assessed insulin
sensitivity by hyperinsulinaemic-euglycaemic clamp and by OGTT.
Results Cortisol clearance was strongly inversely correlated with insulin sensitivity (M value) (r = −0.61, p = 0.002). Cortisol clearance was increased in people with fatty liver compared with those without (mean±SD: 243 ± 10 vs 158 ± 36 ml/min;
p = 0.014). Multiple regression modelling showed that the relationship between cortisol clearance and insulin sensitivity was
independent of body fat. The relationship between fatty liver and insulin sensitivity was significantly influenced by body
fat and cortisol clearance.
Conclusions/interpretation Cortisol clearance is strongly associated with insulin sensitivity, independently of the amount of body fat. The relationship
between fatty liver and insulin sensitivity is mediated in part by both fatness and cortisol clearance.
Electronic supplementary material The online version of this article (doi:) contains supplementary material, which is available to authorised users. 相似文献
15.
Aims/hypothesis The association between increased (visceral) fat mass, insulin resistance and type 2 diabetes mellitus is well known. Yet,
it is unclear whether the mere increase in intra-abdominal fat mass, or rather functional alterations in fat tissue in obesity
contribute to the development of insulin resistance in obese patients. Here we attempted to isolate the metabolic effect of
increased fat mass by fat tissue transplantation.
Methods Epididymal fat pads were removed from male C57Bl6/J mice and transplanted intraperitoneally into male littermates (recipients),
increasing the combined perigonadal fat mass by 50% (p < 0.005). At 4 and 8 weeks post-transplantation, glucose and insulin tolerance tests were performed, and insulin, NEFA and
adipokines measured.
Results Circulating levels of NEFA, adiponectin and leptin were not significantly different between transplanted and sham-operated
control mice, while results of the postprandial insulin tolerance test were similar between the two groups. In contrast, under
fasting conditions, the mere increase in intra-abdominal fat mass resulted in decreased plasma glucose levels (6.9 ± 0.4 vs
8.1 ± 0.3 mmol/l, p = 0.03) and a ∼20% lower AUC in the glucose tolerance test (p = 0.02) in transplanted mice. Homeostasis model assessment of insulin resistance (HOMA-IR) was 4.1 ± 0.4 in transplanted
mice (vs 6.2 ± 0.7 in sham-operated controls) (p = 0.02), suggesting improved insulin sensitivity. Linear regression modelling revealed that while total body weight positively
correlated, as expected, with HOMA-IR (β: 0.728, p = 0.006), higher transplanted fat mass correlated with lower HOMA-IR (β: −0.505, p = 0.031).
Conclusions/interpretation Increasing intra-abdominal fat mass by transplantation of fat from normal mice improved, rather than impaired, fasting glucose
tolerance and insulin sensitivity, achieving an effect opposite to the expected metabolic consequence of increased visceral
fat in obesity. 相似文献
16.
Exercise training reduces fatty acid availability and improves the insulin sensitivity of glucose metabolism 总被引:2,自引:0,他引:2
Shojaee-Moradie F Baynes KC Pentecost C Bell JD Thomas EL Jackson NC Stolinski M Whyte M Lovell D Bowes SB Gibney J Jones RH Umpleby AM 《Diabetologia》2007,50(2):404-413
Aims/hypothesis It is not known whether the beneficial effects of exercise training on insulin sensitivity are due to changes in hepatic and
peripheral insulin sensitivity or whether the changes in insulin sensitivity can be explained by adaptive changes in fatty
acid metabolism, changes in visceral fat or changes in liver and muscle triacylglycerol content. We investigated the effects
of 6 weeks of supervised exercise in sedentary men on these variables.
Subjects and methods We randomised 17 sedentary overweight male subjects (age 50 ± 2.6 years, BMI 27.6 ± 0.5 kg/m2) to a 6-week exercise programme (n = 10) or control group (n = 7). The insulin sensitivity of palmitic acid production rate (Ra), glycerol Ra, endogenous glucose Ra (EGP), glucose uptake
and glucose metabolic clearance rate were measured at 0 and 6 weeks with a two-step hyperinsulinaemic–euglycaemic clamp [step
1, 0.3 (low dose); step 2, 1.5 (high dose) mU kg−1 min−1]. In the exercise group subjects were studied >72 h after the last training session. Liver and skeletal muscle triacylglycerol
content was measured by magnetic resonance spectroscopy and visceral adipose tissue by cross-sectional computer tomography
scanning.
Results After 6 weeks, fasting glycerol, palmitic acid Ra (p = 0.003, p = 0.042) and NEFA concentration (p = 0.005) were decreased in the exercise group with no change in the control group. The effects of low-dose insulin on EGP
and of high-dose insulin on glucose uptake and metabolic clearance rate were enhanced in the exercise group but not in the
control group (p = 0.026; p = 0.007 and p = 0.04). There was no change in muscle triacylglycerol and liver fat in either group.
Conclusions/interpretation Decreased availability of circulating NEFA may contribute to the observed improvement in the insulin sensitivity of EGP and
glucose uptake following 6 weeks of moderate exercise.
Electronic supplementary material Supplementary material is available in the online version of this article at and is accessible to authorised users. 相似文献
17.
Stavrakis S Terrovitis J Tsolakis E Drakos S Dalianis A Bonios M Koudoumas D Malliaras K Nanas J 《Journal of cardiovascular translational research》2011,4(1):99-105
Recanalization of an infarct-related artery does not predictably reflect tissue reperfusion. We examined the relationship
between coronary blood flow (CBF) pattern during reperfusion and infarcted (IA) and no-reflow (NR) area in a porcine ischemia–reperfusion
model. The mid-left anterior descending artery of 18 pigs was occluded for 1 h and reperfused for 2 h. CBF during reperfusion
was measured with a transit-time ultrasound flowmeter, while systemic arterial and left atrial pressures were monitored. IA
and NR were measured with triphenyl tetrazolium chloride and thioflavin staining, respectively. In 13 pigs, early systolic
retrograde CBF developed within the first 30 min and persisted throughout reperfusion. No retrograde CBF was observed in five
pigs. Mean retrograde CBF at 2 h of reperfusion predicted a larger IA (r = 0.71; p = 0.001). Time-to-development of retrograde CBF was inversely related to IA (r = −0.55; p = 0.019) and NR (r = −0.62; p = 0.006). A larger IA (OR 1.12, 95% CI 1.01–1.24, p = 0.037) and NR (OR 1.09, 95% CI 1.01–1.18, p = 0.037) predicted the presence of retrograde CBF. Retrograde CBF during recanalization of the infarct-related artery predicts
IA and NR and might be used as an index of successful reperfusion at the tissue level. 相似文献
18.
D. K. Coletta A. Sriwijitkamol E. Wajcberg P. Tantiwong M. Li M. Prentki M. Madiraju C. P. Jenkinson E. Cersosimo N. Musi R. A. DeFronzo 《Diabetologia》2009,52(4):723-732
Aims/hypothesis The molecular mechanisms by which thiazolidinediones improve insulin sensitivity in type 2 diabetes are not fully understood.
We hypothesised that pioglitazone would activate the adenosine 5′-monophosphate-activated protein kinase (AMPK) pathway and
increase the expression of genes involved in adiponectin signalling, NEFA oxidation and mitochondrial function in human skeletal
muscle.
Methods A randomised, double-blind, parallel study was performed in 26 drug-naive type 2 diabetes patients treated with: (1) pioglitazone
(n = 14) or (2) aggressive nutritional therapy (n = 12) to reduce HbA1c to levels observed in the pioglitazone-treated group. Participants were assigned randomly to treatment using a table of random
numbers. Before and after 6 months, patients reported to the Clinical Research Center of the Texas Diabetes Institute for
a vastus lateralis muscle biopsy followed by a 180 min euglycaemic–hyperinsulinaemic (80 mU m−2 min−1) clamp.
Results All patients in the pioglitazone (n = 14) or nutritional therapy (n = 12) group were included in the analysis. Pioglitazone significantly increased plasma adiponectin concentration by 79% and
reduced fasting plasma NEFA by 35% (both p < 0.01). Following pioglitazone, insulin-stimulated glucose disposal increased by 30% (p < 0.01), and muscle AMPK and acetyl-CoA carboxylase (ACC) phosphorylation increased by 38% and 53%, respectively (p < 0.05). Pioglitazone increased mRNA levels for adiponectin receptor 1 and 2 genes (ADIPOR1, ADIPOR2), peroxisome proliferator-activated receptor gamma, coactivator 1 gene (PPARGC1) and multiple genes involved in mitochondrial function and fat oxidation. Despite a similar reduction in HbA1c and similar improvement in insulin sensitivity with nutritional therapy, there were no significant changes in muscle AMPK
and ACC phosphorylation, or the expression of ADIPOR1, ADIPOR2, PPARGC1 and genes involved in mitochondrial function and fat oxidation. No adverse (or unexpected) effects or side effects were reported
from the study.
Conclusions/interpretations Pioglitazone increases plasma adiponectin levels, stimulates muscle AMPK signalling and increases the expression of genes
involved in adiponectin signalling, mitochondrial function and fat oxidation. These changes may represent an important cellular
mechanism by which thiazolidinediones improve skeletal muscle insulin sensitivity.
Trial registration: NCT 00816218
Funding: This trial was funded by National Institutes of Health Grant DK24092, VA Merit Award, GCRC Grant RR01346, Executive Research
Committee Research Award from the University of Texas Health Science Center at San Antonio, American Diabetes Association
Junior Faculty Award, American Heart Association National Scientist Development Grant, Takeda Pharmaceuticals North America
Grant and Canadian Institute of Health Research Grant.
Electronic supplementary material The online version of this article (doi:) contains supplementary material, which is available to authorised users. 相似文献
19.
The aim of this study was to evaluate the levels of anti-inflammatory interleukin-10 and pro-inflammatory cytokines and their
relationship to endothelial function in patients with idiopathic venous thrombosis. Forty-nine eligible patients of both sexes
with idiopathic venous thrombosis and 48 matched control subjects were studied. Levels of inflammatory markers were determined.
Endothelial function was evaluated by ultrasound measurement of the flow mediated dilatation (FMD) of the brachial artery.
Compared to the control group, patients with idiopathic venous thrombosis had significantly lower levels of interleukin-10
1.81 pg/ml (1.53–2.21) versus 2.71 pg/ml (1.84–3.65), p < 0.001. Patients also had increased levels of pro-inflammatory cytokines: interleukin-6 2.37 pg/ml (1.59–4.09) versus 2.03 pg/ml
(1.49–2.59), p = 0.025, interleukin-8 3.53 pg/ml (2.94–5.30) versus 2.25 pg/ml (1.77–2.90), p < 0.001. Furthermore, decreased FMD was observed in patients: 5.0% (3.9–6.9) versus 12.7% (10.8–15.6), p < 0.001. FMD was related to levels of interleukin-10 (r = 0.33, p = 0.001) and was inversely related to pro-inflammatory cytokines interleukin-6 (r = −0.34, p = 0.001) and interleukin-8 (r = −0.43, p < 0.001). Patients with idiopathic venous thrombosis have decreased levels of IL-10 and increased levels of pro-inflammatory
cytokines. This imbalance indicates that in the stable phase of the disease, patients have an increased systemic inflammatory
response. This inflammatory response could be the consequence of the disease, but most probably is involved in the pathogenesis
of venous thrombosis. 相似文献
20.
Aims/hypothesis The incretin hormones glucagon-like peptide-1 (GLP-1) and glucose-dependent insulinotrophic peptide (GIP) are released from
intestinal endocrine cells in response to luminal glucose. Glucokinase is present in these cells and has been proposed as
a glucose sensor. The physiological role of glucokinase can be tested using individuals with heterozygous glucokinase gene
(GCK) mutations. If glucokinase is the gut glucose sensor, GLP-1 and GIP secretion during a 75 g OGTT would be lower in GCK mutation carriers compared with controls.
Methods We compared GLP-1 and GIP concentrations measured at five time-points during a 75 g OGTT in 49 participants having GCK mutations with those of 28 familial controls. Mathematical modelling of glucose, insulin and C-peptide was used to estimate
basal insulin secretion rate (BSR), total insulin secretion (TIS), beta cell glucose sensitivity, potentiation factor and
insulin secretion rate (ISR).
Results GIP and GLP-1 profiles during the OGTT were similar in GCK mutation carriers and controls (p = 0.52 and p = 0.44, respectively). Modelled variables of beta cell function showed a reduction in beta cell glucose sensitivity (87 pmol
min−1 m−2 [mmol/l]−1 [95% CI 66–108] vs 183 pmol min−1 m−2 [mmol/l]−1 [95% CI 155–211], p < 0.001) and potentiation factor (1.5 min [95% CI 1.2–1.8] vs 2.2 min [95% CI 1.8–2.7], p = 0.007) but no change in BSR or TIS. The glucose/ISR curve was right-shifted in GCK mutation carriers.
Conclusions/interpretation Glucokinase, the major pancreatic glucose sensor, is not the main gut glucose sensor. By modelling OGTT data in GCK mutation carriers we were able to distinguish a specific beta cell glucose-sensing defect. Our data suggest a reduction in
potentiation of insulin secretion by glucose that is independent of differences in incretin hormone release. 相似文献