Oxidized-LDL levels are changed during short-term serum glucose variations and lowered with statin treatment in early Type 2 diabetes: a study of endothelial function and microalbuminuria.

AIMS: To investigate the role of HMG-CoA reductase inhibitor (statin) treatment during serum glucose variations on plasma oxidized LDL (ox-LDL) levels in obese patients with early Type 2 diabetes mellitus (T2D) and its relationship to endothelial biomarkers. METHODS: In a double-blind, randomized crossover study, 15 obese diet-treated T2D patients received cerivastatin (0.4 mg/day) or placebo for 3 months. Circulating ox-LDL levels were measured fasting and during a euglycaemic-hyperinsulinaemic clamp (approximately 5.5 mmol/l; EHC) and a hyperglycemic clamp (approximately 20 mmol/l; HC). An endothelium-dependent flow-mediated dilation (FMD) study was carried out and urinary albumin excretion (UAE) was measured at rest and during EHC. S-ICAM, s-VCAM and basal prothrombotic factors were also measured. RESULTS: During cerivastatin treatment, basal circulating ox-LDL levels decreased by 48% (P<0.001) compared with placebo. Serum ox-LDL levels decreased during EHC and remained unchanged during HC compared with the fasting state; with cerivastatin treatment these levels were lower compared with placebo both in the fasting state and during the clamp studies. FMD was higher with cerivastatin than with placebo (P<0.001) and the increments in FMD correlated with decrements in serum ox-LDL levels (r=0.78, P=0.001). Microalbuminuria increased during EHC but this was blunted during cerivastatin therapy compared with placebo (P<0.05). Basal sICAM-1 and sVCAM-1 levels decreased (P<0.01 and P<0.05, respectively). CONCLUSIONS: In early obese Type 2 diabetic patients, serum ox-LDL levels are influenced by short-term serum glucose variations and lowered with cerivastatin therapy. During cerivastatin treatment, improved flow-mediated endothelium-dependent dilation was associated with decrements in circulating ox-LDL levels and the hyperinsulinaemia-induced urinary albumin excretion was blunted.     

Plasma homocysteine and cognitive function in elderly patients with diabetes mellitus

Background: The purpose of the present paper was to investigate a possible contribution of plasma homocysteine to cognitive impairment. To this end the relationship between plasma homocysteine levels and cognitive performance test results were investigated in elderly patients with diabetes. Methods: A total of 144 elderly patients (39 men and 105 women) with diabetes mellitus, who were free of clinical stroke, were studied. Plasma levels of homocysteine, folate, vitamin B12, vitamin B6, and the C677T polymorphism of methylene tetrahydrofolate reductase were determined. Cognitive function was assessed with the Wechsler Adult Intelligence Scale, Revised (digit symbol substitution, backward digit span, similarities, picture arrangement), Stroop test, Benton Visual Retention Test, and Mini‐Mental State Examination (MMSE). Results: In elderly women with diabetes, elevated homocysteine levels in the plasma were significantly associated with impairment of cognitive performance assessed with the MMSE, digit symbol substitution test, similarities, Stroop test, and Benton visual retention test, but not the backward digit span test. Multiple logistic regression analyses revealed that the associations between the log‐transformed plasma homocysteine level and low scores of the MMSE and digit symbol substitution test remained significant after adjustment for age, education, hemoglobin (Hb)A1c, systolic blood pressures, insulin treatment, serum levels of folate, vitamin B12, and vitamin B6, and the presence of asymptomatic cerebral infarction on brain magnetic resonance images. Conclusions: Elevated plasma homocysteine level was independently associated with cognitive impairment in elderly diabetic women. Because the cause of the association between homocysteine and cognitive impairment remains unclear, future intervention studies are necessary to examine whether reducing plasma homocysteine levels prevents cognitive decline in elderly patients with diabetes mellitus.     

Effects of carvedilol versus metoprolol on endothelial function and oxidative stress in patients with type 2 diabetes mellitus

BACKGROUND: Data suggest that carvedilol possesses antioxidant properties that might provide vascular protection. We sought to compare the effects of carvedilol and metoprolol tartrate on endothelial function and oxidative stress in a head-to-head trial. METHODS: Thirty-four patients with type 2 diabetes mellitus (T2DM) and hypertension were randomized to receive either carvedilol (n = 16) or metoprolol (n = 18) in addition to their current antihypertensive medications for 5 months. The following variables were measured pre- and posttreatment: blood pressure, fasting glucose and insulin, insulin resistance by homeostasis-model assessment, hemoglobin A1c, lipids, C-reactive protein (CRP), 8-isoprostane, asymmetric dimethylarginine, oxidized LDL cholesterol, ultrasound assessment of brachial-artery flow-mediated dilation (FMD), nitroglycerin-induced endothelium-independent dilation (EID), brachial and carotid artery distension, distensibility and compliance, and carotid artery intima-media thickness (cIMT). RESULTS: Both carvedilol and metoprolol treatment resulted in significant and similar decreases in systolic (P < .05) and diastolic (P < .0001) blood pressure. Compared with metoprolol, carvedilol significantly improved FMD (P < .001). No differences between groups were noted for any of the glycemic or lipid variables except for HDL cholesterol, which significantly decreased (P < .05) in the metoprolol group compared with the carvedilol group. No differences were observed between groups for CRP, the markers of oxidative stress, EID, arterial stiffness, or cIMT. CONCLUSIONS: Compared with metoprolol, carvedilol significantly improves endothelial function in patients with T2DM. Changes in glycemic control and oxidative stress do not seem to explain the observed improvements in FMD, which suggests that other mechanisms may be involved.     

Effects of high-dose vitamin E supplementation on oxidative stress and microalbuminuria in young adult patients with childhood onset type 1 diabetes mellitus

INTRODUCTION: The aim of this study was to evaluate the effects of high-dose vitamin E supplementation (1200 mg/day) on reducing both microalbuminuria (MA) and oxidative stress in patients with type 1 diabetes mellitus (T1DM) and persistent MA. METHODS: We performed a 12-month, randomized, placebo-controlled, double-blind cross-over trial in ten Caucasian young adults (7m/3f; mean age 18.87 +/- 2.91 years) with T1DM and persistent MA.At baseline and at end of the treatment period, determination of albumin excretion rate (AER) and HbA(1c) and evaluation of the oxidant/antioxidant status were performed. RESULTS: At the beginning of the study, AER and HbA(1c) were not significantly different between the vitamin E and placebo group. No differences in terms of oxidant and antioxidant status were found between the two groups. This was associated with no significantly different urinary VEGF and TGF-beta levels. After 6 months, no significant differences in AER were observed between the two groups (p = 0.59). However, plasma and LDL-vitamin E content were significantly higher in the vitamin E group compared to the placebo group (p = 0.0001 and p = 0.004, respectively). This was associated with a significantly longer lag phase (p = 0.002) and lower MDA (p = 0.049). However, no statistically significant differences were detected in terms of VEGF and TGF-beta urinary levels. CONCLUSION: These data demonstrate that high-dose vitamin E supplementation reduces markers of oxidative stress and improves antioxidant defence in young patients with T1DM. However, although it positively affects the oxidant/antioxidant status, vitamin E supplementation does not reduce AER in patients with T1DM and persistent MA.     

Homocysteinylation of low-density lipoproteins (LDL) from subjects with Type 1 diabetes: effect on oxidative damage of human endothelial cells.

BACKGROUND: Homocysteine (Hcy) is an independent risk factor for cardiovascular disease (CVD). Individuals with Type 1 and Type 2 diabetes are more susceptible to the effects of homocysteine than non-diabetic subjects. The interaction between homocysteine-thiolactone (Hcy-thiolactone), a reactive product of Hcy, and low-density lipoproteins (LDL) induces the formation of homocystamide-LDL adducts (Hcy-LDL) and it has been suggested that homocysteinylation could increase atherogenicity of lipoproteins. AIM: The aim of the study was to compare the effect of in vitro homocysteinylation of LDL isolated from healthy control subjects (C-LDL) and from Type 1 diabetic patients (DM-LDL) and to investigate the effect of homocysteinylated LDL (Hcy-C-LDL and Hcy-DM-LDL) on peroxynitrite production of endothelial cells. METHODS: The in vitro homocysteinylation of LDL isolated from control (n = 12) and DM subjects (n = 12) was carried out by incubating lipoproteins with Hcy-thiolactone. The reaction was verified by quantifying the increase in sulphydryl groups (-SH groups) in Hcy-LDL with respect to control LDL. Control and homocysteinylated LDL were incubated with human aortic endothelial cells (HAEC) in culture. Peroxynitrite production in cells treated in different experimental conditions was assayed by a fluorimetric method. RESULTS: The increase in -SH groups after incubation with homocysteine was greater in LDL from diabetic subjects compared with LDL from control subjects (P < 0.001). In addition, peroxynitrite production from HAEC incubated with Hcy-LDL from diabetic patients was greater than after incubation with Hcy-LDL from control subjects and untreated LDL from diabetic patients (P < 0.001). CONCLUSIONS: These results show that LDL from diabetic patients is more susceptible to in vitro homocysteinylation than LDL from non-diabetic individuals and demonstrate that the compositional changes in Hcy-LDL from diabetic subjects have cytotoxic effects on human endothelial cells.     

Reduced plasma total homocysteine concentrations in Type 1 diabetes mellitus is determined by increased renal clearance.

INTRODUCTION: Elevated plasma levels of total homocysteine are related to the development of vascular complications. Patients with diabetes mellitus are particularly at risk for the development of these complications. Several factors determine plasma total homocysteine including renal function. AIMS: As early Type 1 diabetes is characterized by a relative glomerular hyperfiltration, increased renal clearance could contribute to decreased levels of homocysteine as observed in Type 1 diabetes mellitus. Therefore we investigated the relationship between plasma total homocysteine and the glomerular filtration rate (GFR). METHODS: In 92 Type 1 diabetes patients and 44 control subjects, we measured GFR and effective renal plasma flow (ERPF) by means of continuous infusion of inulin and p-aminohippurate. Fasting plasma total homocysteine was measured using high performance liquid chromatography. RESULTS: GFR (121 +/- 21 resp. 104 +/- 14 ml/min; P < 0.001) and ERPF (563 +/- 127 resp. 516 +/- 121 ml/min; P = 0.05) were significantly higher in Type 1 diabetes patients as compared with control subjects. Plasma total homocysteine was reduced in Type 1 diabetes patients as compared with control subjects (11.0 +/- 4.5 resp. 13.4 +/- 7 micromol/l; P = 0.01). Plasma total homocysteine was strongly correlated with GFR (Type 1 diabetes patients: r = -0.43, P < 0.001; control subjects: r = -0.39, P = 0.01). CONCLUSION: GFR is a major determinant of plasma total homocysteine levels in Type 1 diabetes patients as well as control subjects. The reduced plasma total homocysteine levels in diabetes patients can be explained by an increased GFR.     

Autonomic nerve function in adolescents with Type 1 diabetes mellitus: relationship to microalbuminuria.

AIMS: Thirty adolescent patients with Type 1 diabetes mellitus and microalbuminuria were studied for evidence of early autonomic neuropathy. METHODS: Using tests involving cardiovascular and pupillary reflexes, the adolescents were compared with a normoalbuminuric group of patients with diabetes, who were matched for age, sex, puberty and duration of diabetes. RESULTS: There was an increased prevalence of autonomic nerve dysfunction in the patients with microalbuminuria. These patients had higher resting heart rates (86 beats/min in the microalbuminuric group vs. 77 beats/min in normoalbuminuric controls, P = 0.002), and impaired pupillary dilatation in darkness (pupillary diameter % 56.5% vs. 62.5%, P = 0.003). Patients with microalbuminuria also had poorer long term glycaemic control (mean HbA1C 8.7% vs. 7.8%, P = 0.002) and higher blood pressures (systolic 125 vs. 116 mmHg, P = 0.001; diastolic 69 vs. 62 mmHg, P = 0.0001; mean arterial pressure 90 vs. 83 mmHg, P = 0.002) than those with normal urinary albumin excretion. CONCLUSIONS: Microalbuminuria and autonomic nerve dysfunction co-exist in patients with Type 1 DM. Longitudinal studies will determine whether these findings have implications for the identification of patients at higher risk of progression of early renal complications.     

同型半胱氨酸对老年2型糖尿病患者大血管病变的影响

目的 探讨血清总同型半胱氨酸(tHcy)水平与2型糖尿病(T2DM)患者大血管病变间的关系,并分析影响T2DM患者tHcy代谢的因素. 方法 167例老年T2DM 患者分为2组:无大血管并发症组(75例)和T2DM合并大血管病变组(92例);42例正常体检老人作为正常对照组.酶联免疫吸附法测定血清tHcy浓度;自动生化分析仪测定空腹血糖(FBS)、尿素氮(BUN)、肌酐(CREA)、总胆固醇(TC)和三酰甘油(TG)、低密度脂蛋白胆固醇(LDL-C)、高密度脂蛋白胆固醇(HDL-C)、糖化血红蛋白(HbA1c);电化学发光仪测定血清胰岛素(INS).对各指标的组间差异进行统计学分析. 结果 tHcy在T2DM合并大血管病患者组血浆浓度较T2DM无大血管并发症组和对照组高,差异具有统计学意义(P＜ 0.05),血清Hcy水平仅与空腹INS水平呈正相关(r= 0.56,P＜0.01). 结论 tHcy参与了T2DM大血管病变的发病过程,tHcy水平可能与胰岛素抵抗有关.     

Breastfeeding habits in families with Type 1 diabetes.

AIMS: Breastfeeding is acknowledged to be beneficial for child development. Women with diabetes may be more likely not to breastfeed their children because of neonatal morbidity and instability in diabetes control. The aim of this study was to assess the effect of maternal Type 1 diabetes on breastfeeding habits. METHODS: Full breastfeeding and any breastfeeding were reported in the first year of life in 1560 children born in Germany between 1989 and 2004. Of those, 997 children had a mother with Type 1 diabetes, and the remaining 563 children had a father or sibling with Type 1 diabetes. RESULTS: Fewer children of mothers with Type 1 diabetes were breastfed than children of non-diabetic mothers (77 vs. 86%; P < 0.0001) and, amongst breastfed children, there was a shorter duration of full breastfeeding (12 vs. 17 weeks; P < 0.0001) and any breastfeeding (20 vs. 26 weeks, P < 0.0001) in children of mothers with Type 1 diabetes compared with children of non-diabetic mothers. Other factors associated with reduced frequency and duration of breastfeeding were pre-term delivery (P < 0.0001), young maternal age (P < 0.0001), and firstborn children (P < 0.0001). After stratification for each of these factors, breastfeeding remained significantly less frequent and of less duration in children of mothers with Type 1 diabetes as compared with children of non-diabetic mothers. CONCLUSIONS: Mothers with Type 1 diabetes breastfeed their children less than international recommendations. Counselling to increase frequency and duration of breastfeeding may be warranted in this population.     

Plasma and urinary vascular endothelial growth factor and diabetic nephropathy in Type 2 diabetes mellitus.

AIMS: Vascular endothelial growth factor (VEGF) has been implicated in the pathogenesis of diabetes mellitus. We determined whether alterations of plasma and urinary VEGF levels are related to diabetic nephropathy in Type 2 diabetic patients. METHODS: One hundred and seven patients and 47 healthy controls were studied. Study subjects were divided into four groups using urinary albumin-to-creatinine ratio (ACR): a non-diabetic healthy control group (n = 47), a normoalbuminuric diabetic group (n = 37), a microalbuminuric diabetic group (n = 37) and an overt proteinuric diabetic group (n = 33). VEGF levels were measured by enzyme-linked immunosorbent assay. RESULTS: (i) Urinary VEGF concentrations were significantly higher in the diabetic groups, even at the normoalbuminuric stage (log VEGF/Cr, normoalbuminuria; 4.33 +/- 1.06 vs. control; 3.53 +/- 0.79, P = 0.009). Urinary VEGF excretions increased as diabetic nephropathy advanced. (ii) Plasma and urinary VEGF levels were higher in hypertensive diabetic patients than in the normotensive individuals with diabetes. (iii) In those with diabetes, plasma VEGF levels were found to be positively correlated with plasma urea (r = 0.398, P = 0.039) and urinary ACR (r = 0.251, P = 0.044), and urinary VEGF to be positively correlated with urinary ACR (r = 0.645, P < 0.001), and creatinine (r = 0.336, P = 0.009), and to be negatively correlated with serum albumin (r = -0.557, P < 0.001). Urinary VEGF and serum creatinine were independently correlated with urinary ACR. CONCLUSIONS: Urinary excretion of VEGF increased during the earlier stage of diabetic nephropathy and was significantly correlated with urinary albumin excretion. This suggests that urinary VEGF might be used as a sensitive marker of diabetic nephropathy and for predicting disease progression.     

Effects of insulin dependence on inflammatory process, thrombotic mechanisms and endothelial function, in patients with type 2 diabetes mellitus and coronary atherosclerosis

BACKGROUND: Type 2 diabetes mellitus (T2DM) is characterized by endothelial dysfunction, increased thrombogenicity and abnormal inflammatory response. HYPOTHESIS: We hypothesizsed that insulin dependence/exogenous insulin administration may affect thrombotic/inflammatory status and endothelial function in patients with T2DM and coronary artery disease (CAD). METHODS: Fifty-five patients with T2DM + CAD (26 insulin-treated (INS) and 29 under oral biguanide + sulphonylurea (TABL)) were recruited. Endothelial function was assessed by gauge-strain plethysmography, and serum levels of inflammatory and thrombotic markers were determined by enzyme linked immunosorbent assay. RESULTS: There was no significant difference in endothelium-dependent dilation (EDD) between the study groups, while EDD was correlated with fasting glucose levels in both INS (r = - 0.776, p = 0.0001) and TABL (r = - 0.702, p = 0.0001). Patients in INS group had higher levels of interleukin-6 (IL-6), tumor necrosis factor alpha (TNF-alpha), monocyte chemoattractant protein (MCP-1) and vascular cell adhesion molecule (sVCAM-1), compared to TABL. However, TNF-alpha was negatively correlated with protein C (PrtC) only in INS (r = - 0.726, p = 0.01) but not in TABL group (r = - 0.066, p = 0.738). Similarly, sVCAM-1 was correlated with PrtC only among INS patients (r = - 0.451, p = 0.046) but not in TABL (r = 0.069, p = 0.727). In multivariate analysis, insulin dependence was a predictor of IL-6, TNF-alpha, MCP-1 and sVCAM-1 levels independently from the patients' demographic characteristics, the angiographic extend of CAD or the duration of diabetes. CONCLUSIONS: Insulin treatment in patients with type 2 diabetes mellitus affects the expression of inflammatory cytokines and subsequently modifies the thrombotic mechanisms in patients with coronary atherosclerosis, independently from the duration of diabetes and the extend of coronary artery disease.     

Microvascular endothelial function in subjects with Type 2 diabetes and the effect of lipid-lowering therapy.

AIMS: Abnormalities of microvascular and endothelial function are present in subjects with Type 2 diabetes. Although statin therapy improves cardiovascular risk in diabetes, dyslipidaemia in diabetes may be more responsive to combined statin and fibrate therapy. We examined the effect of cerivastatin and fenofibrate on microvascular function in subjects with Type 2 diabetes with no clinical evidence of cardiovascular disease and near normal lipid levels. METHODS: Age-, sex-, lipid- and blood pressure-matched subjects with Type 2 diabetes were randomized in double-blind fashion to one of four treatment groups: group 1 placebo/placebo (n=12), group 2 fenofibrate/placebo (n=10), group 3 cerivastatin/placebo (n=20) and group 4 cerivastatin/fenofibrate (n=11). The subjects were recruited from the Lipid in Diabetes Study. Microvascular function was assessed by skin blood flow response to iontophoresis of acetylcholine and sodium nitroprusside and by skin maximum hyperaemia to local heating. Measurements were carried out at baseline and 3 months later. RESULTS: Although all lipid parameters improved in groups 2-4 after 3 months' therapy, no difference was detected in skin blood flow to iontophoresis or maximum hyperaemia in any of the groups. Highly sensitive c-reactive protein (Hs-CRP) did not change with therapy. CONCLUSIONS: In conclusion, we were unable to demonstrate any improvement in microvascular endothelial function in non-hyperlipidaemic Type 2 diabetic subjects treated with single or combination lipid-lowering therapy.     

Abnormal liver function tests in patients with Type 1 diabetes mellitus: prevalence,clinical correlations and underlying pathologies

Aims To determine the prevalence of elevated alanine transaminase (ALT) in a large cohort of patients with Type 1 diabetes and to examine the clinical correlations and causes. Methods Patients with Type 1 diabetes mellitus were prospectively recruited and ALT, glycated haemoglobin and lipid profile were measured. Patients with Type 2 diabetes mellitus were recruited as a comparison group. Patients with abnormal ALT were investigated for underlying causes. Prevalence of abnormal ALT was analysed at three separate cut‐offs and multivariable analysis used to identify independent risk factors. Results Nine hundred and eleven with Type 1 diabetes and 963 with Type 2 diabetes were included. The prevalence of elevated ALT was dependent on the cut‐off value: > 30 IU/l in males and > 19 IU/l in females, > 50 and > 63 IU/l was 34.5, 4.3 and 1.9%, respectively, in Type 1 diabetes and 51.4, 8.2 and 3.7%, respectively, in Type 2 diabetes. In Type 1 diabetes an elevated ALT was associated with worse glycaemic control, age > 55 years and elevated triglycerides. Investigation of these patients revealed a cause in 43.6% of patients, predominantly non‐alcoholic fatty liver disease (NAFLD). Conclusions Elevated ALT is not uncommon in Type 1 diabetes and is associated with NAFLD‐related risk factors. Patients with Type 1 diabetes and elevated ALT should be investigated as significant abnormalities may be found which are amenable to interventions.     

Plasma concentrations of VCAM-1 and ICAM-1 are elevated in patients with Type 1 diabetes mellitus with microalbuminuria and overt nephropathy.

AIMS: Elevated urinary albumin excretion is associated with macrovascular atherosclerotic complications in Type 1 diabetes mellitus. Adhesion molecules mediate leucocyte adhesion to the endothelium early in the atherosclerotic process. The present study tests the hypothesis that microalbuminuria and diabetic nephropathy are associated with elevated plasma concentrations of soluble vascular adhesion molecule (sVCAM)-1, soluble intercellular adhesion molecule (sICAM)-1, and soluble E-selectin (sE-selectin) aiming to illustrate factors of potential pathogenetic relevance for the excess cardiovascular disease in diabetic patients with renal complications. METHODS: Soluble adhesion molecule concentrations were measured by enzyme-linked immunosorbent assays (ELISA) in healthy controls (n = 16) and in 59 Type 1 diabetic patients: group 1-patients with normoalbuminuria (n = 16); group 2-patients with microalbuminuria (n = 15); group 3-patients with macroalbuminuria and normal serum creatinine (n = 15), group 4-patients with macroalbuminuria and moderately elevated serum creatinine (n = 13). RESULTS: Plasma concentrations of sVCAM-1 and sICAM-1 were similar in healthy controls and normoalbuminuric Type 1 diabetic patients, but the concentrations were increased by the presence of microalbuminuria and overt nephropathy (P < 0.001 and P < 0.0001, ANOVA). Concentrations of sE-selectin did not differ between diabetic patients and controls. CONCLUSIONS: Plasma concentration of sICAM-1 is elevated in Type 1 diabetic patients with microalbuminuria and the concentrations of sICAM-1 as well as sVCAM-1 are elevated in patients with macroalbuminuria and normal s-creatinine. The elevated plasma concentrations of these soluble adhesion molecule concentrations in patients with renal complication can be of pathogenetic importance for the development of atherosclerosis and plasma soluble adhesion molecule concentrations may provide additional information on cardiovascular risk.     

Angiotensin converting enzyme inhibition and arterial endothelial function in adults with Type 1 diabetes mellitus.

AIMS: Arterial endothelial dysfunction is a key early event in atherogenesis, and occurs in asymptomatic adults with Type 1 diabetes mellitus (DM). As angiotensin converting enzyme (ACE) inhibitors have been reported to reverse microvascular endothelial dysfunction acutely, we assessed the longer term effect of ACE inhibition on large vessel endothelial physiology in a randomized, crossover double-blind controlled clinical trial. METHODS: Flow-mediated arterial dilatation (FMD), which is largely due to endothelial release of nitric oxide, was assessed by vascular ultrasound in 20 Type 1 DM subjects with known endothelial dysfunction. These subjects, aged 28+/-5 years, were studied before and after 12 weeks oral therapy with either the ACE inhibitor perindopril 4 mg daily or the diuretic hydrene (triamterene 50 mg with hydrochlorothiazide 25 mg) daily. RESULTS: Although perindopril lowered both systolic and diastolic blood pressure by 2.7/3.2 mmHg, respectively (F3,78 = 4.7, P= 0.006; F3,78 = 3.2, P = 0.03), there was no significant effect of either perindopril or hydrene on FMD (baseline FMD before perindopril 4.6+/-2.5%, after 4.1+/-3.4%, baseline FMD before hydrene 5.4+/-3.6%, after 6.0+/-3.3%; F3,78= 1.9, P=0.1). Glycaemic control deteriorated slightly on hydrene whilst lipid levels, heart rate, resting blood flow and the arterial responses to nitroglycerine, a smooth muscle dilator, were unaffected by the treatment given. CONCLUSION: ACE inhibitor therapy for 3 months did not improve arterial endothelial function in Type 1 DM subjects.     

老年冠心病合并糖尿病患者血管内皮功能的变化

目的探讨老年冠心病患者以及冠心病合并糖尿病患者肱动脉内皮依赖性舒张功能(EDD)、非内皮依赖性舒张功能(EID)、血浆一氧化氮(NO)、内皮素(ET)的水平,为临床防治提供依据。方法采用高分辨率超声诊断系统分别检测35例老年冠心病患者(冠心病组,年龄62~91岁)以及32例老年冠心病合并糖尿病患者(冠心病合并糖尿病组,年龄65~89岁)肱动脉的EDD及EID;同时采用还原、比色法测定NO水平;采用放射免疫法检测ET水平,并分别与40例健康老年人(健康对照组,年龄61~86岁)进行对比。结果老年冠心病合并糖尿病组肱动脉的EDD、EID以及血浆NO水平均显著低于老年冠心病组和健康对照组(P<0.05),而老年冠心病组的EDD、EID以及血浆NO水平亦显著低于健康对照组(P<0.05);老年冠心病合并糖尿病组的ET却显著高于老年冠心病组和健康对照组(P<0.05),老年冠心病组ET水平显著高于健康对照组(P<0.05)。结论(1)老年冠心病及冠心病合并糖尿病组肱动脉EDD及EID均受损;(2)老年冠心病及冠心病合并糖尿病组均存在血管内皮功能失调,且冠心病合并糖尿病组内皮功能紊乱更严重;(3)改善血管内皮功能、控制血糖是减少心血管事件的重要措施之一。     

Altered chemokine levels in individuals at risk of Type 1 diabetes mellitus.

AIMS: The hypothesis was tested in an exploratory study that individuals at high risk of developing Type 1 diabetes mellitus have altered systemic levels of cytokines and chemokines. SUBJECTS AND METHODS: Forty-two non-diabetic first-degree relatives of patients with Type 1 diabetes mellitus were recruited. Of these, 18 had multiple islet autoantibodies (islet cell antibody, glutamic acid decarboxylase antibody, IA-2 antibody). Follow-up for 9-11 years confirmed high vs. moderate diabetes risk in islet autoantibody-positive vs. -negative relatives. Cytokines and chemokines were determined by enzyme-linked immunosorbent assay (ELISA). RESULTS: Serum concentrations of classic Th1-associated cytokines (IFN-gamma, IL-12, IL-18) or Th2/Treg-associated cytokines (IL-5, IL-10, IL-13) did not significantly differ in high vs. moderate diabetes risk group. However, of six chemokines analysed, levels of CCL3 and CCL4 were increased (P = 0.0442 and P = 0.0334) while CCL2 was decreased (P = 0.0318) in the multiple islet autoantibody-positive group. No significant differences were seen for CCL5, CCL11, CXCL10. There was a significant correlation between the two closely related chemokines CCL3 and CCL4 in individuals at risk (r = 0.84, P = 0.00005), but not in the autoantibody-negative group. CONCLUSION: Relatives at high risk of developing Type 1 diabetes mellitus have abnormal cellular immune regulation at the level of systemic chemokines. The up-regulation of CCL3 and CCL4 vs. down-regulation of CCL2 suggests opposed functions of these chemokines in the disease process. These findings need to be confirmed by independent studies.     

Coeliac disease in children with Type 1 diabetes mellitus: the effect of the gluten-free diet.

PATIENTS AND METHODS: We assessed the frequency of coeliac disease in 281 children with Type 1 diabetes and the effect of gluten-free diet (GFD) in newly diagnosed cases. Serological screening was performed using anti-gliadin and anti-endomysium antibodies. Data were obtained about clinical symptoms, height and weight-for-height. RESULTS: A small intestinal biopsy was recommended to 18 patients (6.4%) with positive serological results and 12 children agreed. Nine of them had coeliac disease. Three out of nine coeliac children complained about gastrointestinal symptoms. On a GFD, the symptoms disappeared in two patients. Iron-deficiency anaemia was present in four subjects and disappeared in the three patients who accepted the GFD. In three patients (33%), coeliac disease was asymptomatic. Height and weight-for-height were in the normal range for all patients. For well-complying patients, there was a significant increase in height standard deviation at diagnosis and on follow-up (-0.28 vs. +0.35) (P = 0.03). Changes in weight-for-height were not significant (-4.0% vs. +1.4%) (P = 0.28). There was a trend to an improvement in HbA(1c) (8.0 vs. 7.3%) (P = 0.05). CONCLUSIONS: Serological screening is effective. There is a therapeutic benefit for some screening-detected patients, but confirmatory studies are needed.     

Statin therapy improves brachial artery vasodilator function in patients with Type 1 diabetes and microalbuminuria.

AIMS: Type 1 diabetes mellitus patients with microalbuminuria have endothelial dysfunction associated with the degree of albuminuria but not with LDL-cholesterol levels. Lipid-lowering agents such as statins may still be of benefit as they can correct endothelial dysfunction by both lipid and non-lipid mechanisms. We therefore examined the effects of atorvastatin on brachial artery endothelial dysfunction in these patients. METHODS: In a double-blind, randomized crossover study, 16 Type 1 diabetes mellitus patients with microalbuminuria received 6 weeks of atorvastatin 40 mg/day or placebo, separated by a 4-week washout. Brachial artery, endothelium-dependent, flow-mediated dilatation (FMD) and endothelium-independent, glyceryl trinitrate-mediated dilatation (GTNMD) were measured. RESULTS: Compared with placebo, atorvastatin produced a significant decrease in apolipoprotein B (34.2%), LDL-cholesterol (44.1%) (all P < 0.001), and oxidized-LDL (35.7%, P = 0.03). There was a non-significant increase in plasma cGMP (P = 0.13) on atorvastatin. FMD and GTNMD increased significantly on atorvastatin (FMD: atorvastatin +1.8 +/- 0.4%; placebo +0.2 +/- 0.4%, P = 0.007); (GTNMD: atorvastatin +1.3 +/- 0.9%; placebo -1.2 +/- 0.6%, P = 0.04). An increase in cGMP was independently correlated with an increase in FMD on atorvastatin (adjusted (R2) 0.41, P = 0.02). CONCLUSION: Atorvastatin improves endothelium-dependent and independent vasodilator function of the brachial artery in Type 1 diabetes mellitus patients with microalbuminuria. This may relate to pleiotropic effects of statins, in particular reduced oxidative stress and increased availability of nitric oxide.