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.     

Predictors of the development of microalbuminuria in patients with Type 1 diabetes mellitus: a seven-year prospective study

Aims To determine risk factors for the development of persistent microalbuminuria (albumin excretion rate (AER) ≥ 30 μg/min) in Type 1 diabetes mellitus. Methods One hundred and forty-eight initially normotensive Type 1 diabetic patients with normal albumin excretion (< 30 μg/min) were followed prospectively in hospital diabetes outpatient clinics for a median of 7 years. Main outcome measures were: progression to persistent microalbuminuria (albumin excretion rate ≥ 30 μg/min on at least two consecutive occasions); rate of change of albumin excretion rate; development of arterial hypertension (systolic blood pressure > 160 mmHg and/or diastolic blood pressure > 95 mmHg or commencement of antihypertensive therapy). Results In a median follow-up period of 7 years (range 6 months to 8 years), 14 patients progressed to persistent microalbuminuria, a cumulative incidence of 11% (95% confidence interval 6.36–16.94). AER remained persistently < 30 μg/min in 109 subjects and 25 developed intermittent microalbuminuria. In those who developed persistent microalbuminuria, baseline AER (16.2 (13.9–19.1) vs. 5.2 (3.8–9.2) μg/min, P < 0.01), blood pressure (136 (123–148)/80 (74–85) vs. 121 (118–124)/72 (70–73) mmHg, P < 0.05), and HbA₁ (10.2 (9.1–11.4) vs. 9.0 (8.7–9.4)%, P < 0.05) were higher than in those who continued to have persistent normoalbuminuria, retinopathy was more severe and height (1.64 (1.57–1.71) vs. 1.70 (1.69–1.72) m, P < 0.05) less. In multivariate analysis, baseline AER was the strongest predictor of the development of persistent microalbuminuria (P < 0.0001), followed by mean arterial pressure (P = 0.02) and HbA₁ (P = 0.05). Conclusions The level of AER, raised blood pressure and poor glycaemic control are the most important predictors of the development of microalbuminuria in Type 1 diabetes.     

Enhanced albuminuric response to atrial natriuretic peptide in normoalbuminuric patients with Type 1 diabetes mellitus--a pilot study.

AIMS: To ascertain whether intravenous infusion of atrial natriuretic peptide (ANP) can induce microalbuminuria in patients with Type 1 diabetes mellitus (DM), as already demonstrated in patients with microalbuminuria, and to compare the albuminuric response to ANP infusion in Type 1 DM and a matched group of healthy non-diabetic controls. METHODS: Eight normoalbuminuric DM patients participated in a three limb, randomized, double-blind, placebo-controlled study. Subjects were kept euglycaemic by insulin infusion, and subsequently water-loaded (20 ml/kg orally plus urinary losses). When in steady state, a 30-min infusion of either placebo, ANP 0.025 mg x kg(-1).min(-1) or ANP 0.05 mg x kg(-1) x min(-1) was administered intravenously. Urine was collected every 15 min for 90 min for the estimation of albumin-creatinine ratio (ACR). In addition, eight nondiabetic volunteers received a single infusion of ANP 0.025 mg x kg(-1) x min(-1). RESULTS: ACR was unaltered by placebo in DM subjects (1.4 +/- 0.7-1.7 +/- 1.1 mg/mmol, mean +/- SD, ANOVA, P > 0.9), and by low dose ANP in controls (1.4 +/- 0.9-2.6 +/- 1.9 mg/mmol, P = 0.4). ACR increased with low dose ANP (1.3 +/- 0.5-14.6 +/- 13.6 mg/mmol, P = 0.02), and high dose ANP (1.3 +/- 0.7-26.4 +/- 31 mg/mmol, P = 0.01) in DM subjects. The ACR response to low dose ANP was greater in the DM than control subjects (P = 0.02). CONCLUSIONS: ANP increases urine albumin excretion rate in normoalbuminuric Type 1 DM patients, and this effect is more pronounced than in healthy volunteers.     

Increased left ventricular mass index and nocturnal systolic blood pressure in patients with Type 2 diabetes mellitus and microalbuminuria.

AIMS: To compare left ventricular mass (LVM) index and function in patients with Type 2 diabetes mellitus with and without microalbuminuria and to investigate the clinical determinants of left ventricular hypertrophy. METHODS: Echocardiography, electrocardiography and 24-h ambulatory blood pressure monitoring were performed in microalbuminuric (n = 29) and normoalbuminuric (n = 29) patients with Type 2 diabetes and no clinical evidence of heart disease. Groups were individually matched for age, sex and diabetes duration and smoking status. RESULTS: LVM index (62 (34-87) vs. 52 (33-89) g/m2.7, P = 0.04) and LVH prevalence, using two out of three definitions, were greater in patients with microalbuminuria (LVM/height2.7: 72 vs. 59%, P = 0.27, LVM/height: 66 vs. 38%, P = 0.04, LVM/body surface area: 59 vs. 31%, P = 0.03). Night-time systolic blood pressure (126 (99-163) vs. 120 (104-157) mmHg, P = 0.005) and the night/day systolic blood pressure ratio (0.92 (0.08) vs. 0.88 (0.06), P = 0.04) were higher in those with microalbuminuria. Systolic and diastolic function were similar in both groups. Linear regression analyses showed that body mass index (BMI) was significantly related to loge LVM index (R2 = 11.8%, P = 0.005) and a relationship with night/day systolic blood pressure was also suggested (R2 = 4.6%, P = 0.057). CONCLUSIONS: In patients with Type 2 diabetes, LVH is more common and severe in those with microalbuminuria. Its presence may be related to raised night/day systolic blood pressure ratio and is significantly related to BMI. The high prevalence of LVH strengthens the case for echocardiographic screening in Type 2 diabetes to identify high risk patients who might benefit from aggressive cardiovascular risk factor intervention.     

不同剂量氯沙坦对高血压病并发Ⅱ型糖尿病患者微量白蛋白尿及血管内皮功能的影响

目的探讨不同剂量氯沙坦对高血压病并发Ⅱ型糖尿病患者微量白蛋白尿及血管内皮功能的影响。方法将31例伴有持续微量白蛋白尿的高血压病并发Ⅱ型糖尿病患者随机分为2组,分别接受氯沙坦50mg/d（A组,16例）及100mg/d（B组,15例）口服治疗16周,检测并比较两组患者治疗前后尿白蛋白排泄率（UAER）、肱动脉血流介导的血管舒张反应（FMD）。结果A、B两组患者经氯沙坦治疗16周后平均UAER水平分别由（114±31）μg/min、（108±30）μg/min降至（92±26）μg/min、（74±28）μg/min（均P<0.01）,B组降低程度更为显著（P<0.05）;A、B两组患者治疗后平均FMD内径变化率分别由治疗前（6.5±1.9）%、（6.8±1.0）%增至（7.0±1.2）%、（7.2±1.1）%（均P<0.01）,B组的增加程度更为显著（P<0.05）。UAER与FMD内径变化率呈负向线性关系（r=-0.78,P<0.05）。结论与每日使用50mg氯沙坦相比,每日使用100mg氯沙坦可以更为显著地降低这类患者尿微量白蛋白的排泄,更为有效地改善其血管内皮功能,并且具有良好的安全性及耐受性。     

Blood pressure control, microalbuminuria and cardiovascular risk in Type 2 diabetes mellitus.

Type 2 (noninsulin-dependent) diabetes mellitus (DM) affects about 3% of the UK population. Diabetes often coexists with a cluster of other potent cardiovascular risk factors, including hypertension, dyslipidaemia and increased tendency for thrombosis, and increases the risk of early death from cardiovascular causes by about threefold. Microalbuminuria or proteinuria also may be present, further increasing the risk of cardiovascular mortality. Cardiovascular risk factors must be treated aggressively in patients with Type 2 diabetes and control of blood pressure at 140/85 mm Hg or lower is a priority. The management of hypertension in patients from some ethnic groups demands special consideration because they have a high incidence of diabetes and hypertensive complications. Patients must be urged to adopt appropriate lifestyle changes in the first instance but additional drug treatment for hypertension is usually required. All the major classes of antihypertensive agents lower blood pressure in Type 2 diabetic patients but have different effects on metabolic risk factors in different ways. Low-dose thiazide diuretics, beta-blockers, calcium channel blockers and angiotensin converting enzyme (ACE) inhibitors have been shown to reduce cardiovascular risk. Individually, the effects of low-dose thiazide diuretics and beta-blockers on glucose and lipid metabolism is clinically insignificant, though in combination much larger metabolic effects are seen. ACE inhibitors and calcium channel blockers have no, or small, beneficial effects on glucose and lipid metabolism, while the greater beneficial effects of alpha1-blockers on lipid profiles may render them especially useful in the Type 2 diabetic patient. Long-acting calcium-channel blockers and ACE inhibitors protect renal function and are suitable as first line therapy in patients with microalbuminuria or proteinuria. Until results from the current batch of randomized, placebo-controlled trials comparing different classes of antihypertensive agents are available, the choice of antihypertensive agent is difficult. Addressing overall cardiovascular risk factors, rather than hypertension alone, is essential in the management of the hypertensive Type 2 diabetic patient.     

The relationship between flow-mediated dilatation and left ventricular function in type 2 diabetic patients with microalbuminuria

Objective The aim of this study was to assess the relationship between flow-mediated dilatation (FMD) and left ventricular (LV) systolic and diastolic function in type 2 diabetic patients with or without microalbuminuria. Research Design and Methods We prospectively evaluated 68 consecutive patients (36 women, 32 men; mean age 57±11 yr) with type 2 diabetes mellitus (DM). Patients were divided into two groups according to whether or not they had microalbuminuria: group 1 (n=29, mean age 58±10 yr) with microalbuminuria and group 2 (n=39, mean age 56±10 yr) without microalbuminuria. LV function was assessed by classical methods and Doppler tissue imaging (DTI). Left ventricular ejection fraction (EF), interventricular (IVS) and posterior wall (PW) thickness, peak early (E) and late (A) transmitral filling velocities, their ratio (E/A) and deceleration time of the mitral E wave (DT), LV isovolumetric relaxation time (IVRT), flow propagation of velocity (Vp), and E/Vp were evaluated by conventional echocardiography. Early diastolic (Em), late diastolic (Am), and peak systolic (Sm) mitral annular velocities were measured. Em/Am and the ratio of early diastolic mitral inflow velocity to Em (E/Em), which is a reasonably good index for predicting elevated LV filling pressure, were calculated by DTI. Endothelial function, measured as flow-mediated dilatation of the brachial artery using ultrasound, was calculated in two groups. Results FMD was lower in those with microalbuminuria than those without (8.8±6.44% vs 12.6±7.24%, p=0.03). Group 1 had longer DT (223±39 ms vs 199±37 ms, p=0.01) and longer IVRT (109±13 ms vs 100 ±13 ms, p=0.03) than that of group 2 with conventional echocardiography. Group 1 had significantly lower Em/Am (0.79±0.27 cm/s vs 1.02±0.44 cm/s, p=0.01), lower Vp (40.4±9.98 vs 50.4±19.01 cm/s, p=0.01) than that of group 2. Group 1 had significantly higher serum creatinine (1±0.33 mg/dL vs 0.7±0.19, p=0.001). In logistic regression analysis, FMD was the only variable independently related to microalbuminuria. FMD was positively correlated with EF (r=0.43, p=0.02) and E/A (r=0.40, p=0.03), and negatively correlated with E/Em (r=0.41, p=0.04) and E/Vp (r=0.41), p=0.04) only in patients with microalbuminuria. Conclusion It was found that left ventricular diastolic function and FMD are impaired in type 2 diabetic patients with microalbuminuria. FMD may be related to LV diastolic dysfunction only in patients with microalbuminuria.     

Alterations in serum lipids and apolipoproteins in male Type 1 (insulin-dependent) diabetic patients with microalbuminuria

Summary The relationships between serum lipid, apolipoprotein levels and urinary albumin excretion were investigated in 20 male Type 1 (insulin-dependent) diabetic patients with microalbuminuria (overnight urinary albumin excretion between 10 and 200 g/min), in 18 male Type 1 diabetic patients without microalbuminuria and in 18 male control subjects. In the microalbuminuric patients low density lipoprotein cholesterol was higher than in the control subjects (p<0.05); the high density lipoprotein/low density lipoprotein cholesterol ratio was lower than in the normoalbuminuric diabetic patients (p<0.05), and in the control subjects (p<0.01); apolipoprotein B was higher than in the normoalbuminuric patients (p<0.05); the apolipoprotein A₁/B ratio was lower than in the normoalbuminuric diabetic patients (p<0.05). Serum triglyceride was higher in the microalbuminuric diabetic patients and in the control subjects than in the normoalbuminuric diabetic patients (p<0.05, for both), but was not different between the microalbuminuric diabetic patients and the control subjects. No significant differences between the 3 groups were present with respect to serum cholesterol, high density lipoprotein cholesterol and apolipoprotein A₁. In the 2 combined Type 1 diabetic groups there were significant correlations between urinary albumin excretion and the high density lipoprotein/low density lipoprotein cholesterol ratio (R -0.40, p<0.02), apolipoprotein B (R0.35, p<0.05) and the apolipoprotein A₁/B ratio (R -0.44, p<0.01). These results indicate microalbuminuria related differences in lipid and apolipoprotein levels in male Type 1 diabetic patients, which may contribute to an increased risk of cardiovascular disease.     

Paternal phenotype is associated with microalbuminuria in young adults with Type 1 diabetes mellitus of short duration.

AIMS: Susceptibility to diabetic nephropathy has not yet been causally linked to any genetic factors. We investigated in nuclear families whether parental ambulatory blood pressure, lipids and urine albumin excretion were early markers of risk of microalbuminuria in young adults with Type 1 diabetes. SUBJECTS AND METHODS: A subset of 98 young adults from the Oxford Regional Prospective Study were followed from diagnosis until aged >or= 16 years and duration of diabetes >or= 5 years (probands). Of these subjects, 24 developed microalbuminuria (males >or= 3.5 mg/mmol; females >or= 4 mg/mmol) and were designated cases, whereas 74 were controls. Family medical history, 24-h ambulatory blood pressure, urine albumin to creatinine ratio (ACR), non-fasting lipid profile and apolipoproteins (A1 and B) were measured in mothers and fathers. RESULTS: The prevalence of a parental hypertension (taking anti-hypertensive medication or daytime blood pressure > 140/90 mmHg), was similar in cases and controls (29% vs. 35%; chi2 test, P = 0.3). The systolic blood pressure night to day ratio and also ACR were higher in the fathers of cases when compared with the fathers of controls [systolic 0.88 (0.08), n = 14 vs. 0.85 (0.12), n = 53, P = 0.041]; [ACR median (IQ range) 0.6 mg/mmol (0.2-16.9) vs. 0.47 mg/mmol (0.3-3.7), P = 0.049]. Paternal night-time systolic blood pressure, night to day systolic blood pressure ratio and ACR were correlated with an index of susceptibility to albuminuria (r = 0.25, P = 0.042, n = 69 and r = 0.28, P = 0.022, n = 0.67 and r = 0.24, P = 0.029, n = 0.85, respectively). CONCLUSIONS: Higher paternal ACR and night to day ratio of ambulatory blood pressure, but not parental hypertension or maternal factors, are associated with microalbuminuria in young adults with Type 1 diabetes.     

Insulin resistance,hypertension and microalbuminuria in patients with Type 2 (non-insulin-dependent) diabetes mellitus

Summary We examined the impact of hypertension and microalbuminuria on insulin sensitivity in patients with Type 2 (non-insulin-dependent) diabetes mellitus using the euglycaemic insulin clamp technique in 52 Type 2 diabetic patients and in 19 healthy control subjects. Twenty-five diabetic patients had hypertension and 19 had microalbuminuria. Hypertension per se was associated with a 27% reduction in the rate of total glucose metabolism and a 40% reduction in the rate of non-oxidative glucose metabolism compared with normotensive Type 2 diabetic patients (both p<0.001). Glucose metabolism was also impaired in normotensive microalbuminuric patients compared with normotensive normoalbuminuric patients (29.4±2.2 vs 40.5±2.8 mol · kg lean body mass^–1 · min^–1; p=0.012), primarily due to a reduction in non-oxidative glucose metabolism (12.7±2.9 vs 21.1±2.6 mol · kg lean body mass^–1 ·min^–1; p=0.06). In a factorial ANOVA design, however, only hypertension (p=0.008) and the combination of hypertension and microalbuminuria (p=0.030) were significantly associated with the rate of glucose metabolism. The highest triglyceride and lowest HDL cholesterol concentrations were observed in Type 2 diabetic patients with both hypertension and microalbuminuria. Of note, glucose metabolism was indistinguishable from that in control subjects in Type 2 diabetic patients without hypertension and microalbuminuria (40.5±2.8 vs 44.4±2.8 mol · kg lean body mass^–1 · min^–1). We conclude that insulin resistance in Type 2 diabetes is predominantly associated with either hypertension or microalbuminuria or with both.     

Atrial natriuretic peptide increases urinary albumin excretion in men with Type 1 diabetes mellitus and established microalbuminuria

Raised plasma concentrations of atrial natriuretic peptide (ANP) have been reported in patients with Type 1 (insulin dependent) diabetes mellitus (DM) who have poor glycaemic control and are associated with the presence of microalbuminuria. To test the hypothesis that elevations in plasma ANP concentration increase urinary albumin excretion in Type 1 DM, we have studied the effects of intravenous infusions of ANP in eight such subjects with established microalbuminuria. Blood glucose was maintained between 4 and 7 mmol l⁻¹ in all subjects for the duration of studies; after euglycaemia had been established, a standard oral water load (20 ml kg⁻¹ plus replacement of urinary losses) was given. Once steady state diuresis was attained, subjects received intravenous infusion of either placebo (0.9 % saline), low dose (2.5 pmol kg⁻¹ min⁻¹) or high dose (5.0 pmol kg⁻¹ kg min⁻¹) ANP solution in a randomized, double-blind protocol. Infusion of ANP caused a dose-dependent increase in urinary albumin excretion rate (placebo, 11.3 (SD 8.9) to 8.7 (SD 6.8) μg min⁻¹; low dose ANP, 12.4 (SD 9.9) to 26.5 (SD 27.5) μg min⁻¹, p < 0.01; high dose ANP 10.3 (SD 7.3) to 36.6 (SD 28.5) μg min⁻¹, p < 0.001, ANOVA). Only high dose ANP caused an increase in urine flow. Blood glucose remained unchanged in all studies. We conclude that intravenous infusions of ANP cause a dose-dependent increase in urinary albumin excretion rate in Type 1 DM subjects with microalbuminuria. These data support the hypothesis that ANP has albuminuric actions which may contribute to microalbuminuria in Type 1 DM. © 1998 John Wiley & Sons, Ltd.     

The impact of Type 2 diabetes and microalbuminuria on future cardiovascular events in patients with clinically manifest vascular disease from the Second Manifestations of ARTerial disease (SMART) study

Aims Type 2 diabetes mellitus and microalbuminuria are important risk factors for cardiovascular disease (CVD). Whether these two complications are important and independent risk factors for future CVD events in a high‐risk population with clinically manifest vascular disease is unknown. The objectives of this study were to examine the impact of Type 2 diabetes and microalbuminuria on future CVD events. Methods Patients with clinically manifest vascular disease (coronary, cerebral and peripheral vascular disease) from the Second Manifestation of Arterial disease study were followed up for 4 years. Data obtained from 1996–2006 were analysed. At baseline, there were 804 patients with Type 2 diabetes mellitus (mean age 60 years) and 2983 patients without. Incident CVD (n = 458) was defined as hospital‐verified myocardial infarction, stroke, vascular death and the composite of these vascular events. Results Both Type 2 diabetes [hazard ratio (HR) 1.42, 95% confidence interval (CI) 1.16, 1.75] and microalbuminuria (HR 1.86, 95% CI 1.49, 2.33) increased the risk of new cardiovascular events in univariate analyses. From multivariable models, presence of diabetes remained significantly and independently related to incident CVD (HR 1.42, 95% CI 1.11, 1.80). Presence of microalbuminuria also remained significantly independently related to incident CVD (HR 1.38, 95% CI 1.07, 1.77). In diabetes‐stratified analyses, the effect of microalbuminuria on CVD risk was observed only in patients with diabetes. In microalbuminuria‐stratified analyses, the significant and independent effect of diabetes on CVD risk was shown only in the non‐microalbuminuric group. Conclusions In this high‐risk population, both microalbuminuria and Type 2 diabetes are important and independent risk factors for future CVD.     

Endothelium-dependent and independent vasodilation studied at normoglycaemia in Type I diabetes mellitus with and without microalbuminuria

Aims/hypothesis. We examined whether endothelial function is impaired in patients with Type I (insulin-dependent) diabetes mellitus under conditions of near-normoglycaemia compared with age-matched healthy control subjects. Our aim was to determine whether microalbuminuria is associated with endothelial dysfunction in Type I diabetes. Methods. Endothelial function, measured as post-ischaemic flow-mediated dilatation of the brachial artery using ultrasound, was compared among 17 microalbuminuric and 17 normoalbuminuric diabetic patients, and 17 control subjects. Glyceryl trinitrate-mediated dilatation of the brachial artery was used to measure endothelium-independent function. All diabetic patients were studied at near-normoglycaemia, using insulin and 5 % dextrose infusions to maintain blood glucose between 3.5 and 8.0 mmol/l. Results. Flow-mediated dilatation was significantly lower in microalbuminuric diabetic patients (3.2 ± 0.3 %) compared with normoalbuminuric diabetic patients (5.4 ± 0.6 %) and control subjects (7.9 ± 0.6 %, p < 0.001). Normoalbuminuric diabetic patients also had significantly lower flow-mediated dilatation than control subjects (p = 0.01). Glyceryl trinitrate mediated dilatation was significantly lower in the microalbuminuric patients compared with the control subjects (11.9 ± 1.1 % vs 20.0 ± 1.2 %, p = 0.001). Albumin excretion rate and glycated haemoglobin showed a significant negative independent correlation with flow-mediated dilatation (both p < 0.05). Conclusion/interpretation. Type I diabetic patients show endothelial dysfunction at near-normoglycaemia compared with the control subjects, and this abnormality is more marked in diabetic patients with microalbuminuria. Endothelial dysfunction in Type I diabetes is related to the albumin excretion rate and glycaemic control. The presence of endothelial dysfunction in normoalbuminuric diabetic patients suggests it could precede microalbuminuria as an early risk marker for cardiovascular disease. [Diabetologia (2001) 44: 593–601] Received: 6 November 2000 and in revised form: 11 January 2001     

Plasma homocysteine, oxidative stress and endothelial function in patients with Type 1 diabetes mellitus and microalbuminuria.

AIMS: The purpose of this study was to examine the associations between endothelial function, plasma homocysteine and oxidative stress in patients with Type 1 diabetes mellitus (DM) and microalbuminuria compared with DM patients with normoalbuminuria and non-diabetic control subjects. We wished to test the hypothesis that increased cardiovascular risk in patients with Type 1 diabetes and microalbuminuria may be in part as a result of hyperhomocysteinaemia-mediated oxidative stress leading to impaired endothelial function. METHODS: We measured forearm blood flow, total plasma homocysteine, total antioxidant status (TAOS) and whole blood glutathione in 31 DM patients, 16 with microalbuminuria and 15 with normoalbuminuria, and 15 non-diabetic control subjects. RESULTS: Plasma homocysteine levels were significantly higher in the microalbuminuric diabetic patients compared with the normoalbuminuric patients and the control subjects. TAOS was significantly lower in the micoalbuminuric and normoalbuminuric diabetic patients compared with the control subjects, although TAOS levels were similar in both groups of diabetic patients. There was no difference in forearm blood flow between the groups and no association between measured endothelial function and antioxidant defence/oxidative stress and homocysteine in each group. There was no association between plasma total homocysteine and TAOS or whole blood glutathione within the groups. CONCLUSIONS: We have found mild hyperhomocysteinaemia in microalbuminuric DM patients compared with normoalbuminuric DM patients and non-diabetic subjects and some evidence for reduced antioxidant defence in DM patients. These findings add to our understanding of the increased risk of vascular disease in patients with Type 1 diabetes.     

1型糖尿病患儿生长障碍与甲状腺功能及皮质醇变化的关系研究

目的　探讨 1型糖尿病 (T1DM)患儿生长障碍与甲状腺功能及皮质醇变化的关系。方法　 1用化学发光免疫法检测 30例 T1DM患儿 (T1DM组 )及 4 1例正常儿童 (对照组 )的 T3、T4 、TSH、FT3、FT4 及皮质醇 ;用放射免疫法检测两组抗甲状腺球蛋白抗体 (TG- Ab)及抗甲状腺微粒体抗体 (TM- Ab) ,并进行比较。2比较两组间各指标的差异。3分析 T1DM患儿 TSH与生长速度 (GV)、皮质醇与空腹血糖的相关性。结果　 1T1DM组 T3、 T4 、 FT3均较对照组显著降低 ,TSH、皮质醇、 TG- Ab及 TM- Ab均较对照组显著升高。2 T1DM组 TSH、 TG- Ab及 TM- Ab异常率最高 ,但与其他指标异常率无显著性差异。3T1DM组 TSH与 GV呈负相关(r=- 0 .4 14 ,P>0 .0 5 )。4 T1DM组皮质醇与空腹血糖呈正相关 (r=0 .73,P<0 .0 5 )。结论　 1T1DM患儿可并发桥本病。2 T1DM患儿生长障碍的部分原因与甲状腺功能低下及皮质醇升高有关。     

Coenzyme Q10 improves endothelial dysfunction of the brachial artery in Type II diabetes mellitus

Aim/hypothesis: We assessed whether dietary supplementation with coenzyme Q₁₀ improves endothelial function of the brachial artery in patients with Type II (non-insulin-dependent) diabetes mellitus and dyslipidaemia. Methods: A total of 40 patients with Type II diabetes and dyslipidaemia were randomized to receive 200 mg of coenzyme Q₁₀ or placebo orally for 12 weeks. Endothelium-dependent and independent function of the brachial artery was measured as flow-mediated dilatation and glyceryl-trinitrate-mediated dilatation, respectively. A computerized system was used to quantitate vessel diameter changes before and after intervention. Arterial function was compared with 18 non-diabetic subjects. Oxidative stress was assessed by measuring plasma F₂-isoprostane concentrations, and plasma antioxidant status by oxygen radical absorbance capacity. Results: The diabetic patients had impaired flow-mediated dilation [3.8 % (SEM 0.5) vs 6.4 % (SEM 1.0), p = 0.016], but preserved glyceryl-trinitrate-mediated dilation, of the brachial artery compared with non-diabetic subjects. Flow-mediated dilation of the brachial artery increased by 1.6 % (SEM 0.3) with coenzyme Q₁₀ and decreased by –0.4 % (SEM 0.5) with placebo (p = 0.005); there were no group differences in the changes in pre-stimulatory arterial diameter, post-ischaemic hyperaemia or glyceryl-trinitrate-mediated dilation response. Coenzyme Q₁₀ treatment resulted in a threefold increase in plasma coenzyme Q₁₀ (p < 0.001) but did not alter plasma F₂-isoprostanes, oxygen radical absorbance capacity, lipid concentrations, glycaemic control or blood pressure. Conclusion/interpretation: Coenzyme Q₁₀ supplementation improves endothelial function of conduit arteries of the peripheral circulation in dyslipidaemic patients with Type II diabetes. The mechanism could involve increased endothelial release and/or activity of nitric oxide due to improvement in vascular oxidative stress, an effect that might not be reflected by changes in plasma F₂-isoprostane concentrations. [Diabetologia (2002) 45: 420–426] Received: 14 August 2001 and in revised form: 15 November 2001     

Renal function and insulin sensitivity during simvastatin treatment in Type 2 (non-insulin-dependent) diabetic patients with microalbuminuria

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.     

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.     

Reduced endogenous secretory receptor for advanced glycation end products (esRAGE) in young people with Type 1 diabetes developing microalbuminuria

Aims The endogenous secretory receptor for advanced glycation end products (esRAGE) appears to work as a scavenger for AGEs and it has been implicated in the pathogenesis of diabetic complications. The aim of the present study was to perform a longitudinal evaluation of esRAGE in young people with Type 1 diabetes (T1D) in relation to the development of microalbuminuria (MA). Methods Serum esRAGE levels were measured in longitudinally collected blood samples from 49 T1D patients with MA (MA+) and 49 matched normoalbuminuric patients (MA?), followed in the Oxford Regional Prospective Study. esRAGE levels were compared between MA+ and MA? subjects in relation to the time of MA onset. Results Overall, esRAGE levels were significantly lower in MA+ than in MA? subjects (0.727 ± 0.396 vs. 0.936 ± 0.433 ng/ml; P = 0.015). These differences between the two groups were present both before (0.725 ± 0.410 vs. 0.956 ± 0.505 ng/ml, P = 0.038) and after the onset of MA (0.750 ± 0.433 vs. 0.948 ± 0.418 ng/ml, P = 0.04). In a longitudinal analysis there was no effect of age, duration, glycated haemoglobin (HbA_1c) or body mass index standard deviation scores on esRAGE levels (all P > 0.05). In a Cox model, esRAGE levels significantly contributed to the probability of developing MA [Exp(B)(95% confidence interval): 0.34(0.12–0.98); P = 0.04), independently of HbA_1c. Conclusions In this longitudinal study of young people with T1D, esRAGE levels were reduced in MA+ subjects, even before the onset of MA, and appeared to be related to its development, thus suggesting a potential role of esRAGE in the pathogenesis of this complication.