Chronic treatment with tadalafil improves endothelial function in men with increased cardiovascular risk

OBJECTIVE: Erectile dysfunction (ED) is often associated with a cluster of risk factors for coronary artery disease and reduced endothelial function. Acute and chronic administration of oral sildenafil, a phosphodiesterase type 5 (PDE5) inhibitor, improves endothelial function in patients with ED. Tadalafil (TAD) is a new PDE5 inhibitor with a long half life that allows alternate day administration. Aim of the study was to evaluate whether chronic therapy (4 weeks) with TAD improves endothelial function in patients with increased cardiovascular risk and whether this effect is sustained after discontinuation of therapy. METHODS: We randomized 32 patients with increased cardiovascular risk to receive either TAD 20 mg on alternate days or matching placebo (PLB) for 4 weeks. Patients underwent evaluation of brachial artery flow-mediated dilation (FMD), nitrite/nitrate and endothelin-1 plasma levels at baseline, at the end of treatment period and after two-weeks follow-up. RESULTS: At 4 weeks, FMD was significantly improved by TAD (from 4.2+/-3.2 to 9.3+/-3.7%, p<0.01 vs. baseline), but was not modified by PLB (from 4.1+/-2.8 to 4.0+/-3.4%, p=NS). At 6 weeks the benefit in FMD was sustained in patients that received TAD (9.1+/-3.9% vs. 4.2+/-3.2%, p=0.01 vs. baseline; 9.1+/-3.9% vs. 9.3+/-3.7%, vs. 4 weeks, p=NS) while no changes in FMD were observed in patients randomized to PLB. Also, compared to baseline, a net increase in nitrite/nitrate levels (38.2+/-12.3 vs. 52.6+/-11.7 and 51.1+/-3.1, p<0.05) and a decrease in endothelin-1 levels (3.3+/-0.9 vs. 2.9.+/-0.7 and 2.9+/-0.9, p<0.05) was found both at four and six-weeks after TAD; these changes were inversely correlated as shown by regression analysis (adjusted R2=0.81, p<0.0001). CONCLUSIONS: Chronic therapy with TAD improves endothelial function in patients with increased cardiovascular risk regardless their degree of ED. The benefit of this therapy is sustained for at least two weeks after the discontinuation of therapy. Larger studies are needed in order to assess the possible clinical implications of chronic therapy with TAD.     

Effect of glyburide on glycemic control, insulin requirement, and glucose metabolism in insulin-treated diabetic patients

Glycemic control and glucose metabolism were examined in 5 patients with insulin-dependent diabetes mellitus (IDDM) and 8 insulin-treated non-insulin-dependent diabetes mellitus (NIDDM) patients before and after 2 mo of therapy with glyburide (20 mg/day). Glycemic control was assessed by daily insulin requirement, 24-h plasma glucose profile, glucosuria, and glycosylated hemoglobin. Insulin secretion was evaluated by glucagon stimulation of C-peptide secretion, and insulin sensitivity was determined by a two-step euglycemic insulin clamp (1 and 10 mU X kg-1. X min-1) performed with indirect calorimetry and [3-3H]glucose. In the IDDM patients, the addition of glyburide produced no change in daily insulin dose (54 +/- 8 vs. 53 +/- 7 U/day), mean 24-h glucose level (177 +/- 20 vs. 174 +/- 29 mg/dl), glucosuria (20 +/- 6 vs. 35 +/- 12 g/day) or glycosylated hemoglobin (10.1 +/- 1.0 vs. 9.5 +/- 0.7%). Furthermore, there was no improvement in basal hepatic glucose production (2.1 +/- 0.2 vs. 2.4 +/- 0.1 mg X kg-1 X min-1), suppression of hepatic glucose production by low- and high-dose insulin infusion, or in any measure of total, oxidative, or nonoxidative glucose metabolism in the basal state or during insulin infusion. C-peptide levels were undetectable (less than 0.01 pmol/ml) in the basal state and after glucagon infusion and remained undetectable after glyburide therapy. In contrast to the IDDM patients, the insulin-treated NIDDM subjects exhibited significant reductions in daily insulin requirement (72 +/- 6 vs. 58 +/- 9 U/day), mean 24-h plasma glucose concentration (153 +/- 10 vs. 131 +/- 5 mg/dl), glucosuria (14 +/- 5 vs. 4 +/- 1 g/day), and glycosylated hemoglobin (10.3 +/- 0.7 vs. 8.0 +/- 0.4%) after glyburide treatment (all P less than or equal to .05). However, there was no change in basal hepatic glucose production (1.7 +/- 0.1 vs. 1.7 +/- 0.1 mg X kg-1 X min-1), suppression of hepatic glucose production by insulin, or insulin sensitivity during the two-step insulin-clamp study. Both basal (0.14 +/- 0.05 vs. 0.32 +/- 0.05 pmol/ml, P less than .05) and glucagon-stimulated (0.24 +/- 0.07 vs. 0.44 +/- 0.09 pmol/ml) C-peptide levels rose after 2 mo of glyburide therapy and both were correlated with the decrease in insulin requirement (basal: r = .65, P = .08; glucagon stimulated: r = .93, P less than .001).(ABSTRACT TRUNCATED AT 400 WORDS)     

Angiotensin II infusion increases plasma erythropoietin levels via an angiotensin II type 1 receptor-dependent pathway.

BACKGROUND: Angiotensin-converting enzyme inhibitors (ACEIs) have been shown to lower hematocrit and erythropoietin (EPO), but a direct link between angiotensin II (Ang II) and EPO in humans has not been shown. METHODS: Placebo or Ang II was infused for six hours in nine healthy male volunteers with and without blockade of the Ang II subtype 1 receptor (AT1R). EPO concentrations were measured 3, 6, 12, and 24 hours after the start of the infusion. RESULTS: Ang II raised the mean arterial pressure by about 20 mm Hg. Consistent with the known diurnal variation, EPO levels rose significantly (P < or = 0.02) during the day in all groups. During Ang II infusion, EPO levels rose to significantly higher levels after 6 and 12 hours compared with placebo [9.9 +/- 3.5 vs. 7.2 +/- 3.1 mU/mL (3 h, P = NS); 16.9 +/- 4.5 vs. 8.8 +/- 3.7 mU/mL (6 h, P = 0.01); 17.0 +/- 8.6 vs. 11.1 +/- 4.7 mU/mL (12 h, P = 0.01)] and returned to baseline after 24 hours (7.9 +/- 3.8 vs. 10.6 +/- 8.6 mU/mL, P = NS). With AT1R blockade, blood pressure remained normal during Ang II infusion, and EPO levels were never significantly different from placebo [6.8 +/- 4.8, 10.5 +/- 5.6, 13.1 +/- 9.0, and 12.4 +/- 10.1 mU/mL at 3, 6, 12, and 24 h after infusion, respectively, P = NS]. CONCLUSIONS: Ang II increases EPO levels in humans. This increase requires the participation of AT1R.     

Effect of fluvastatin on endothelium-dependent brachial artery vasodilation in patients after renal transplantation

BACKGROUND: Hypercholesterolemia may affect both endothelial function and arterial distensibility (DC). Renal transplant recipients (NTX) exhibit advanced structural and functional alterations of arterial vessel walls. The aim of this double-blind, randomized trial was to evaluate the effects of fluvastatin (FLU) on brachial artery flow-mediated vasodilation (FMD) and DC in hypercholesterolemic NTX. METHODS: Eighteen NTX received FLU 40 mg/day and 18 NTX placebo (PLA). Before and after six months of treatment, the brachial artery diameter and DC at rest were measured by a Doppler frequency analysis in the M mode, and then changes in diameter during reactive hyperemia (to assess endothelial-dependent FMD) and after 400 microg sublingual nitroglycerin (to assess endothelium-independent vasodilation-NMD). RESULTS: FLU, but not PLA, treatment resulted in significant decreases in total (from 288 +/- 10 to 239 +/- 8 mg/dL, P < 0.05) and low-density lipoprotein cholesterol (from 182 +/- 779 to 138 +/- 8 mg/dL, P < 0.05). Blood pressure did not differ between FLU- and PLA-treated patients and was not affected by either treatment. Also, the brachial artery baseline diameter was not different between groups and was not affected by FLU or PLA. Brachial artery flow at rest and during reactive hyperemia as measured by pulsed Doppler did not differ between groups. Brachial artery FMD increased with FLU from 0.23 +/- 0.08 to 0.54 +/- 0.08 mm (P < 0.05), whereas PLA did not alter FMD (0.22 +/- 0.07 vs. 0.14 +/- 0.05 mm at baseline and after six months of PLA treatment, respectively, P = NS). In contrast, NMD did not change significantly with either treatment (0.76 +/- 0.13 vs. 0.83 +/- 0.15 mm at baseline and after 6 months of FLU treatment, respectively, P = NS, and 0.64 +/- 0.09 vs. 0.66 +/- 0.10 mm at baseline and after 6 months of PLA treatment, respectively, P = NS). Also, brachial artery DC was not altered by FLU (6.4 +/- 1.0 vs. 5.8 +/- 0.6 x 10-3/kPa, P = NS) or PLA treatment (5.8 +/- 0.6 vs. 6.8 +/- 0.8 x 10-3/kPa, P = NS). CONCLUSIONS: In hypercholesterolemic NTX, the HMG-CoA reductase inhibitor FLU significantly improves brachial artery FMD as a measure of endothelial function after six months of treatment. In contrast, FLU does not have a beneficial effect on brachial artery DC.     

The thiazolidinedione rosiglitazone (BRL-49653) lowers blood pressure and protects against impairment of endothelial function in Zucker fatty rats.

Human obesity is associated with insulin resistance, hyperinsulinemia, and a predisposition to hypertension and vascular disease, the origin of which may lie in impairment of endothelial function. We tested the effects of the thiazolidinedione rosiglitazone on blood pressure and endothelial function in insulin-resistant fatty Zucker rats, which display hypertension and abnormal endothelial cell function. We studied fatty Zucker rats given rosiglitazone maleate (50 micromol/kg diet; n = 8) for 9-12 weeks (treated fatty), untreated fatty rats (n = 8), and lean rats (n = 8) given diet alone. At the end of the study, systolic blood pressure was significantly higher in untreated fatty (147 +/- 5 mmHg) than in lean rats (125 +/- 2 mmHg; P < 0.05), but rosiglitazone treatment prevented the development of hypertension in fatty rats (123 +/- 1 mmHg). Fasting hyperinsulinemia in untreated fatty rats (28.7 +/- 6.0 ng/ml) was significantly lowered by rosiglitazone (7.0 +/- 1.4 ng/ml; P < 0.05 vs. untreated fatty), but remained significantly higher than the levels seen in lean rats (1.5 +/- 0.4 ng/ml; P < 0.01). Mesenteric arteries were studied in a myograph. Maximal acetylcholine chloride (1.1 micromol/l)-induced relaxation of norepinephrine hydrochloride (NE)-induced constriction was impaired in untreated fatty (62.4 +/- 3.4%) vs. lean (74.3 +/- 3.5%; P = 0.01) rats; this defect was partially prevented by rosiglitazone (66.5 +/- 3.0%; P = 0.01 vs. untreated fatty). Insulin (50 mU/l) significantly attenuated the contractile response to NE in lean rats (14.7 +/- 3.3%; P = 0.02); this vasodilator effect of insulin was absent in untreated fatty rats at concentrations of 50-5,000 mU/l, but was partially restored by rosiglitazone (9.7 +/- 2.5% attenuation; P = 0.02 vs. no insulin). Thus, rosiglitazone prevents the development of hypertension and partially protects against impaired endothelial function associated with insulin resistance. These latter effects may contribute to the drug's antihypertensive properties.     

Insulin secretion and sensitivity after simultaneous pancreas-kidney transplantation estimated by continuous infusion of glucose with model assessment

BACKGROUND: Monitoring of insulin secretion and sensitivity after pancreas transplantation remains a practical problem. METHODS: We introduced the simple structural model, continuous infusion of glucose with model assessment (CIGMA), to obtain insulin secretion and insulin sensitivity estimations after 35 successful simultaneous pancreas-kidney transplantations. Eighteen non-diabetic kidney transplant recipients were used as control group. RESULTS: The baseline characteristics were equal between the two groups except for higher fasting insulin levels in the pancreas transplant group. After the 1-hr CIGMA glucose load, the pancreas transplant group reached a mean +/- SD blood glucose of 8.2+/-1.7 mmol/L compared with 7.3+/-1.0 mmol/L in the control group (P = 0.05). Concurrent stimulated insulin and C-peptide levels were 48+/-28 mU/L and 2.3+/-0.9 nmol/L in the pancreas transplant group compared with 36+/-21 mU/L and 2.9+/-1.1 nmol/L in the control group (P = 0.1 and P = 0.03, respectively). Both the CIGMA estimation for secretion as well as the CIGMA estimation for sensitivity were lower in pancreas transplant group (P = 0.003 and P = 0.01, respectively). Mean +/- SE coefficients of variation for the model estimations were 15+/-4% for secretion and 17+/-6% for sensitivity. CONCLUSIONS: We conclude that CIGMA can be used clinically to evaluate carbohydrate metabolism in pancreas-kidney transplant recipients. These patients have a reduction in insulin secretory capacity and evidence of more insulin resistance than non-diabetic kidney transplant recipients.     

Failure of a midnocturnal insulin infusion to suppress the increased insulin need for breakfast in insulin-dependent diabetic patients

Insulin requirements for meals were measured in eight insulin-dependent diabetic patients, using a closed-loop insulin infusion system. Patients required more insulin for breakfast than for an isocaloric lunch (35.7 +/- 5.5 mU/kcal/3 h versus 26.9 +/- 5.1 mU/kcal/3 h, P less than 0.02) or an isocaloric supper (35.7 +/- 5.5 mU/kcal/3 h versus 26.6 +/- 6.6 mU/kcal/3 h, P = 0.05). To determine whether this insulin resistance at breakfast might be due to low basal insulin levels overnight, the insulin needs for breakfast were compared after an overnight fast (day 1) and after a midnocturnal (0200 h-0500 h) insulin infusion (day 2). Breakfast insulin requirements were similar on both days (35.7 +/- 5.5 mU/kcal/3 h versus 37.7 +/- 5.1 mU/kcal/3 h, P = NS). Whereas nonobese diabetic patients required approximately 60% more insulin for breakfast than for other meals, obese diabetic patients in this study did not demonstrate insulin resistance at breakfast. These findings provide a basis for the common clinical practice of allocating more insulin for breakfast than for other meals. The absence of an increased insulin need at breakfast in our obese patients cautions against a similar algorithm for obese diabetic patients. We postulate that growth hormone may be a cause for morning insulin resistance.     

Rosiglitazone improves downstream insulin receptor signaling in type 2 diabetic patients

Thiazolidinediones (TZDs) improve glycemic control and insulin sensitivity in patients with type 2 diabetes. To determine whether the TZD-induced improvement in glycemic control is associated with enhanced insulin receptor signaling in skeletal muscle, 20 type 2 diabetic patients received a 75-g oral glucose tolerance test (OGTT) and euglycemic insulin (80 mU x m(-2) x min(-1)) clamp with [3-(3)H]glucose/indirect calorimetry/vastus lateralis muscle biopsies before and after 16 weeks of rosiglitazone treatment. Six age-matched nondiabetic subjects served as control subjects. RSG improved fasting plasma glucose (185 +/- 8 to 139 +/- 5 mg/dl), mean plasma glucose during the OGTT (290 +/- 9 to 225 +/- 6 mg/dl), HbA(1c) (8.5 +/- 0.3 to 7.1 +/- 0.3%), insulin-mediated total-body glucose disposal (TGD) (6.9 +/- 0.7 to 9.2 +/- 0.8 mg x kg(-1) fat-free mass x min(-1)) (all P < 0.001), and decreased fasting plasma free fatty acid (FFA) (789 +/- 59 to 656 +/- 50 micro Eq/l) and mean FFA during the OGTT (644 +/- 41 to 471 +/- 35 micro Eq/l) (both P < 0.01). Before RSG treatment, insulin infusion did not significantly increase insulin receptor tyrosine phosphorylation (0.95 +/- 0.10 to 1.08 +/- 0.13 density units; NS) but had a small stimulatory effect on insulin receptor substrate (IRS)-1 tyrosine phosphorylation (1.05 +/- 0.10 to 1.21 +/- 0.12 density units; P < 0.01) and the association of p85 with IRS-1 (0.94 +/- 0.06 to 1.08 +/- 0.06 activity units; P < 0.01). RSG therapy had no effect on basal or insulin-stimulated insulin receptor tyrosine phosphorylation but increased insulin stimulation of IRS-1 tyrosine phosphorylation (1.13 +/- 0.11 to 1.56 +/- 0.17 density units; P < 0.01 vs. prerosiglitazone) and p85 association with IRS-1 (1.00 +/- 0.06 to 1.27 +/- 0.07 activity units; P < 0.05 vs. prerosiglitazone). In control and type 2 diabetic subjects, TGD/nonoxidative glucose disposal correlated positively with the insulin-stimulated increments in IRS-1 tyrosine phosphorylation (r = 0.52/r = 0.57, P < 0.01) and inversely with the plasma FFA concentration during the insulin clamp (r = -0.55/r = -0.53, P < 0.01). However, no significant association between plasma FFA concentrations during the insulin clamp and the increment in either IRS-1 tyrosine phosphorylation or the association of p85 with IRS-1 was observed. In conclusion, in type 2 diabetic patients, rosiglitazone treatment enhances downstream insulin receptor signaling in muscle and decreases plasma FFA concentration while improving glycemic control.     

不同麻醉和镇痛方法对胸科手术胰岛素抵抗及相关因素影响的研究

目的 研究不同麻醉和术后镇痛方式对胸科手术后胰岛素抵抗(insulin resistance,IR)的影响及相关因素.方法 60例胸科手术患者按随机数字表法随机分为两组:对照组(GA组,n=30),实验组(GEA组,n=30).GA组行全麻+术后静脉镇痛;GEA组行硬膜外麻醉复合全麻+术后硬膜外镇痛.分别于麻醉前、术毕...     

Relationships among natriuresis, atrial natriuretic peptide and insulin in insulin-dependent diabetes.

Insulin-dependent diabetic patients have a large exchangeable body sodium pool, secondary to sodium retention. The pathogenesis of impaired natriuresis in insulin dependent diabetes remains to be elucidated. The present study examines the role of hyperinsulinemia, impaired atrial natriuretic release, and resistance to atrial natriuretic peptide action in determining sodium retention in normotensive and hypertensive insulin-dependent diabetic patients. Eight insulin-dependent diabetic patients had significantly higher daily sodium excretion rate (147 +/- 16 mmol/day; mean +/- SE) during conventional insulin treatment (daily plasma glucose: 11.6 +/- 1.2 mmol/liter; daily plasma insulin: 27 +/- 3 microU/ml) than during intensified insulin treatment (daily sodium excretion rate: 91 +/- 12, P less than 0.01; daily plasma glucose: 6.8 +/- 0.7, P less than 0.01; daily plasma insulin: 44 +/- 4, P less than 0.01). Daily sodium excretion rate was also significantly lower (107 +/- 13, P less than 0.01) in the same diabetic patients during intensified insulin treatment along with hyperglycemic clamp (daily plasma glucose: 12.8 +/- 0.3, NS; plasma insulin 48 +/- 4, P less than 0.01). Seven control subjects had lower extracellular liquid volume than eight insulin-dependent diabetic patients (11.0 +/- 0.8 l/1.73 m2 vs. 14.8 +/- 0.9, P less than 0.05) and also had baseline plasma atrial natriuretic peptide concentrations (18 +/- 5 pg/ml vs. 37 +/- 4, P less than 0.05). Atrial natriuretic peptide response to saline challenge was blunted in insulin-dependent diabetic patients when saline was administered on the basis of body surface area (90 mmol/1.73 m2.90 min) but not when administered on the basis of extracellular liquid volume (ECV) (8.2 mmol/liter ECV.90 min).(ABSTRACT TRUNCATED AT 250 WORDS)     

Statin therapy improves brachial artery endothelial function in nephrotic syndrome

BACKGROUND: Patients with nephrotic syndrome have impaired endothelial function probably related to dyslipidemia. This study evaluated the effects of statin therapy on dyslipidemia and endothelial function in patients with nephrotic syndrome. METHODS: A sequential, open-label study of the effects of statins on endothelial dysfunction in 10 nephrotic patients treated with an angiotensin-converting enzyme (ACE) inhibitor or angiotensin II (Ang II) receptor antagonist. Endothelial function was assessed at baseline, after 12 weeks of treatment with statins, and after an 8-week washout. Brachial artery endothelial function was measured as post-ischemic flow-mediated dilation (FMD) using ultrasonography. Endothelium-independent, glyceryl trinitrate-mediated vasodilation (GTNMD) also was measured. RESULTS: Serum lipids were significantly lower following statin: total cholesterol mean 8.2 +/- 0.4 (standard error) mmol/L versus 5.2 +/- 0.3 mmol/L, triglycerides 2.6 +/- 0.4 mmol/L versus 1.6 +/- 0.2 mmol/L, non-HDL-cholesterol 6.7 +/- 0.4 mmol/L versus 3.7 +/- 0.2 mmol/L (all P < 0.001). There was a trend to an increase in serum albumin (31.0 +/- 1.3 g/L vs. 33.8 +/- 1.5 g/L; P = 0.078) and FMD improved significantly following treatment (3.7 +/- 1.1% vs. 7.0 +/- 0.8%, P < 0.01). After washout, FMD deteriorated significantly to 3.5 +/- 1.4% (P < 0.05) versus week 12 FMD. GTNMD was unchanged. In multivariate regression, reduction in non-high-density lipoprotein (HDL)-cholesterol (beta - 0.736, P = 0.027) and increase in serum albumin (beta 0.723, P = 0.028), but not the on-treatment level of non-HDL-cholesterol, were significant independent predictors of improvement in FMD after adjusting for change in resting brachial artery diameter. Changes in serum lipoprotein and albumin concentrations off treatment were not associated with deterioration in FMD. CONCLUSION: Statin therapy significantly improves dyslipidemia and brachial artery endothelial function in patients with nephrotic syndrome. Improvement in brachial artery endothelial function may be in part related to a non-lipid effect of statins. The findings also suggest a role for dyslipidemia in endothelial dysfunction and the risk for cardiovascular disease in nephrotic syndrome.     

Obesity blunts insulin-mediated microvascular recruitment in human forearm muscle

We have previously shown that skeletal muscle capillaries are rapidly recruited by physiological doses of insulin in both humans and animals. This facilitates glucose and insulin delivery to muscle, thus augmenting glucose uptake. In obese rats, both insulin-mediated microvascular recruitment and glucose uptake are diminished; however, this action of insulin has not been studied in obese humans. Here we used contrast ultrasound to measure microvascular blood volume (MBV) (an index of microvascular recruitment) in the forearm flexor muscles of lean and obese adults before and after a 120-min euglycemic-hyperinsulinemic (1 mU . min(-1) . kg(-1)) clamp. We also measured brachial artery flow, fasting lipid profile, and anthropomorphic variables. Fasting plasma glucose (5.4 +/- 0.1 vs. 5.1 +/- 0.1 mmol/l, P = 0.05), insulin (79 +/- 11 vs. 38 +/- 6 pmol/l, P = 0.003), and percent body fat (44 +/- 2 vs. 25 +/- 2%, P = 0.001) were higher in the obese than the lean adults. After 2 h of insulin infusion, whole-body glucose infusion rate was significantly lower in the obese versus lean group (19.3 +/- 3.2 and 37.4 +/- 2.6 mumol . min(-1) . kg(-1) respectively, P < 0.001). Compared with baseline, insulin increased MBV in the lean (18.7 +/- 3.3 to 25.0 +/- 4.1, P = 0.019) but not in the obese group (20.4 +/- 3.6 to 18.8 +/- 3.8, NS). Insulin increased brachial artery diameter and flow in the lean but not in the obese group. We observed a significant, negative correlation between DeltaMBV and BMI (R = -0.482, P = 0.027) in response to insulin. In conclusion, obesity eliminated the insulin-stimulated muscle microvascular recruitment and increased brachial artery blood flow seen in lean individuals.     

Endothelial dysfunction relates to folate status in children and adolescents with type 1 diabetes

Endothelial dysfunction occurs early in the development of vascular disease in diabetes. Total plasma homocyst(e)ine (tHcy) is associated with endothelial dysfunction. We therefore aimed to assess endothelial function in children with type 1 diabetes in relation to tHcy and its determinants. Endothelial function was assessed in 36 children with type 1 diabetes aged 13.7 +/- 2.2 years and 20 age- and sex-matched control subjects using ultrasound assessment of flow-mediated dilatation (FMD) and glyceryl trinitrate (GTN)-dependent brachial artery responses. von Willebrand factor (vWF) and thrombomodulin, markers of endothelial activation, were measured in 64 children with type 1 diabetes and 52 control subjects. Fasting glucose, tHcy, serum and red cell folate, vitamin B12, HbA(1c), creatinine, and lipids were also measured. FMD (5.2 +/- 4.7 vs. 9.1 +/- 4.0%, P = 0.002) and the ratio of FMD:GTN-induced dilatation (0.22 +/- 0.39 vs. 0.41 +/- 0.29%, P = 0.008) were significantly lower in diabetic subjects, indicating endothelial dysfunction. In diabetic subjects, red cell folate correlated independently with FMD (beta = 0.42, P = 0.028) and the ratio of FMD:GTN-induced dilatation (beta = 0.59, P < 0.001). Resting vessel diameter correlated independently with tHcy (beta = -0.51, P < 0.001) and height (beta = 0.65, P < 0.001). vWF correlated independently with HbA(1c) (beta = 0.38, P = 0.003), and thrombomodulin correlated independently with red cell folate (beta = -0.38, P = 0.005), tHcy (beta = -0.37, P = 0.004), diastolic blood pressure (beta = -0.28, P = 0.025), and creatinine clearance (beta = 0.26, P = 0.033). Children with type 1 diabetes have early endothelial dysfunction. Better folate status is associated with better endothelial function, as measured by higher FMD, higher FMD:GTN ratio, and lower thrombomodulin. Folate may therefore protect against endothelial dysfunction in children with diabetes.     

Intramyocellular lipid is associated with resistance to in vivo insulin actions on glucose uptake, antilipolysis, and early insulin signaling pathways in human skeletal muscle

To examine whether and how intramyocellular lipid (IMCL) content contributes to interindividual variation in insulin action, we studied 20 healthy men with no family history of type 2 diabetes. IMCL was measured as the resonance of intramyocellular CH(2) protons in lipids/resonance of CH(3) protons of total creatine (IMCL/Cr(T)), using proton magnetic resonance spectroscopy in vastus lateralis muscle. Whole-body insulin sensitivity was measured using a 120-min euglycemic-hyperinsulinemic (insulin infusion rate 40 mU/m(2). min) clamp. Muscle biopsies of the vastus lateralis muscle were taken before and 30 min after initiation of the insulin infusion to assess insulin signaling. The subjects were divided into groups with high IMCL (HiIMCL; 9.5 +/- 0.9 IMCL/Cr(T), n = 10) and low IMCL (LoIMCL; 3.0 +/- 0.5 IMCL/Cr(T), n = 10), the cut point being median IMCL (6.1 IMCL/Cr(T)). The groups were comparable with respect to age (43 +/- 3 vs. 40 +/- 3 years, NS, HiIMCL versus LoIMCL), BMI (26 +/- 1 vs. 26 +/- 1 kg/m(2), NS), and maximal oxygen consumption (33 +/- 2 vs. 36 +/- 3 ml. kg(-1). min(-1), NS). Whole-body insulin-stimulated glucose uptake was lower in the HiIMCL group (3.0 +/- 0.4 mg. kg(-1). min(-1)) than the LoIMCL group (5.1 +/- 0.5 mg. kg(-1). min(-1), P < 0.05). Serum free fatty acid concentrations were comparable basally, but during hyperinsulinemia, they were 35% higher in the HiIMCL group than the LoIMCL group (P < 0.01). Study of insulin signaling indicated that insulin-induced tyrosine phosphorylation of the insulin receptor (IR) was blunted in HiIMCL compared with LoIMCL (57 vs. 142% above basal, P < 0.05), while protein expression of the IR was unaltered. IR substrate-1-associated phosphatidylinositol (PI) 3-kinase activation by insulin was also lower in the HiIMCL group than in the LoIMCL group (49 +/- 23 vs. 84 +/- 27% above basal, P < 0.05 between HiIMCL and LoIMCL). In conclusion, IMCL accumulation is associated with whole-body insulin resistance and with defective insulin signaling in skeletal muscle independent of body weight and physical fitness.     

Insulin therapy improves insulin-stimulated endothelial function in patients with type 2 diabetes and ischemic heart disease.

Blunted insulin-stimulated endothelial function may be a mechanism for the development of atherothrombotic disease in type 2 diabetes, but it is unknown whether hypoglycemic drug therapy can modulate this abnormality. We studied patients with type 2 diabetes and stable ischemic heart disease (n = 28) and lean, healthy control subjects (n = 31). Forearm blood flow was measured by venous occlusion plethysmography during dose-response studies of acetylcholine (ACh) and sodium nitroprusside (SNP) infused into the brachial artery. In the patients and 10 healthy control subjects, ACh was repeated after intrabrachial infusion of insulin. Patients were restudied after 2 months of insulin therapy with four daily subcutaneous injections (treatment group, n = 19) or without hypoglycemic drug therapy (time control group, n = 9). Insulin infusion raised venous serum insulin in the forearm to high physiological levels (133 +/- 14.6 mU/l in patients) with a minor increase in systemic venous serum insulin. This increased the ACh response by 149 +/- 47, 110 +/- 33, 100 +/- 45, and 106 +/- 44% during the four ACh doses in healthy control subjects (P < 0.0001) but had no effect in patients (P = 0.3). After 2 months, HbA(1c) in the treatment group had decreased from 10.0 +/- 0.4 to 7.5 +/- 0.2%. Although neither the ACh response (P = 0.09) nor the SNP response (P = 0.4) had changed significantly, insulin stimulation had a significant effect, as the ACh response increased by 58 +/- 25, 84 +/- 66, 120 +/- 93, and 69 +/- 36% (P = 0.0002). In the time control group, insulin stimulation remained without effect after 8 weeks (P = 0.7). In conclusion, insulin therapy partly restores insulin-stimulated endothelial function in patients with type 2 diabetes and ischemic heart disease.     

Muscle glucose uptake is effectively activated by ischemia in type 2 diabetic subjects

It has previously been shown that Wortmannin, a phosphatidylinositol 3-kinase inhibitor, inhibits glucose transport activated by insulin but not by ischemia, suggesting the importance of an activating mechanism that bypasses the insulin signal. To evaluate the relevance of this insulin-independent pathway in insulin-resistant subjects, the ability of ischemia to stimulate glucose uptake was investigated in 9 patients with type 2 diabetes and in 9 healthy control subjects (fasting glucose level 9.4 +/- 0.8 vs. 5.1 +/- 0.1 mmol/l, P < 0.001, in type 2 diabetic patients and control subjects, respectively; fasting insulin level insulin 8.1 +/- 2.6 vs. 4.5 +/-0.7 mU/l, P < 0.05, respectively) matched for sex, age, and BMI. Arterial plasma and interstitial concentrations of glucose and lactate (measured by subcutaneous and muscle microdialysis) were recorded in the forearm before, during, and after ischemia induced locally for 20 min. During ischemia, the muscle interstitial glucose concentration decreased significantly from 7.7 +/- 0.6 to 5.4 +/- 0.4 mmol/l (P < 0.01) and from 4.4 +/- 0.3 to 3.6 +/- 0.3 mmol/l (P < 0.05) in type 2 diabetic patients and control subjects, respectively. The arterial-interstitial (A-I) glucose concentration difference was 1.7 +/- 0.6 and 0.7 +/- 0.3 mmol/ at basal, and it increased significantly to 3.5 +/- 0.7 (P < 0.01) and 1.4 +/-0.3 mmol/l (P < 0.05) during ischemia in each group, respectively. Interstitial lactate increased significantly during ischemia from 0.8 +/- 0.1 to 1.1 +/- 0.1 mmol/l (P < 0.05) and from 0.5 +/- 0.1 to 0.9 +/- 0.2 mmol/l (P < 0.05), respectively. The A-I glucose concentration difference was abolished immediately postischemia and regained after approximately 15 min, whereas high interstitial lactate levels remained elevated throughout the study. Subcutaneous interstitial glucose concentrations remained unchanged during ischemia and postischemia in both groups, whereas the interstitial lactate concentration in adipose tissue increased during ischemia from 1.4 +/- 0.2 to 2.0 +/- 0.2 mmol/l (P < 0.05) and from 1.1 +/- 0.1 to 1.8 +/- 0.3 mmol/l (P < 0.05) in type 2 diabetic patients and control subjects, respectively. Plasma glucose and lactate levels were unchanged in both groups during the study period. The results show that in muscle, but not in adipose tissue, glucose uptake is efficiently activated by ischemia in insulin-resistant type 2 diabetic subjects, suggesting the activation of a putative alternative pathway to the insulin signal in muscle cells.     

C-Reactive protein in adults with chronic spinal cord injury: increased chronic inflammation in tetraplegia vs paraplegia

Study design:Cross-sectional.Objectives:In community-dwelling adults with chronic spinal cord injury (SCI), to (1) quantify C-reactive protein (CRP), a marker of inflammation and cardiovascular disease (CVD) risk; (2) determine factors associated with CRP.Setting:Hamilton, Ontario, Canada.Methods:We examined CVD risk factors in 69 participants. Measurements included length, weight, waist circumference, blood pressure, percent fat mass (bioelectrical impedance analysis) and fasting blood parameters (high-sensitivity CRP, lipids, insulin, glucose, insulin resistance by homeostasis model assessment (HOMA)).Results:Mean CRP of the group was 3.37+/-2.86 mg-l(-1), consistent with the American Heart Association (AHA) definition of high risk of CVD. CRP was 74% higher in persons with tetraplegia (4.31+/-2.97) than those with paraplegia (2.47+/-2.47 mg l(-1), P=0.002), consistent with high CVD risk. Participants with high CRP (3.1-9.9 mg l(-1)) had greater waist circumference, BMI, percent fat mass and HOMA values than those with lower CRP (相似文献   

Endothelial dysfunction in type-2 diabetics with early diabetic nephropathy is associated with low circulating adiponectin.

BACKGROUND: Type-2 diabetes and diabetic kidney disease have additive effects on cardiovascular risk. Furthermore, the degree of proteinuria is an independent predictor of mortality in this patient group. We hypothesized that altered kidney clearance and/or metabolism of vasoactive peptides occurring during proteinuria could link early diabetic nephropathy to cardio vascular disease (CVD). METHODS: We performed a cross-sectional study of 85 incident patients (51 +/- 5 years, 49 males) with type-2 diabetes and 38 age- and sex-matched controls. We further divided patients by the presence of minor (<500 mg/day; n = 40) or severe (>/=500 mg/day; n = 45) proteinuria. Clinical and anthropometric data, along with ultrasonographic flow-mediated dilatation (FMD) of the brachial artery and carotid intima-media thicknesses (CIMT), were recorded in each group. Circulating NAMPT/visfatin, adiponectin (normalized to BMI), AHSG/fetuin-A and hsCRP levels were also measured using commercial ELISA. RESULTS: Plasma NAMPT/visfatin, CIMT, HOMA index and hsCRP levels were all significantly higher in diabetics than in control subjects, and all but CIMT correlated with proteinuria (rho = 0.46; P < 0.001, rho = 0.54; P > 0.05, rho = 0.32; P = 0.003, rho = 0.76; P < 0.001, respectively). FMD, adiponectin and AHSG/fetuin-A levels were significantly lower, and negatively correlated with proteinuria (rho = -0.54; P < 0.001, rho = -0.56; P < 0.001, rho = -0.48; P < 0.001, respectively). In a multivariate regression analysis, the degrees of proteinuria (r(2) = -0.32, P = 0.04) and plasma levels of NAMPT/visfatin (r(2) = -0.33, P = 0.006) were independently related to FMD. CONCLUSIONS: The present study suggests that the presence of proteinuria, regardless of the degree of renal function impairment, is an important predictor of endothelial dysfunction in early diabetic nephropathy and that it is associated with altered circulating levels of NAMPT/visfatin and adiponectin.     

Assessment of hepatic insulin action in obese type 2 diabetic patients

Defects in hepatic insulin action in type 2 diabetes and its possible underlying mechanisms were assessed in euglycemic-hyperinsulinemic clamp studies, using improved tracer methods (constant specific activity technique). Ten obese diabetic patients (age 54 years, BMI 29 +/- 0.5 kg/m(2)) and ten matched control subjects were studied at baseline (after an overnight fast) and during insulin infusions of 20- and 40-mU. m(-2). min(-1). In the diabetic patients, plasma glucose levels were normalized overnight before the studies by low-dose insulin infusion. Hepatic sinusoidal insulin levels were estimated, and plasma levels of free fatty acids (FFAs) and glucagon were determined to assess the direct and indirect effects of insulin on hepatic glucose production (HGP) in type 2 diabetes. Baseline rates of HGP (86 +/- 3 vs. 76 +/- 3 mg. m(-2). min(-1), P < 0.05) were slightly elevated in the diabetic patients compared with control subjects, despite much higher hepatic sinusoidal insulin levels (26 +/- 3 vs. 12 +/- 2 mU/l, P < 0.001). Consequently, a marked defect in the direct (hepatic) effect of insulin on HGP appeared to be present at low insulin levels. However, in response to a small increase in baseline hepatic sinusoidal insulin levels of 11 mU/l (26 +/- 3 to 37 +/- 3 mU/l, P < 0.05) in the 20-mU clamp, a marked suppression of HGP was observed in the diabetic patients (86 +/- 3 to 32 +/- 5 mg. m(-2). min(-1), P < 0.001), despite only minimal changes in FFAs (0.33 +/- 0.05 to 0.25 +/- 0.05 mmol/l, NS) and glucagon (14 +/- 1 to 11 +/- 2 pmol/l, P < 0.05) levels, suggesting that the impairment in the direct effect of insulin can be overcome by a small increase in insulin levels. Compared with control subjects, suppression of HGP in the diabetic patients was slightly impaired in the 20-mU clamp (32 +/- 5 vs. 22 +/- 4 mg. m(-2). min(-1), P < 0.05) but not in the 40-mU clamp (25 +/- 2 vs. 21 +/- 3 mg. m(-2). min(-1), NS). In the 20-mU clamp, hepatic sinusoidal insulin levels in the diabetic patients were comparable with control subjects (37 +/- 3 vs. 36 +/- 3 mU/l, NS), whereas both FFA and glucagon levels were higher (i.e., less suppressed) and correlated with the rates of HGP (R = 0.71, P < 0.02; and R = 0.69, P < 0.05, respectively). Thus, at this insulin level impaired indirect (extrahepatic) effects of insulin seemed to prevail. In conclusion, hepatic insulin resistance is present in obese type 2 diabetic patients but is of quantitative significance only at low physiological insulin levels. Defects in both the direct and the indirect effects of insulin on HGP appear to contribute to this resistance.     

Nonesterified fatty acids and hepatic glucose metabolism in the conscious dog

We used tracer and arteriovenous difference techniques in conscious dogs to determine the effect of nonesterified fatty acids (NEFAs) on net hepatic glucose uptake (NHGU). The protocol included equilibration ([3-(3)H]glucose), basal, and two experimental periods (-120 to -30, -30 to 0, 0-120 [period 1], and 120-240 min [period 2], respectively). During periods 1 and 2, somatostatin, basal intraportal insulin and glucagon, portal glucose (21.3 micromol.kg(-1).min(-1)), peripheral glucose (to double the hepatic glucose load), and peripheral nicotinic acid (1.5 mg.kg(-1).min(-1)) were infused. During period 2, saline (nicotinic acid [NA], n = 7), lipid emulsion (NA plus lipid emulsion [NAL], n = 8), or glycerol (NA plus glycerol [NAG], n = 3) was infused peripherally. During period 2, the NA and NAL groups differed (P < 0.05) in rates of NHGU (10.5 +/- 2.08 and 4.7 +/- 1.9 micromol.g(-1).min(-1)), respectively, endogenous glucose R(a) (2.3 +/- 1.4 and 10.6 +/- 1.0 micromol.kg(-1).min(-1)), net hepatic NEFA uptakes (0.1 +/- 0.1 and 1.8 +/- 0.2 micromol.kg(-1).min(-1)), net hepatic beta-hydroxybutyrate output (0.1 +/- 0.0 and 0.4 +/- 0.1 micromol.kg(-1).min(-1)), and net hepatic lactate output (6.5 +/- 1.7 vs. -2.3 +/- 1.2 micromol.kg(-1).min(-1)). Hepatic glucose uptake and release were 2.6 micro mol. kg(-1). min(-1) less and 3.5 micro mol. kg(-1). min(-1) greater, respectively, in the NAL than NA group (NS). The NAG group did not differ significantly from the NA group in any of the parameters listed above. In the presence of hyperglycemia and relative insulin deficiency, elevated NEFAs reduce NHGU by stimulating hepatic glucose release and suppressing hepatic glucose uptake.