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1.
Renal function and insulin sensitivity during simvastatin treatment in Type 2 (non-insulin-dependent) diabetic patients with microalbuminuria 总被引:1,自引:0,他引:1
Dr. S. Nielsen O. Schmitz N. Møller N. Pøksen I. C. Klausen K. G. M. M. Alberti C. E. Mogensen 《Diabetologia》1993,36(10):1079-1086
Summary The effect of simvastatin (10–20 mg/day) on kidney function, urinary albumin excretion rate and insulin sensitivity was evaluated
in 18 Type 2 (non-insulin-dependent) diabetic patients with microalbuminuria and moderate hypercholesterolaemia (total cholesterol
≥5.5 mmol·l−1). In a double-blind, randomized and placebo-controlled design treatment with simvastatin (n=8) for 36 weeks significantly reduced total cholesterol (6.7±0.3 vs 5.1 mmol·l−1 (p<0.01)), LDL-cholesterol (4.4±0.3 vs 2.9±0.2 mmol·l−1 (p<0.001)) and apolipoprotein B (1.05±0.04 vs 0.77±0.02 mmol·l−1 (p<0.01)) levels as compared to placebo (n=10). Both glomerular filtration rate (mean±SEM) (simvastatin: 96.6±8.0 vs 96.0±5.7 ml·min−1·1.73 m−2, placebo: 97.1±6.7 vs 88.8±6.0 ml·min−1·1.73 m−2) (NS) and urinary albumin excretion rate (geometric mean x/÷ antilog SEM) (simvastatin: 18.4x/÷1.3vs 16.2 x/÷1.2 μg·min−1, placebo 33.1 x/÷ 1.3 vs 42.7 x/÷ 1.3 μg·min−1)(NS) were unchanged during the study. A euglycaemic hyperinsulinaemic clamp was performed at baseline and after 18 weeks
in seven simvastatin-and nine placebo-treated patients. Isotopically determined basal and insulin-stimulated glucose disposal
was similarly reduced before and during therapy in both the simvastatin (2.0±0.1 vs 1.9±0.1 (NS) and 3.1±0.6 vs 3.1±0.7 mg·kg−1·min−1 (NS)) and the placebo group (1.9±0.1 vs 1.8±0.1 (NS) and 4.1±0.6 vs 3.8±0.2 mg·kg−1·min−1 (NS)). No different was observed in glucose storage or glucose and lipid oxidation before and after treatment. Further, the
suppression of hepatic glucose production during hyperinsulinaemia was not influenced by simvastatin (−0.7±0.8 vs −0.7±0.5
mg·kg−1·min−1 (NS)). In conclusion, despite marked improvement in the dyslipidaemia simvastatin had no impact on kidney function or urinary
albumin excretion rate and did not reduce insulin resistance in these microalbuminuric and moderately hypercholesterolaemic
Type 2 diabetic patients. 相似文献
2.
A comparison of the effects of low- and conventional-dose thiazide diuretic on insulin action in hypertensive patients with NIDDM 总被引:3,自引:0,他引:3
R. Harper C. N. Ennis A. P. Heaney B. Sheridan M. Gormley A. B. Atkinson G. D. Johnston P. M. Bell 《Diabetologia》1995,38(7):853-859
Summary In conventional doses, thiazide diuretics impair glucose tolerance and decrease insulin sensitivity, making them an unpopular
choice for treating diabetic patients with hypertension. However, use of low-dose thiazide diuretics may avoid the adverse
metabolic effects seen with conventional doses. In a double-blind, randomised crossover study we assessed peripheral and hepatic
insulin action in 13 hypertensive non-insulin-dependent diabetic patients after a 6-week placebo run-in and following two
12-week treatment periods with either low (1.25 mg) or conventional (5.0 mg) dose bendrofluazide. There were no differences
between doses in their effects on systolic and diastolic blood pressure. Bendrofluazide 1.25 mg had significantly less effect
on serum potassium, uric acid, fasting glucose and HbA1 c concentrations than the 5.00 mg dose. Exogenous glucose infusion rates required to maintain euglycaemia were significantly
different between doses (p < 0.05) with conventional-dose bendrofluazide worsening peripheral insulin resistance compared to baseline (23.8 ± 2.9 vs
27.3 ± 3.5 μmol · kg− 1· min− 1, p < 0.05) and low-dose bendrofluazide producing no change compared to baseline (26.8 ± 3.6 vs 27.3 ± 3.5 μmol · kg− 1· min− 1, p = NS). Postabsorptive endogenous glucose production was higher on treatment with bendrofluazide 5.0 mg compared to 1.25 mg
(11.7 ± 0.5 vs 10.2 ± 0.3 μmol · kg− 1· min− 1, p < 0.05) and suppressed to a lesser extent following insulin (4.0 ± 0.7 vs 2.0 ± 0.4 μmol · kg− 1· min− 1, p < 0.05). Treatment with bendrofluazide 5.0 mg increased postabsorptive endogenous glucose production compared to baseline
(11.7 ± 0.5 vs 10.6 ± 0.4 μmol · kg− 1· min− 1, p < 0.05) whereas bendrofluazide 1.25 mg did not (10.2 ± 0.3 vs 10.6 ± 0.4 μmol · kg− 1· min− 1, p = NS). At a dose of 1.25 mg bendrofluazide is as effective as conventional doses but has less adverse metabolic effects.
In contrast to conventional doses which worsen both hepatic and peripheral insulin resistance, low-dose bendrofluazide has
no effect on insulin action in non-insulin-dependent diabetic subjects. [Diabetologia (1995) 38: 853–859]
Received: 6 September 1994 and in revised form: 29 December 1994 相似文献
3.
Summary To determine whether long-term insulin deficiency alters insulin movement across the endothelium, plasma and lymph dynamics
were assessed in dogs after alloxan (50 mg/kg; n = 8) or saline injection (n = 6). Glucose tolerance (KG) and acute insulin response were assessed by glucose injection before and 18 days after treatment. Two days later, hyperglycaemic
(16.7 mmol/l) hyperinsulinaemic (60 pmol · min−1· kg−1) glucose clamps were carried out in a subset of dogs (n = 5 for each group), with simultaneous sampling of arterial blood and hindlimb lymph. Alloxan induced fasting hyperglycaemia
(12.9 ± 2.3 vs 5.7 ± 0.2 mmol/l; p = 0.018 vs pre-treatment) and variable insulinopenia (62 ± 14 vs 107 ± 19 pmol/l; p = 0.079). The acute insulin response, however, was suppressed by alloxan (integrated insulin from 0–10 min: 155 ± 113 vs
2745 ± 541 pmol · l−1· 10 min−1; p = 0.0027), resulting in pronounced glucose intolerance (KG: 0.99 ± 0.19 vs 3.14 ± 0.38 min−1; p = 0.0002 vs dogs treated with saline). During clamps, steady state arterial insulin was higher in dogs treated with alloxan
(688 ± 60 vs 502 ± 38 pmol/l; p = 0.023) due to a 25 % reduction in insulin clearance (p = 0.045). Lymph insulin concentrations were also raised (361 ± 15 vs 266 ± 27 pmol/l; p = 0.023), such that the lymph to arterial ratio was unchanged by alloxan (0.539 ± 0.022 vs 0.533 ± 0.033; p = 0.87). Despite higher lymph insulin, glucose uptake (Rd) was significantly diminished after injection of alloxan (45.4 ± 2.5 vs 64.3 ± 6.5 μmol · min−1· kg−1; p = 0.042). This was reflected in resistance of target tissues to the lymph insulin signal (ΔRd/Δlymph insulin: 3.389 ± 1.093 vs 11.635 ± 2.057 · 10−6· l · min−1· kg–1· pmol−1· l−1; p = 0.012) which correlated strongly with the KG (r = 0.86; p = 0.0001). In conclusion, alloxan induces insulinopenic diabetes, with glucose intolerance and insulin resistance at the
target tissue level. Alloxan treatment, however, does not alter lymph insulin kinetics, indicating that insulin resistance
of Type 1 (insulin-dependent) diabetes mellitus reflects direct impairment at the cellular level. [Diabetologia (1998) 41:
1327–1336]
Received: 3 November 1997 and in final revised form: 2 June 1998 相似文献
4.
Gomez L Paillard M Price M Chen Q Teixeira G Spiegel S Lesnefsky EJ 《Basic research in cardiology》2011,106(6):1341-1353
Although mitochondria are key determinants of myocardial injury during ischemia–reperfusion (I/R), their interaction with
critical cytoprotective signaling systems is not fully understood. Sphingosine-1-phosphate (S1P) produced by sphingosine kinase-1
protects the heart from I/R damage. Recently a new role for mitochondrial S1P produced by a second isoform of sphingosine
kinase, SphK2, was described to regulate complex IV assembly and respiration via interaction with mitochondrial prohibitin-2.
Here we investigated the role of SphK2 in cardioprotection by preconditioning. Littermate (WT) and sphk2
−/− mice underwent 45 min of in vivo ischemia and 24 h reperfusion. Mice received no intervention (I/R) or preconditioning (PC)
via 5 min I/R before the index ischemia. Despite the activation of PC-cytoprotective signaling pathways in both groups, infarct
size in sphk2
−/− mice was not reduced by PC (42 ± 3% PC vs. 43 ± 4% I/R, p = ns) versus WT (24 ± 3% PC vs. 43 ± 3% I/R, p < 0.05). sphk2
−/− mitochondria exhibited decreased oxidative phosphorylation and increased susceptibility to permeability transition (PTP).
Unlike WT, PC did not prevent ischemic damage to electron transport or the increased susceptibility to PTP. To evaluate the
direct contribution to the resistance of mitochondria to cytoprotection, SphK2, PHB2 or cytochrome oxidase subunit IV was
depleted in cardiomyoblasts. PC protection was abolished by each knockdown concomitant with decreased PTP resistance. These
results point to a new action of S1P in cardioprotection and suggest that the mitochondrial S1P produced by SphK2 is required
for the downstream protective modulation of PTP as an effector of preconditioning protection. 相似文献
5.
R. Frénais K. Ouguerram C. Maugeais P. Mahot P. Maugère M. Krempf T. Magot 《Diabetologia》1997,40(5):578-583
Summary High density lipoprotein (HDL) kinetics were studied by infusing [5,5,5-2H3]-leucine in five subjects with normal glucose tolerance and eight patients with non-insulin-dependent diabetes mellitus (NIDDM)
with poor metabolic control (HbA1 c = 8.16 ± 1.93 %) (mean ± SD). HDL were modelled as a single compartment since no kinetic differences were observed between
HDL2 and HDL3 subclasses. Plasma apolipoprotein AI (apo AI) concentration was significantly lower in NIDDM patients (96.1
± 12.1 vs 124.4 ± 13.1 mg · dl−1, p < 0.01). HDL composition was altered in NIDDM, as an increase in HDL-triglyceride and a decrease in HDL-cholesterol, negatively
correlated (r = −0.780, p < 0.01). The mean fractional catabolic rate (FCR) of apo AI-HDL was significantly higher (0.39 ± 0.16 vs 0.21 ± 0.06 d−1, p < 0.05) while the apo AI-HDL absolute production rate was not significantly greater (13.6 ± 5.1 vs 12.0 ± 4.2 mg · kg−1· d−1) in diabetic patients compared to normal subjects. There were significant correlations between apo AI-HDL FCR and plasma
apo AI concentration (r = −0.580, p < 0.05), plasma triglycerides (r = 0.839, p < 0.001) or HDL-triglyceride levels (r = 0.597, p < 0.05). No correlation was observed between apo AI-HDL FCR and HbA1 c or HDL-cholesterol level. These data support the view that the decrease in plasma apo AI level in patients with NIDDM is
due to an increase of apo AI-HDL FCR, which may itself be related to changes in HDL composition. [Diabetologia (1997) 40:
578–583]
Received: 15 October 1996 and in revised form: 17 January 1997 相似文献
6.
Insulin resistance and coronary artery disease 总被引:5,自引:0,他引:5
Summary The purpose of the present study was to quantitate insulin-mediated glucose disposal in normal glucose tolerant patients
with angiographically documented coronary artery disease (CAD) and to define the pathways responsible for the insulin resistance.
We studied 13 healthy, normal weight, normotensive subjects with angiographically documented CAD and 10 age-, weight-matched
control subjects with an oral glucose tolerance test and a 2-h euglycaemic insulin (40 mU · m−2· min−1) clamp with tritiated glucose and indirect calorimetry. Lean body mass was measured with tritiated water. All CAD and control
subjects had a normal oral glucose tolerance test. Fasting plasma insulin concentration (66 ± 6 vs 42 ± 6 pmol/l, p < 0.05) and area under the plasma insulin curve following glucose ingestion (498 ± 54 vs 348 ± 42 pmol · l−1· min−1, p < 0.001) were increased in CAD vs control subjects. Insulin-mediated whole body glucose disposal (27.8 ± 3.9 vs 38.3 ± 4.4
μmol · kg fat free mass (FFM)−1· min−1, p < 0.01) was significantly decreased in CAD subjects and this was entirely due to diminished non-oxidative glucose disposal
(8.9 ± 2.8 vs 20.0 ± 3.3 μmol · kg FFM−1· min−1, p < 0.001). The magnitude of insulin resistance was positively correlated with the severity of CAD (r = 0.480, p < 0.05). In the CAD subjects basal and insulin-mediated rates of glucose and lipid oxidation were normal and insulin caused
a normal suppression of hepatic glucose production. In conclusion, subjects with angiographically documented CAD are characterized
by moderate-severe insulin resistance and hyperinsulinaemia and should be included in the metabolic and cardiovascular cluster
of disorders that comprise the insulin resistance syndrome or ’syndrome X'. [Diabetologia (1996) 39: 1345–1350]
Received: 6 February 1996 and in revised form: 29 May 1996 相似文献
7.
Arrhythmia phenotype in mouse models of human long QT 总被引:1,自引:0,他引:1
Guy Salama Linda Baker Robert Wolk Jacques Barhanin Barry London 《Journal of interventional cardiac electrophysiology》2009,24(2):77-87
Enhanced dispersion of repolarization (DR) was proposed as a unifying mechanism, central to arrhythmia genesis in the long
QT (LQT) syndrome. In mammalian hearts, K+ channels are heterogeneously expressed across the ventricles resulting in ‘intrinsic’ DR that may worsen in long QT. DR was
shown to be central to the arrhythmia phenotype of transgenic mice with LQT caused by loss of function of the dominant mouse
K+ currents. Here, we investigated the arrhythmia phenotype of mice with targeted deletions of KCNE1 and KCNH2 genes which encode for minK/IsK and Merg1 (mouse homolog of human ERG) proteins resulting in loss of function of IKs and IKr, respectively. Both currents are important human K+ currents associated with LQT5 and LQT2. Loss of minK, a protein subunit that interacts with KvLQT1, results in a marked reduction
of IKs giving rise to the Jervell and Lange–Nielsen syndrome and the reduced KCNH2 gene reduces MERG and IKr.
Hearts were perfused, stained with di-4-ANEPPS and optically mapped to compare action potential durations (APDs) and arrhythmia
phenotype in homozygous minK (minK−/−) and heterozygous Merg1 (Merg+/−) deletions and littermate control mice. MinK−/− mice has similar APDs and no arrhythmias (n = 4). Merg+/− mice had prolonged APDs (from 20 ± 6 to 32 ± 9 ms at the base, p < 0.01; from 18 ± 5 to 25 ± 9 ms at the apex, p < 0.01; n = 8), longer refractory periods (RP) (36 ± 14 to 63 ± 27 at the base, p < 0.01 and 34 ± 5 to 53 ± 21 ms at the apex, p < 0.03; n = 8), higher DR 10.4 ± 4.1 vs. 14 ± 2.3 ms, p < 0.02) and similar conduction velocities (n = 8). Programmed stimulation exposed a higher propensity to VT in Merg+/− mice (60% vs. 10%). A comparison of mouse models of LQT based on K+ channel mutations important to human and mouse repolarization emphasizes DR as a major determinant of arrhythmia vulnerability. 相似文献
8.
Summary To test whether gluconeogenesis is increased in non-insulin-dependent diabetic (NIDDM) patients we infused (post-absorptive
state) healthy subjects and NIDDM patients with [6,6-2H2]glucose (150 min) and [3-13C]lactate (6 h). Liver glutamine was sampled with phenylacetate and its labelling pattern determined (mass spectrometry) after
purification of the glutamine moiety of urinary phenylacetylglutamine. After correction for 13CO2 re-incorporation (control test with NaH13CO3 infusion) this pattern was used to calculate the dilution factor (F) in the hepatic oxaloacetate pool and fluxes through
liver Krebs cycle. NIDDM patients had increased lactate turnover rates (16.18 ± 0.92 vs 12.14 ± 0.60 μmol · kg−1· min−1, p < 0.01) and a moderate rise in glucose production (EGP) (15.39 ± 0.87 vs 12.52 ± 0.28 μmol · kg−1· min−1, p = 0.047). Uncorrected contributions of gluconeogenesis to EGP were 31 ± 3 % (control subjects) and 17 ± 2 % (NIDDM patients).
F was comparable (1.34 ± 0.02 and 1.39 ± 0.09, respectively) and the corrected percent and absolute contributions of gluconeogenesis
were not increased in NIDDM (25 ± 3 % and 3.8 ± 0.5 μmol · kg−1· min−1) compared to control subjects (41 ± 3 % and 5.1 ± 0.4 μmol · kg−1· min−1). The calculated pyruvate carboxylase over pyruvate dehydrogenase activity ratio was comparable (12.1 ± 2.6 vs 11.2 ± 1.4).
Lastly hepatic fatty oxidation, as estimated by the model, was not increased in NIDDM (1.8 ± 0.4 vs 1.6 ± 0.1 μmol · kg−1· min−1). In conclusion, in the patients studied we found no evidence of increased hepatic fatty oxidation, or, despite the increased
lactate turnover rate, an increased gluconeogenesis. [Diabetologia (1998) 41: 212–220]
Received: 4 July 1997 and in revised form: 16 September 1997 相似文献
9.
Perseghin G Lattuada G De Cobelli F Esposito A Costantino F Canu T Scifo P De Taddeo F Maffi P Secchi A Del Maschio A Luzi L 《Diabetologia》2005,48(12):2615-2621
Aims/hypothesis Insulin resistance may be associated with ectopic fat accumulation potentially determined by reduced lipid oxidation. In patients
with type 1 diabetes peripheral insulin resistance is associated with higher intramyocellular lipid content. We assessed whether
these patients are also characterised by intrahepatic fat accumulation and abnormal fat oxidation.
Methods Nineteen patients with type 1 diabetes (6 women, 13 men, age 35±7 years, BMI 23±3 kg/m2, HbA1c 8.7±1.4%) and 19 healthy matched individuals were studied by (1) euglycaemic–hyperinsulinaemic clamp combined with [6,6−2H2]glucose infusion to assess whole–body glucose metabolism; (2) indirect calorimetry to assess glucose and lipid oxidation;
and (3) localised 1H−magnetic resonance spectroscopy of the liver to assess intrahepatic fat content.
Results Patients with type 1 diabetes showed a reduced insulin−stimulated metabolic clearance rate of glucose (4.3±1.3 ml kg−1 min−1) in comparison with normal subjects (6.0±1.6 ml kg−1 min−1; p<0.001). Endogenous glucose production was higher in diabetic patients (p=0.001) and its suppression was impaired during insulin administration (66±30 vs 92±8%; p=0.047) in comparison with normal subjects. Plasma glucagon concentrations were not different between groups. The estimated
hepatic insulin concentration was lower in diabetic patients than in normal subjects (p<0.05), as was the intrahepatic fat content (1.5±0.7% and 2.2±1.0% respectively; p<0.03), the latter in association with a reduced respiratory quotient (0.74±0.05 vs 0.84±0.06; p=0.01) and increased fasting lipid oxidation (1.5±0.5 vs 0.8±0.4 mg kg−1 min−1; p<0.01).
Conclusions/interpretation In patients with type 1 diabetes, insulin resistance was not associated with increased intrahepatic fat accumulation. In fact,
diabetic patients had reduced intrahepatic fat content, which was associated with increased fasting lipid oxidation. The unbalanced
hepatic glucagon and insulin concentrations affecting patients with type 1 diabetes may be involved in this abnormality of
intrahepatic lipid metabolism. 相似文献
10.
Giordano M Lucidi P Ciarambino T Gesuè L Castellino P Cioffi M Gresele P Paolisso G De Feo P 《Diabetologia》2008,51(1):21-28
Aims/hypothesis Diabetic nephropathy is associated with hypoalbuminaemia and hyperfibrinogenaemia. A low-protein diet has been recommended
in patients with diabetic nephropathy, but its effects on albumin and fibrinogen synthesis are unknown.
Methods We compared the effects of a normal (NPD; 1.38 ± 0.08 g kg−1 day−1) or low (LPD; 0.81 ± 0.04 g kg−1 day−1) -protein diet on endogenous leucine flux (ELF), albumin and fibrinogen synthesis (l-[5,5,5,-2H3]leucine infusion), and markers of inflammation in nine type 2 diabetic patients with macroalbuminuria. Six healthy participants
on NPD served as control participants.
Results In comparison with healthy participants, type 2 diabetic patients on an NPD had similar ELF, reduced serum albumin (38 ± 1.1
vs 42 ± 0.8 g/l; p < 0.05), similar fractional synthesis rates (FSR) and absolute synthesis rates (ASR) of albumin, and both increased plasma
fibrinogen concentration [10.7 ± 0.6 vs 7.2 ± 0.5 μmol/l (3.64 ± 0.22 vs 2.45 ± 0.18 g/l); p < 0.05] and fibrinogen ASR [11.03 ± 1.17 vs 6.0 ± 1.8 μmol 1.73 m−2 day−1 (3.7 ± 0.4 vs 1.9 ± 0.3 g 1.73 m−2 day−1); p < 0.01]. After LPD, type 2 diabetic patients had the following changes in comparison with NPD: reduced proteinuria (2.74 ± 0.4
vs 4.51 ± 0.8 g/day; p < 0.05), ELF (1.93 ± 0.08 vs 2.11 ± 0.08 μmol kg−1 min−1; p < 0.05) and total fibrinogen pool; increased serum albumin (42 ± 1 vs 38 ± 1 g/l; p < 0.01) and albumin ASR (14.1 ± 1 vs 9.9 ± 1 g 1.73 m−2 day−1; p < 0.05); and reduced plasma IL-6 levels, which were correlated with albumin ASR (r = −0.749; p < 0.05).
Conclusions/interpretation LPD in type 2 diabetic patients with diabetic nephropathy reduces low-grade inflammatory state, proteinuria, albuminuria,
whole-body proteolysis and ASR of fibrinogen, while increasing albumin FSR, ASR and serum concentration.
ISRCTN ID no: CCT-NAPN-16911 相似文献
11.
Hiroyuki Takinami M.D. Yasuyoshi Iwado M.D. Koji Ohmori M.D. Katsufumi Mizushige M.D. Yoshihiro Nisiyama M.D. Motoomi Okawa M.D. Chietugu Kato M.D. Nagara Tamaki M.D. Shoichi Senda M.D. Masakazu Kohno M.D. 《The International journal of angiology》2005,14(3):133-137
Although myocardial flow reserve (MFR) in congestive heart failure (CHF) has been reported to be impaired, the mechanism has
not been fully shown in humans. Therefore, we performed positron emission tomography to measure myocardial blood flow (MBF)
in patients with CHF and compared it with hemodynamic parameters. Sixteen normal coronary patients with CHF and ten normal
controls were enrolled. 15O-labeled water positron emission tomography was performed at rest and during peak hyperemia induced by adenosine triphosphate.
MFR was calculated as the ratio of peak hyperemic to baseline MBF. All CHF patients underwent cardiac catheterization. Baseline
MBF was similar between CHF patients and normal controls (0.73 ± 0.25 vs. 0.80 ± 0.12 mL/min/g, p = NS). Hyperemic MBF was significantly reduced in CHF patients than in controls (1.68 ± 1.09 vs. 3.21 ± 0.69 mL/min/g, p < 0.05). therefore, MFR was significantly reduced in CHF patients than in controls (2.30 ± 1.30 vs. 4.03 ± 0.90, p < 0.05). There was no significant correlation between baseline MBF and either pulmonary capillary wedge pressure or left
ventricular end-diastolic pressure, while both hyperemic MBF and MFR significantly correlated with both pulmonary capillary
wedge pressure (r = −0.67 and r = −0.75, respectively) and left ventricular end-diastolic pressure (r = −0.51 and r = −0.60, respectively). Despite elevated preload, MBF at rest in CHF patients was compensated to the similar level as that
in controls. However, this compensation may exhaust vasodilatory reserve in the failing human heart. Thus, preload at rest
is a determinant of myocardial vasodilator reserve and preload reduction may ameliorate coronary vasodilator response in CHF
patients. 相似文献
12.
Abstract
Exhaled nitric oxide (eNO) is increasingly used as a marker of disease activity in asthma. Inhaled hypertonic saline has been
shown to induce bronchoconstriction and to decrease eNO in asthmatic subjects, whereas the effects of hypotonic solutions
on eNO in these patients have not been studied. To evaluate the effect of ultrasonically nebulized distilled water (UNDW),
an indirect hypotonic stimulus, on eNO, 17 asthmatic patients were enrolled and eNO from lower airways was measured by chemiluminescence.
UNDW significantly reduced FEV1 ≥ 20% in 9 subjects (UNDW+), but had no effect in eight patients (UNDW−). Baseline eNO concentration were found to be 51.3
± 11.1 ppb in UNDW+ and 32.9 ± 7.5 ppb in UNDW− patients, respectively (p = 0.199, NS). UNDW inhalation significantly decreased eNO (from 51.3 ± 11.1 ppb to 31.0 ± 7.1 ppb in UNDW+ (p < 0.020, n = 9) and from 32.9 ± 7.5 ppb to 26.2 ± 7.3 ppb in UNDW− subjects (p < 0.024, n = 8), respectively). eNO percentage reduction in UNDW+ patients was significantly higher compared with UNDW− subjects (−37
± 4% vs −23 ± 3%, p = 0.021). There was no correlation between FEV1 changes and eNO percentage decreases in both UNDW+ and UNDW− subjects. In UNDW+ patients, acute bronchodilation induced by
salbutamol caused a recovery in both FEV1 and eNO, though eNO levels remained lower than baseline values. We concluded that UNDW inhalation can significantly decrease
eNO in asthmatic patients, either responders or nonresponders to this indirect osmotic challenge; the reduction in eNO levels
was only partly dependent on acute changes in airway caliber. 相似文献
13.
Middlebrooke AR Elston LM Macleod KM Mawson DM Ball CI Shore AC Tooke JE 《Diabetologia》2006,49(10):2263-2271
Aims/hypothesis Adults with type 2 diabetes mellitus have impaired microvascular function. It has been hypothesised that microvascular function
may be restored through regular exercise. The aim of this study was to investigate whether 6 months of regular aerobic exercise
would improve microvascular function in adults with type 2 diabetes.
Materials and methods Fifty-nine patients with type 2 diabetes (32 males, age 62.9±7.6 years, HbA1c 6.8±0.9%) were randomised to either a 6-month aerobic exercise programme (30 min, three times a week, 70–80% of maximal heart
rate) or a ‘standard care’ control group. Before and after the intervention period, microvascular function was assessed as
the maximum skin hyperaemia to local heating and endothelial and non-endothelial responsiveness following the iontophoretic
application of acetylcholine and sodium nitroprusside. Maximal oxygen uptake, as an index of aerobic fitness, was assessed
using a maximal exercise test.
Results No significant improvement was seen in the exercise group compared with the control group for any of the variables measured:
maximal oxygen uptake (control pre: 1.73±0.53 [means±SD] vs post: 1.67±0.40; exercise pre: 1.75±0.56 vs post: 1.87±0.62 l/min,
p=0.10); insulin sensitivity (insulin tolerance test) (control pre: −0.17±0.06 vs post: −0.17±0.06; exercise pre: −0.16±0.1
vs post: −0.17±0.07 mmol l−1 min−1, p=0.97); maximal hyperaemia (control pre: 1.49±0.43 vs post: 1.52±0.57; exercise pre: 1.42±0.36 vs post: 1.47±0.33 V, p=0.85); peak response to acetylcholine (control pre: 1.37±0.47 vs post: 1.28±0.37; exercise pre: 1.27±0.44 vs post: 1.44±0.23 V,
p=0.19) or to sodium nitroprusside (control pre: 1.09±0.50 vs post: 1.10±0.39; exercise pre: 1.12±0.28 vs post: 1.13±0.40 V,
p=0.98).
Conclusions/interpretation In this group of type 2 diabetic patients with good glycaemic control a 6-month aerobic exercise programme did not improve
microvascular function or aerobic fitness. 相似文献
14.
Seghieri G Tesi F Anichini R De Bellis A Barsotti E Mari A Ferrannini E 《Diabetologia》2007,50(11):2234-2238
Aims/hypothesis Gestational diabetes (GDM) carries a high risk of subsequent diabetes. We asked what impact prior GDM has on beta cell function
and insulin action in women who maintain normal glucose tolerance (NGT) for a long time.
Methods Ninety-one women with NGT (aged 41 ± 8 years, mean±SD) were studied (by mathematical modelling of the C-peptide response to
an OGTT) 7 [6] years (median [interquartile range]) after the index pregnancy, during which 52 had GDM (pGDM) and 39 had NGT
(pNGT). In all women an OGTT had also been performed at 29 ± 3 weeks of the index pregnancy.
Results Women with pGDM were matched with women with pNGT for age, familial diabetes, time and weight gain since index pregnancy,
parity, BMI (25.4 ± 3.9 vs 26.8 ± 6.4 kg/m2), and fasting (4.64 ± 0.56 vs 4.97 ± 0.46 mmol/l) and 2 h plasma glucose levels (5.91 ± 1.14 vs 5.91 ± 1.21 mmol/l). Nonetheless,
fasting (49 [29] vs 70 [45] pmol min−1 m−2, p < 0.001) and total insulin secretion (32 [17] vs 48 [21] nmol m−2, p < 0.0001) and beta cell glucose sensitivity (slope of the insulin secretion/plasma glucose concentration–response function)
(95 [71] vs 115 [79] pmol min−1 m−2 (mmol/l)−1, p = 0.025) were reduced in the pGDM group compared with the pNGT group, while insulin sensitivity was preserved (424 [98] vs
398 [77] ml min−1 m−2). At index pregnancy, women with pGDM and those with pNGT had similar age and BMI. However, both insulin sensitivity (359
[93] vs 417 [92] ml min−1 m−2, p = 0.0012) and the insulin/glucose incremental area ratio (an empirical index of beta cell function; 98 [74] vs 138 [122]
pmol/mmol, p = 0.028) were reduced in women with pGDM.
Conclusions Even in women who maintain normal insulin sensitivity, impaired beta cell function is carried over into the NGT status several
years after a GDM pregnancy. 相似文献
15.
Aims/hypothesis The aim of this study was to investigate whether intrahepatic and intramyocellular fat are related to insulin resistance in
these respective tissues or to the metabolic syndrome.
Methods Hepatic (insulin 1.8 pmol kg−1 min−1 combined with [3-3H]glucose) and muscle (insulin 6.0 pmol kg−1 min−1) insulin sensitivity were measured on separate occasions in 45 non-diabetic men (age 42 ± 1 years, BMI 26.2 ± 0.6 kg/m2) using the euglycaemic–hyperinsulinaemic clamp. Liver fat and intramyocellular lipid (IMCL) were measured by proton magnetic
resonance spectroscopy and body composition by magnetic resonance imaging. We also determined fasting serum insulin and adiponectin
concentrations, components of the metabolic syndrome and maximal oxygen consumption.
Results In participants with high [median 12.0% (interquartile range 5.7–18.5%)] vs low [2.0% (1.0–2.0%)] liver fat, fasting serum
triacylglycerols (1.6 ± 0.2 vs 1.0 ± 0.1 mmol/l, p = 0.002) and fasting serum insulin (55 ± 4 vs 32 ± 2 pmol/l, p < 0.0001) were increased and serum HDL-cholesterol (1.26 ± 0.1 vs 1.48 ± 0.1 mmol/l, p = 0.02) and fasting serum adiponectin (9.5 ± 1.2 vs 12.2 ± 1.2 μg/ml, p = 0.05) decreased. In participants with high [19.5% (16.0–26.0%)] vs low [5.0% (2.3–7.5%)] IMCL, these parameters were comparable.
Liver fat was higher in participants with [10.5% (3.0–18.0%)] than in those without [2.0% (1.5–6.0%), p = 0.010] the metabolic syndrome, even independently of obesity, while IMCL was comparable. Insulin suppression of glucose
rate of appearance and serum NEFA was significantly impaired in the high liver fat group.
Conclusions/interpretation Fat accumulation in the liver rather than in skeletal muscle is associated with features of the metabolic syndrome, i.e. increased
fasting serum triacylglycerols and decreased fasting serum HDL-cholesterol, as well as with hyperinsulinaemia and low adiponectin. 相似文献
16.
Risk and mechanism of dexamethasone-induced deterioration of glucose tolerance in non-diabetic first-degree relatives of NIDDM patients 总被引:5,自引:0,他引:5
Summary We tested the hypothesis that glucose intolerance develops in genetically prone subjects when exogenous insulin resistance
is induced by dexamethasone (dex) and investigated whether the steroid-induced glucose intolerance is due to impairment of
beta-cell function alone and/or insulin resistance. Oral glucose tolerance (OGTT) and intravenous glucose tolerance tests
with minimal model analysis were performed before and following 5 days of dex treatment (4 mg/day) in 20 relatives of non-insulin-dependent
diabetic (NIDDM) patients and in 20 matched control subjects (age: 29.6 ± 1.7 vs 29.6 ± 1.6 years, BMI: 25.1 ± 1.0 vs 25.1
± 0.9 kg/m2). Before dex, glucose tolerance was similar in both groups (2-h plasma glucose concentration (PG): 5.5 ± 0.2 [range: 3.2–7.0]
vs 5.5 ± 0.2 [3.7–7.4] mmol/l). Although insulin sensitivity (Si) was significantly lower in the relatives before dex, insulin
sensitivity was reduced to a similar level during dex in both the relatives and control subjects (0.30 ± 0.04 vs 0.34 ± 0.04
10–4 min–1 per pmol/l, NS). During dex, the variation in the OGTT 2-h PG was greater in the relatives (8.5 ± 0.7 [3.9–17.0] vs 7.5 ±
0.3 [5.7–9.8] mmol/l, F-test p < 0.05) which, by inspection of the data, was caused by seven relatives with a higher PG than the maximal value seen in the
control subjects (9.8 mmol/l). These “hyperglycaemic” relatives had diminished first phase insulin secretion (?1) both before
and during dex compared with the “normal” relatives and the control subjects (pre-dex ?1: 12.6 ± 3.6 vs 26.4 ± 4.2 and 24.6
± 3.6 (p < 0.05), post-dex ?1: 22.2 ± 6.6 vs 48.0 ± 7.2 and 46.2 ± 6.6 respectively (p < 0.05) pmol · l–1· min–1 per mg/dl). However, Si was similar in “hyperglycaemic” and “normal” relatives before dex (0.65 ± 0.10 vs 0.54 ± 0.10 10−4
· min–1 per pmol/l) and suppressed similarly during dex (0.30 ± 0.07 vs 0.30 ± 0.06 10−4 · min–1 per pmol/l). Multiple regression analysis confirmed the unique importance of low pre-dex beta-cell function to subsequent
development of high 2-h post-dex OGTT plasma glucose levels (R
2 = 0.56). In conclusion, exogenous induced insulin resistance by dex will induce impaired or diabetic glucose tolerance in
those genetic relatives of NIDDM patients who have impaired beta-cell function (retrospectively) prior to dex exposure. These
subjects are therefore unable to enhance their beta-cell response in order to match the dex-induced insulin resistant state.
[Diabetologia (1997) 40: 1439–1448]
Received: 20 January 1997 and in final revised form: 17 July 1997 相似文献
17.
Jocken JW Goossens GH van Hees AM Frayn KN van Baak M Stegen J Pakbiers MT Saris WH Blaak EE 《Diabetologia》2008,51(2):320-327
Aims/hypothesis Obesity is characterised by increased triacylglycerol storage in adipose tissue. There is in vitro evidence for a blunted
beta-adrenergically mediated lipolytic response in abdominal subcutaneous adipose tissue (SAT) of obese individuals and evidence
for this at the whole-body level in vivo. We hypothesised that the beta-adrenergically mediated effect on lipolysis in abdominal
SAT is also impaired in vivo in obese humans.
Methods We investigated whole-body and abdominal SAT glycerol metabolism in vivo during 3 h and 6 h [2H5]glycerol infusions. Arterio–venous concentration differences were measured in 13 lean and ten obese men after an overnight
fast and during intravenous infusion of the non-selective beta-adrenergic agonist isoprenaline [20 ng (kg fat free mass)−1 min−1].
Results Lean and obese participants showed comparable fasting glycerol uptake by SAT (9.7 ± 3.4 vs 9.3 ± 2.5% of total release, p = 0.92). Furthermore, obese participants showed an increased whole-body beta-adrenergically mediated lipolytic response versus
lean participants. However, their fasting lipolysis was blunted [glycerol rate of appearance: 7.3 ± 0.6 vs 13.1 ± 0.9 μmol
(kg fat mass)−1 min−1, p < 0.01], as was the beta-adrenergically mediated lipolytic response per unit SAT [Δ total glycerol release: 140 ± 71 vs 394 ± 112 nmol
(100 g tissue)−1 min−1, p < 0.05] compared with lean participants. Net triacylglycerol flux tended to increase in obese compared with lean participants
during beta-adrenergic stimulation [Δ net triacylglycerol flux: 75 ± 32 vs 16 ± 11 nmol (100 g tissue)−1 min−1, p = 0.06].
Conclusions/interpretation We demonstrated in vivo that beta-adrenergically mediated lipolytic response is impaired systematically and in abdominal SAT
of obese versus lean men. This may be important in the development or maintenance of increased triacylglycerol stores and
obesity. 相似文献
18.
Aims/hypothesis We tested the hypothesis that diabetic glomerulosclerosis would develop more rapidly in animals with fewer glomeruli.
Methods We studied the female offspring of Wistar rats that had been fed a low-protein diet (LPD) containing 6% protein or a normal-protein
diet (NPD) containing 18% protein during pregnancy. Streptozotocin diabetes was induced at 12 weeks and animals were killed
at 40 weeks.
Results Non-diabetic LPD offspring were of lower birthweight than the NPD offspring (5.19±0.64 vs 6.45±0.67 g, p<0.001) and had fewer glomeruli (27,402±3,137 vs 34,203±6,471, p<0.05). Glomerular volume correlated inversely with glomerular number (r=−0.64, p=0.035), but total glomerular filtration surface area was reduced in the LPD animals (4,770±541 vs 5,779±1,302 mm2, p=0.05). Other renal structural and functional parameters were similar. In LPD and NPD diabetic animals, glomerular volume
and basement membrane width were significantly increased compared to their respective controls. Podocyte density was lowest
in the LPD diabetic animals (not significant), and the area covered by each podocyte was greater in the LPD diabetic group
(2.40±0.693 ×10−3 mm2) than in the LPD control group (1.68±0.374 ×10−3 mm2, p<0.001) and in the NPD diabetic animals (1.71±0.291 ×10−3 mm2, p<0.05). There was no difference in any other structural or functional parameter between the LPD and NPD diabetic animals.
Conclusions/interpretation A decrease in glomerular number was not deleterious to renal structure and function over 40 weeks in this animal model. Further
work in models with progressive renal impairment and hypertension is necessary to clarify the impact of glomerular number
on the development of renal disease. 相似文献
19.
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
20.
Paganelli MO Martins LC Chaud MV Ferreira-Melo SE Sabha M do Prado JF Hyslop S Tanus-Santos JE Moreno H 《Cardiovascular toxicology》2006,6(1):63-67
Bupropion has been used to treat psychic depression and as a therapy for smoking cessation, the latter mainly in association
with nicotine. However, there have been no detailed studies of the hemodynamic effects of the association of bupropion with
nicotine during replacement therapy. In this study, we evaluated the effects of such an association on the cardiovascular
parameters in anesthetized dogs. Bupropion, either alone or together with nicotine, had no significant effect on the cardiac
index (Cl; 4.7±0.2 vs 4.3±0.1 and 3.5±0.3 vs 3.4±0.3 L.min−1.m2, respectively; mean±SEM) and mean arterial pressure (MAP; 134±5.0 vs 145±11.0 and 118±5.0 vs 133±10.5 mmHg, respectively).
There was a slight but significant increase in the systemic vascular resistance index (SVRI; 2165±93 vs 2645±126 and 2335±100
vs 2737±200 dyn.cm−5m−2, respectively). However, there was a significant increase in the mean pulmonary artery pressure (MPAP; 20±0.8 vs 25±1.6 and
18±1.3 vs 25±1.6 mmHg, respectively; p<0.05) and pulmonary vascular resistance index (IRVP; 194±11 vs 272±21 and 206±32 vs 307±42 dyn.cm−5m−2, respectively; p<0.05). These results show that bupropion alone or in association with nicotine does not markedly affect most hemodynamic
parameters of the systemic circulation, although the significant increase in MPAP and IRVP can elevate the pulmonary pressure. 相似文献