Cardiovascular morbidity and early mortality cluster in parents of type 1 diabetic patients with diabetic nephropathy

OBJECTIVE: A familial predisposition was proposed to be a determinant of the increased morbidity and mortality from cardiovascular disease in type 1 diabetic patients with diabetic nephropathy. The insertion allele of an insertion/deletion polymorphism in the ACE (ACE/ID) gene seems to protect against coronary heart disease in nondiabetic and diabetic subjects. The aim of the present study was to evaluate these hypotheses in parents of a large group of type 1 diabetic patients with and without diabetic nephropathy. RESEARCH DESIGN AND METHODS: We investigated cardiovascular morbidity and mortality of parents of 163 type 1 diabetic patients with nephropathy and parents of 163 sex- and age-matched normoalbuminuric patients with type 1 diabetes. RESULTS: Kaplan-Meier curves showed that total parental mortality was significantly increased in parents of type 1 diabetic patients with nephropathy (121 of 244 [ approximately 50%] ) as compared with parents of normoalbuminuric type 1 diabetic patients (119 of 269 [approximately 44%]) (P = 0.008 [log-rank test]) partially due to an increase in cardiovascular deaths (48 of 244 [approximately 20%] vs. 42 of 269 [approximately 16%], P<0.05). In addition, more patients with nephropathy, as compared with the normoalbuminuric group, had at least one parent with fatal/nonfatal cardiovascular disease (46% [95% CI 38-54] vs. 36% [28-44], P = 0.05). Fathers of patients homozygous for the I-allele of the ACE/ID polymorphism had significantly less myocardial infarction as compared with other genotypes (P = 0.03), regardless of the nephropathic state of the offspring. CONCLUSIONS: Cardiovascular morbidity and early mortality clusters in parents of type 1 diabetic patients with diabetic nephropathy The ACE/ID polymorphism helps explain the increased morbidity from cardiovascular disease.     

Elevated plasma asymmetric dimethylarginine as a marker of cardiovascular morbidity in early diabetic nephropathy in type 1 diabetes

OBJECTIVE: Increased plasma concentration of asymmetric dimethylarginine (ADMA), an endogenous inhibitor of nitric oxide synthase, has been associated with endothelial dysfunction, insulin resistance, and atherosclerosis in nondiabetic populations. In end-stage renal failure, circulating ADMA is elevated and a strong predictor of cardiovascular outcome. This study investigated the relation between ADMA and diabetic micro- and macrovascular complications in a large cohort of type 1 diabetic patients with and without early diabetic nephropathy. RESEARCH DESIGN AND METHODS: ADMA concentrations in plasma were determined by a high-performance liquid chromatography method in 408 type 1 diabetic patients with overt diabetic nephropathy (252 men; mean age 42.7 years [SD 11.0], mean duration of diabetes 28 years [SD 9], median serum creatinine level 102 micromol/l [range 52-684]). A group of 192 patients with longstanding type 1 diabetes and persistent normoalbuminuria served as control subjects (118 men; mean age 42.6 years [SD 10.2], mean duration of diabetes 27 years [SD 9]). RESULTS: In patients with diabetic nephropathy, mean +/- SD plasma ADMA concentration was elevated 0.46 +/- 0.08 vs. 0.40 +/- 0.08 micromol/l in normoalbuminuric patients (P<0.001). An increase in plasma ADMA of 0.1 micromol/l increased the odds ratio of nephropathy to 2.77 (95% CI 1.89-4.05) (P<0.001). Circulating ADMA increased in nephropathy patients with declining kidney function, as indicated by elevated values in the lower quartiles of glomerular filtration rate (<76 ml.min(-1).1.73 m(-2)) (P<0.001 ANOVA). Mean ADMA levels were similar in patients with or without diabetic retinopathy (P>0.2). However, in 44 patients with nephropathy and history of myocardial infarction and/or stroke, ADMA was significantly elevated at 0.48 +/- 0.08 micromol/l compared with 0.46 +/- 0.08 micromol/l in patients without major cardiovascular events (P=0.05). CONCLUSIONS: Elevated circulating ADMA may contribute to the excess cardiovascular morbidity and mortality in early diabetic nephropathy.     

Coagulation and inflammation in overt diabetic nephropathy: association with hyperhomocysteinemia

BACKGROUND: Diabetic nephropathy, especially when advanced, is associated with high prevalence of atherosclerotic cardiovascular disease in which inflammation and coagulation may play pathogenic roles. We investigated the relationships between diabetic nephropathy and coagulation, fibrinolysis, or inflammation in patients with Type 2 diabetes. METHODS: We evaluated markers of inflammation and coagulation in 105 Type 2 diabetic patients with various grades of nephropathy and 49 healthy control subjects, in association with plasma total homocysteine (tHcy) measurements. RESULTS: Plasma tHcy concentrations were significantly higher in diabetic patients than in controls (8.96 +/- 3.04 vs. 6.92 +/- 1.36 micromol/l, P < 0.0001). Plasma concentrations of interleukin (IL)-6 were significantly higher in diabetic patients than in control subjects (P < 0.0001). In diabetic patients, plasma tHcy correlated positively with urinary albumin, fibrinogen, IL-6 and plasmin-alpha2-antiplasmin complex (PAP), while plasma tHcy correlated negatively with creatinine clearance (Ccr) and protein C activity. After adjustment for Ccr, IL-6 and protein C activity were significantly associated with plasma tHcy. Plasma tHcy concentrations were significantly higher in patients with overt albuminuria than in those with normoalbuminuria or microalbuminuria, as were plasma concentrations of fibrinogen, prothrombin F1+2, and interleukin-6. CONCLUSIONS: Diabetic nephropathy is associated with elevated markers for both coagulation and inflammation. High plasma homocysteine may be a link between diabetic nephropathy and both chronic inflammation and hypercoagulability, increasing cardiovascular risk.     

Early disturbances of ambulatory blood pressure load in normotensive type I diabetic patients with microalbuminuria.

OBJECTIVE--To compare 24-h ABP in normotensive type 1 diabetic patients with and without microalbuminuria. RESEARCH DESIGN AND METHODS--The study was a retrospective comparison of cases and matched control subjects. The first phase included 35 type 1 diabetic patients, normotensive by OMS criteria. The 23 patients with normoalbuminuria (< 15 micrograms/min) were compared with 12 patients with microalbuminuria (> or = 15 micrograms/min). In the second phase, the 12 microalbuminuric patients were paired by sex- and age-matched with 12 normoalbuminuric patients and 12 nondiabetic healthy control subjects. We measured casual systolic and diastolic BP and HR, 24-h ABP and AHR (recorded with a Spacelabs automatic recorder), and microalbuminuria. RESULTS--No correlation between microalbuminuria and casual BP was observed. Microalbuminuria was correlated significantly with diastolic 24-h APR and nocturnal systolic and diastolic ABP (r = 0.35, 0.38, and 0.33, respectively; P < 0.05) and with AHR during all time periods (24-h, r = 0.46; day, r = 0.39; night, r = 0.39; P < 0.05). Normo- and microalbuminuric patients did not differ in casual BP and HR. However, microalbuminuric patients had a significant increase in systolic 24-h ABP (119.1 +/- 8.2 vs. 113.1 +/- 8.1, P = 0.05), diastolic 24-h ABP (74.9 +/- 7.5 vs. 70.2 +/- 5.7, P = 0.04), nocturnal systolic ABP (112.8 +/- 7.1 vs. 105.8 +/- 7.9, P = 0.01), and AHR during all time periods. The same results were observed when patients were paired by age and sex. CONCLUSIONS--Normotensive microalbuminuric type 1 patients, although strictly comparable with normoalbuminuric patients for casual BP and HR, have an increased ABP and HR, especially during the night. This difference might reflect dysautonomia. Ambulatory measurement of BP and HR is more appropriate than casual measurements in hemodynamic studies of incipient diabetic nephropathies and could be proposed as an interesting tool for an early prediction of diabetic nephropathy.     

糖尿病肾病患者尿液 NGAL 蛋白的定性及定量检测比较

目的：明确尿液中性粒细胞明胶酶相关脂质运载蛋白（NGAL）的定性及定量检测在糖尿病肾病早期诊断中的意义。方法将74例糖尿病患者按其24 h 尿微量清蛋白排泄率（UAER）分为正常蛋白尿组26例（DN1组,UAER＜30 mg/24 h）,微量蛋白尿组24例（DN2组,UAER 介于30～300 mg/24 h）及大量蛋白尿组24例（DN3组,UAER＞300 mg/24 h）,同时建立对照组25例。同时测定各组尿 NGAL 蛋白的活性及水平并比较两种检测结果。结果各组患者尿 NGAL 活性条带均较对照组明显清晰（P ＝0．000）,大量蛋白尿组 NGAL 活性较正常蛋白尿组高（P ＜0．05）,微量蛋白尿组与正常蛋白尿组比较差异无统计学意义（P ＞0．05）;定量检测则提示大量蛋白尿组 NGAL 水平与其他3组存在区别,大量蛋白尿组 NGAL 排出量高于微量蛋白尿组、正常蛋白尿组及对照组（P ＝0．000）,对照组与正常蛋白尿组、微量蛋白尿组三者间两两比较差异无统计学意义（P ＞0．05）。结论对糖尿病肾病患者而言,尿 NGAL 蛋白活性检测比尿微量蛋白排泄率检测及 NGAL 定量检测敏感,有可能成为糖尿病肾病早期诊断的新型指标。     

Effects of the early ACE inhibition in diabetic nonthrombolyzed patients with anterior acute myocardial infarction

OBJECTIVE: The aim of the present study was to evaluate the clinical efficacy of the ACE inhibitor zofenopril in a cohort of diabetic patients with nonthrombolyzed anterior acute myocardial infarction who were enrolled in the Survival of Myocardial Infarction Long-Term Evaluation (SMILE) trial. RESEARCH DESIGN AND METHODS: Among the overall population of 1,512 patients, 303 (20.0%) had diabetes. The primary end point of this study was the effect of treatment on the 6-week combined occurrence of death and severe congestive heart failure (CHF). Secondary end points included the evaluation of the 6-week rate of major cardiovascular events as well as the 1-year survival rate. RESULTS: After 6 weeks of double-blind treatment, zofenopril significantly reduced both the incidence of the primary end point (8.6 vs. 18.3%; P = 0.019) and the 6-week incidence of severe CHF (0 vs. 7.3%; P = 0.001) in diabetic patients, and the effect was greater than that observed in nondiabetic patients. Conversely, 1-year mortality was significantly reduced among nondiabetic patients (9.1 vs. 13.8%; P = 0.010), whereas in the diabetic population, the decrease did not reach statistical significance (13.7 vs. 16.5%; P = 0.52). CONCLUSIONS: The present data suggest that the clinical outcome of patients with diabetes and myocardial infarction can be significantly improved by early treatment with zofenopril. The lesser effect on 1-year mortality seems to suggest that long-term treatment is probably needed to maintain the benefits of the early ACE inhibition in patients with diabetes.     

Reduced cardiovascular morbidity and mortality in hypertensive diabetic patients on first-line therapy with an ACE inhibitor compared with a diuretic/beta-blocker-based treatment regimen: a subanalysis of the Captopril Prevention Project.

OBJECTIVE: The Captopril Prevention Project (CAPPP) evaluated the effects of an ACE inhibitor-based therapeutic regimen on cardiovascular mortality and morbidity in hypertension. One planned subanalysis of the CAPPP was to evaluate the outcome in the diabetic patient group. RESEARCH DESIGN AND METHODS: In the CAPPP, 572 (4.9% of 10,985 hypertensive patients) had diabetes at baseline and were studied according to a prospective, randomized, open, blinded, end point trial design. Patients aged 25-66 years with diastolic blood pressure > or =100 mmHg were included and randomized to receive either captopril or conventional antihypertensive treatment (diuretics and/or beta-blockers). RESULTS: The primary end point, fatal and nonfatal myocardial infarction and stroke as well as other cardiovascular deaths, was markedly lower in the captopril than in the conventional therapy group (relative risk [RR] = 0.59; P = 0.018). Specifically, cardiovascular mortality, defined as fatal stroke and myocardial infarction, sudden death, and other cardiovascular death, tended to be lower in the captopril group (RR = 0.48; P = 0.084), and no difference was observed between the study groups for stroke (RR = 1.02; P = 0.96). Myocardial infarctions were less frequent in the captopril group than in the conventional therapy group (RR = 0.34; P = 0.002). Furthermore, total mortality was lower in the captopril as compared with the conventional therapy group (RR = 0.54; P = 0.034). Patients with impaired metabolic control seemed to benefit the most from ACE inhibitor-based therapy. CONCLUSIONS: Captopril is superior to a diuretic/beta-blocker antihypertensive treatment regimen in preventing cardiovascular events in hypertensive diabetic patients, especially in those with metabolic decompensation.     

Glomerular filtration rate, cardiorenal end points, and all-cause mortality in type 2 diabetic patients

OBJECTIVE: Chronic kidney disease (CKD) predicts cardiovascular disease (CVD) in the general population. We investigated the effects of stages of renal function using the estimated glomerular filtration rate (eGFR) on all-cause mortality and cardiovascular end points in a prospective cohort of Chinese type 2 diabetic patients. RESEARCH DESIGN AND METHODS: Between 1995 and 2000, 4,421 patients without macrovascular disease or end-stage renal disease were recruited. Renal function was assessed by eGFR, as calculated by the abbreviated Modification of Diet in Renal Disease Study Group formula. Clinical end points included all-cause mortality, cardiovascular end point (cardiovascular death, new admissions due to angina, myocardial infarction, stroke, revascularization, or heart failure), and renal end point (reduction in eGFR by >50%, progression of eGFR to stage 5, or dialysis or renal death). RESULTS: After a median follow-up period of 39.4 months (interquartile range 20.3-55), all-cause mortality rate increased from 1.2% (95% CI 0.8-1.7) to 18.3% (9.1-27.5) (P for trend <0.001) as renal function deteriorated from stage 1 (eGFR > or =90 ml/min per 1.73 m(2)) to stage 4 (15-29 ml/min per 1.73 m(2)). The respective rate of new cardiovascular end points also increased from 2.6% (2.0-3.3) to 25.3% (15.0-35.7) (P for trend <0.001). After adjustment for covariates (age, sex, albuminuria, use of renin-angiotensin-aldosterone system [RAAS] inhibitors, lipids, blood pressure, and glycemic control), hazard ratios across different stages of eGFR (> or =90, 60-89, 30-59, and 15-29 ml/min per 1.73 m(2)) for all-cause mortality were 1.00, 1.27, 2.34, and 9.82 (P for trend <0.001), for cardiovascular end points were 1.00, 1.04, 1.05, and 3.23 (P for trend <0.001), and for renal end points were 1.00, 1.36, 3.34, and 27.3 (P for trend <0.001), respectively. CONCLUSIONS: Chinese type 2 diabetic patients with reduced eGFR were at high risk of developing cardiovascular end points and all-cause mortality, independent of albuminuria and metabolic control.     

Vascular endothelial markers, von Willebrand factor and thrombomodulin index, are specifically elevated in type 2 diabetic patients with nephropathy: comparison of primary renal disease

To elucidate the hypothesis that albuminuria in diabetic subjects reflects widespread vascular damage, plasma markers for vascular endothelial damage was measured in diabetic subjects with various degrees of albuminuria and compared to results in patients with primary renal disease. The groups consisted of 31 non-diabetic patient controls with normoalbuminuria, 109 type 2 diabetic patients with normo- micro- and macro-albuminuria, and 16 proteinuric patients with primary renal disease. Endothelial markers, plasma von Willebrand factor (vWF) and thrombomodulin (TM), were measured by enzyme-linked immunosolvent assay and enzyme immunoassay (EIA) methods, respectively. Plasma vWF levels were similar in controls (119+/-7%, mean+/-S.E.M.) and diabetic patients with normoalbuminuria (139+/-6), but significantly elevated in diabetic patients with microalbuminuria (174+/-11) and macroalbuminuria (204+/-17), while the level was not increased in patients with primary renal disease (124+/-11). Because plasma TM level was strongly affected by kidney function, TM index (TM (FU/ml)/serum creatinine (mg %)) was used as an endothelial marker. The TM index was substantially increased in diabetic patients with overt nephropathy compared with controls (5.29+/-2.98 vs. 2.35+/-0.85), whereas this was not observed in patients with primary renal disease (3.25+/-0.29). Both vWF and TM index were significantly higher in diabetic patients with retinopathy than in the patients without retinopathy. These results suggest that generalized vascular endothelial damage occurs in diabetic nephropathy including the microalbuminuric stage, which is not attributed to kidney damage per se.     

血清铁调素-25水平与2型糖尿病肾病中肾功能不良进展的相关性研究

目的分析血清铁调素-25与2型糖尿病肾病中肾功能不良进展之间是否具有相关性。方法该研究试验设计为巢式病例对照设计,220例患者资料来源于2015年4月至2019年6月在徐州市中心医院住院的2型糖尿病肾病患者。血清铁调素-25水平采用ELISA法检测,以肾功能不良进展(肾替代疗法或血清肌酐加倍)作为结局指标。采用多因素Cox回归分析为主要的分析方法,配合以肾小球滤过率(GFR)为分层因素的分层分析。结果Cox分析显示血清铁调素-25水平与2型糖尿病所致的慢性肾病患者的肾功能不良进展之间不具有相关性(HR=1.18,95%CI:0.97~1.45)。分层分析显示GFR是以上关系的效应修饰因素:GFR低[<51.8 mL/(min·1.73 m 2)]时,血清铁调素-25水平与2型糖尿病肾病不良进展之间呈正相关(HR=2.56,95%CI:1.50~4.40),而GFR高的时候,血清铁调素-25水平与2型糖尿病肾病不良进展之间呈负相关(HR=0.00,95%CI:0.00~0.21)。结论血清铁调素-25水平在部分人群中对2型糖尿病肾病不良进展具有预测作用。     

Dissociation between urinary pyrraline and pentosidine concentrations in diabetic patients with advanced nephropathy

It has been reported that the concentrations of both pyrraline and pentosidine, well-characterized advanced glycation end products, are increased in the urine of diabetic patients. To determine factors that influence the urinary excretion of pyrraline or pentosidine, we compared pyrraline or pentosidine concentrations with glycemic-control indexes, urinary albumin excretion, and urinary β2-microglobulin in patients with type 2 diabetes. The study was conducted in 39 age-matched healthy control subjects and 50 diabetic patients, including 22 patients with normoalbuminuria, 15 with microalbuminuria, and 13 with macroalbuminuria. Both urinary pyrraline and pentosidine were measured in early-morning urine specimens with the use of high-pressure liquid chromatography. The urinary pentosidine concentration was significantly higher in diabetic patients than in control subjects (P < .01). In contrast, the urinary pyrraline concentration was significantly lower in diabetic patients than in control subjects (P < .001). Urinary pentosidine concentrations were greater in diabetic patients with macroalbuminuria and microalbuminuria than in those with normoalbuminuria. However, urinary pyrraline concentrations were significantly lower in diabetic patients with advanced nephropathy. Both the hemoglobin A_1c (HbA_1c) and the preceding year's mean HbA_1c were lower in patients with macroalbuminuria than in those with normoalbuminuria or microalbuminuria. Urinary pyrraline, but not pentosidine, showed a significantly positive correlation with the preceding year's mean HbA_1c (P<0.01). Multivariate analysis disclosed that urinary β-2-microglobulin was independently correlated with the urinary concentrations of pentosidine and pyrraline (P < .05 for both). We conclude that the urinary concentration of pentosidine is greater in diabetic patients with overt nephropathy, whereas the urinary pyrraline concentration is significantly lower in diabetic patients with overt nephropathy. Because urinary pyrraline is more directly influenced by glycemia than by pentosidine, the difference in glycemic control among diabetic patients with various grades of nephropathy may be responsible for a dissociation between urinary pyrraline and pentosidine concentrations in patients with overt diabetic nephropathy.     

胱抑素C及同型半胱氨酸的血清含量与糖尿病肾病患者肾小球滤过率的相关性研究

目的:通过检测血胱抑素C(CystatinC,CysC)、同型半胱氨酸(Homocysteine,Hcy)浓度及尿白蛋白清除率(urinealbumin excretionrate,UAER)在糖尿病肾病(diabetic nephropathy,DN)进程中的变化以及与肾小球滤过率(glomerular filtration rate,GFR)的相关性,探讨其在DN诊断中的价值。方法:共47例患者,根据肾小球滤过率将其分为早期糖尿病肾病组(early-DN组,GFR≥60mL/min)及晚期糖尿病肾病组(end-DN组,GFR<60mL/min),比较两组间CysC、Hcy的变化以及与肾小球滤过率的相关性。结果:end-DN组CysC、UAER均高于early-DN组(P<0.01)。相关分析显示肾小球滤过率与CysC、Hcy、UAER负相关(r=-0.584,P=0.000;r=-0.547,P=0.000;r=-0.507,P=0.000),在慢性肾脏病(chronic kidney disease,CKD)Ⅱ、Ⅲ期,肾小球滤过率与CysC、Hcy负相关(r=-0.617,P=0.000;r=-0.431,P=0.018)。结论:糖尿病患者中,伴随慢性肾脏病进程,CysC、Hcy、UAER逐渐升高,尤其在CKDⅡ、Ⅲ期,CysC、Hcy联合检测与UAER比较,能更好的反应糖尿病肾病肾小球滤过功能异常。     

Amadori-albumin correlates with microvascular complications and precedes nephropathy in type 1 diabetic patients

BACKGROUND: Amadori-albumin, a major glycated protein, is involved in experimental hyperglycaemia-induced microvascular complications, and is associated with advanced nephropathy in Type I diabetic patients in humans. Our aim was to assess the association of Amadori-albumin with early nephropathy and with retinopathy in Type I diabetic patients and the involvement of chronic low-degree inflammation therein. DESIGN AND METHODS: Amadori-albumin, the Amadori product of haemoglobin (HbA1c), C-reactive protein, and fibrinogen levels were measured in the EUCLID study, a 2-year randomised, double-blind, placebo-controlled trial of lisinopril in 447 Type I diabetic patients. Retinal photographs were taken in 341 patients at baseline and 294 at follow up. RESULTS: Amadori-albumin was positively associated with albumin the excretion rate and retinopathy status (P = 0.0001 and P = 0.02 for trend, respectively) and with the progression from normoalbuminuria to (micro)albuminuria (38.6 U mL(-1) in nonprogressors, 44.3 U mL-1 in progressors; P = 0.02), but not with the development or progression of retinopathy during a 2-year follow up. Amadori-albumin levels at baseline were associated with C-reactive protein and fibrinogen (P = 0.0007 and P = 0.0001, respectively). C-reactive protein and fibrinogen were also associated with albumin excretion rates (P = 0.03 and P = 0.01, respectively) and retinopathy status (P = 0.02 and P = 0.0006, respectively). Adjustment for these inflammatory markers did not markedly attenuate the association between Amadori-albumin and the albumin excretion rate, while adjustment for fibrinogen, but not C-reactive protein, abolished the association between Amadori-albumin and retinopathy. Lisinopril had no impact on the association between the levels of Amadori-albumin and albumin excretion rates or retinopathy. CONCLUSIONS: Amadori-albumin was associated with early nephropathy and with retinopathy in Type I diabetic patients and preceded an increase in albumin excretion rate, but not retinopathy. A chronic low-degree inflammation does not appear to be involved in Amadori-albumin-associated microvascular complications in Type I diabetes.     

Natural history and prognostic factors of diabetic nephropathy in type 2 diabetes

BACKGROUND: The causes and mechanisms of increased mortality of patients with diabetic nephropathy are unclear, and its natural history is poorly understood. Aim: To evaluate risk factors for mortality in type 2 diabetic patients with nephropathy. DESIGN: Retrospective study of clinical and biochemical parameters in diabetic nephropathic patients and controls sampled from a secondary care register. METHODS: We studied 170 type 2 diabetic patients (from 1987 to 1995) with nephropathy (proteinuria >0.5 g/24 h) and 170 non-nephropathic patients. Follow-up was until death or December 1997. Details of demographics, clinical and treatment history were obtained from medical records. RESULTS: Mean follow-up was 5.3 years. Of the patients with nephropathy at baseline, 63 (37%) died compared with 14 (8%) non-nephropathic patients (chi(2)=53.8, p<0.0001). Age- and sex-adjusted all-cause mortality rates were 8.1 (6.4, 9.8) and 1.4 (0.5, 2.2) deaths per 100 person-years, respectively (rate ratio 5.8). Forty-four patients (57%) died from cardiovascular causes (rate ratio 5.4). Mortality was directly proportional to degree of proteinuria: 0.5-2 g/24 h, 4.6 (2.9-7.1); >2 g/24 h, 9.9 (7.3-13.5) per 100 patient-years. A 36% (5-78%) excess risk of mortality was observed for each log unit increase in proteinuria. Multivariate Cox regression analyses confirmed a five-fold excess risk for all-cause and cardiovascular mortality in patients with nephropathy compared with those without. This was independent of other risk factors including baseline age [5% (1-8%)/year], creatinine [2.5 (1.12-5.6)/10 micromol/l] and glycaemic control (HbA(1c)) [15% (1-31%) per 1% rise]. CONCLUSIONS: Proteinuria is a potentially preventable and reversible risk factor associated with high mortality in type 2 diabetic patients. Prevention of the development of overt nephropathy and improvement in diabetes control may reduce mortality in these patients.     

Primary prevention of cardiovascular events with low-dose aspirin and vitamin E in type 2 diabetic patients: results of the Primary Prevention Project (PPP) trial

OBJECTIVE: We investigated in general practice the efficacy of antiplatelets and antioxidants in primary prevention of cardiovascular events in people with type 2 diabetes. RESEARCH DESIGN AND METHODS: The Primary Prevention Project (PPP) is a randomized, open trial with a two-by-two factorial design aimed to investigate low-dose aspirin (100 mg/day) and vitamin E (300 mg/day) in the prevention of cardiovascular events in patients with one or more cardiovascular risk factors. The primary end point was a composite end point of cardiovascular death, stroke, or myocardial infarction. A total of 1,031 people with diabetes in the PPP, aged >/=50 years, without a previous cardiovascular event were enrolled by 316 general practitioners and 14 diabetes outpatient clinics. RESULTS: The PPP trial was prematurely stopped (after a median of 3.7 years) by the independent data safety and monitoring board because of a consistent benefit of aspirin compared with the control group in a population of 4,495 patients with one or more major cardiovascular risk factors. In diabetic patients, aspirin treatment was associated with a nonsignificant reduction in the main end point (relative risk [RR] = 0.90, 95% CI 0.50-1.62) and in total cardiovascular events (0.89, 0.62-1.26) and with a nonsignificant increase in cardiovascular deaths (1.23, 0.69-2.19). In nondiabetic subjects, RRs for the main end point, total cardiovascular events, and cardiovascular deaths were 0.59 (0.37-0.94), 0.69 (0.53-0.90), and 0.32 (0.14-0.72), respectively. No significant reduction in any of the end points considered could be found with vitamin E in either diabetic or nondiabetic subjects. CONCLUSIONS: Our data suggest a lower effect of primary prevention of cardiovascular disease (CVD) with low-dose aspirin in diabetic patients as opposed to subjects with other cardiovascular risk factors. If confirmed, these findings might indicate that the antiplatelet effects of aspirin in diabetic patients are overwhelmed by aspirin-insensitive mechanisms of platelet activation and thrombus formation, thus making the balance between benefits and harms of aspirin treatment unfavorable. Further large-scale trials investigating the role of aspirin in the primary prevention of CVD in diabetic patients are urgently needed.     

Serum adiponectin is increased in type 1 diabetic patients with nephropathy

OBJECTIVE: To elucidate whether serum adiponectin is associated with renal function, low-grade inflammatory markers, metabolic control, and insulin resistance in type 1 diabetic patients with and without nephropathy. RESEARCH DESIGN AND METHODS: A total of 189 type 1 diabetic patients from the Finnish Diabetic Nephropathy Study were divided into three groups based on their urinary albumin excretion rate (AER): patients with normal AER (n = 66) had no antihypertensive medication, while patients with microalbuminuria (n = 63) or macroalbuminuria (n = 60) were all treated with an ACE inhibitor. Renal function was estimated with the Cockcroft-Gault formula. Adiponectin was measured by an in-house time-resolved immunofluorometric assay. RESULTS: Adiponectin concentrations were higher in women than in men, but since there was no significant difference in sex distribution between the groups, data were pooled. Adiponectin concentrations were higher in patients with macroalbuminuria (19.8 +/- 12.0 mg/l) than in patients with microalbuminuria (13.1 +/- 4.8 mg/l) or normoalbuminuria (11.8 +/- 4.2 mg/l). In a univariate analysis, adiponectin was positively associated with creatinine (r = 0.41; P < 0.0001), AER (r = 0.33; P < 0.0001), interleukin-6 (r = 0.22; P = 0.002), systolic blood pressure (r = 0.22; P = 0.004), HbA(1c) (r = 0.17; P = 0.02), total cholesterol (r = 0.16; P = 0.03), and HDL cholesterol (r = 0.16; P = 0.03) and negatively with estimated glomerular filtration rate (GFR; r = -0.52; P < 0.0001) and waist-to-hip ratio (WHR; r = -0.16; P = 0.03). In a multiple linear regression analysis including the above variables, estimated GFR, AER, and WHR were independently associated with adiponectin levels (r(2) = 0.32). CONCLUSIONS: Serum adiponectin concentrations are increased in type 1 diabetic patients with nephropathy, and levels are further associated with renal insufficiency.     

Relation between serum 3-deoxyglucosone and development of diabetic microangiopathy

OBJECTIVE: 3-Deoxyglucosone (3-DG), a highly reactive intermediate of the glycation reaction, has been suggested to contribute to the development of diabetes complications. To verify this hypothesis, we assessed the relation between serum 3-DG concentrations and the severity of diabetic microangiopathy in diabetic patients. RESEARCH DESIGN AND METHODS: We conducted a high-performance liquid chromatography assay to determine the serum 3-DG concentrations of 110 diabetic patients with different degrees of severity of diabetic microangiopathy and 57 age-matched control subjects. RESULTS: The fasting serum 3-DG level in diabetic patients was significantly (P < 0.001) higher than that in control subjects (353 +/- 110 vs. 199 +/- 53 nmol/l). The 3-DG levels were significantly (P < 0.001) elevated even in the diabetic patients showing normoalbuminuria (n = 62, 322 +/- 79 nmol/l) compared with control subjects. The 3-DG levels were further elevated in the patients with microalbuminuria (n = 30, 383 +/- 146 nmol/l) and overt proteinuria (n = 18, 410 +/- 100 nmol/l) (P = 0.027 and P < 0.001 vs. normoalbuminuria group, respectively). This phenomenon was basically reproduced in a category of retinopathy. Furthermore, the diabetic patients with low nerve conduction velocity showed a tendency to display higher 3-DG levels. CONCLUSIONS: The present results show that the fasting serum 3-DG level is elevated in diabetic patients and that the patients with relatively higher 3-DG levels were prone to suffer from more severe complications, indicating a possible association of 3-DG with diabetic microangiopathy.     

Diabetic nephropathy. Future avenue.

Diabetes mellitus has become the leading cause of ESRF in the United States. Patients with diabetic nephropathy suffer high cardiovascular morbidity and mortality. Because only 40% of diabetic patients eventually develop diabetic kidney disease, it may be possible to devise primary prevention measures targeted at the subset of patients at risk. Recently, a predisposition to hypertension, a family history of diabetic nephropathy, and a family history of CVD disease each have been associated independently with the development of diabetic renal complication in IDDM. Risk factors for macrovascular damage, including raised arterial BP, dyslipidemia, and insulin resistance, can be detected early in the course of progression to diabetic nephropathy. These risk indicators recently have been shown to be already present at the stage of normoalbuminuria in those patients who eventually will progress to microalbuminuria. Treatment of established renal disease can only delay the onset of ESRF, and lowering of microalbuminuria has been shown to retard the onset of persistent proteinuria. However, no study to date has demonstrated prevention of renal disease in these patients. The ultimate aim should, therefore, be the prevention of the transition from normoalbuminuria to microalbuminuria in individuals who are at higher risk of diabetic renal disease and CVD.     

Influence of caffeine on heart rate variability in patients with long-standing type 1 diabetes

OBJECTIVE: The effect of caffeine on cardiovascular health remains controversial. Patients with long-standing type 1 diabetes are at risk of autonomic failure and sudden cardiac death. We investigated the effects of caffeine on autonomic dysfunction (as assessed by heart rate variability [HRV]) in this high-risk group and in a control population. RESEARCH DESIGN AND METHODS: Using a randomized blinded, placebo-controlled, crossover design trial, we examined 2 weeks of caffeine consumption (250 mg twice daily) on HRV in 20 type 1 diabetic patients and 10 matched healthy volunteers. RESULTS: Baseline HRV was blunted in the diabetic patients (P < 0.0005 vs. control subjects) and markedly increased by caffeine in both groups (+103% in the group with diabetes [P = 0.009] and +38% in control subjects [P = 0.002]). The caffeine-associated increase in HRV was not statistically different between the control and the type 1 diabetes groups (P = 0.16). CONCLUSIONS: Modest amounts of caffeine improved autonomic function in diabetic patients and healthy volunteers. For individuals with abnormal HRV, regular caffeine use may have the potential to reduce the risk of cardiovascular events.     

Apolipoprotein E polymorphisms and mortality in Italian type 2 diabetic patients

AIMS: To determine if apolipoprotein E polymorphism is associated with cardiovascular or all-cause mortality in Italian Type 2 diabetic patients. METHODS: A prospective study of mortality in Type 2 diabetic patients (n = 433) as a function of apolipoprotein E phenotype, which was assessed at entry into the study. During follow up (10 years), 110 (25.4%) patients died of which 66 (15.2%) were the result of cardiovascular causes. Cause of death was established from death certificates and clinical records. The clinical status of the survivors was determined at the end of the study. RESULTS: Apolipoprotein E polymorphisms were not associated with excess cardiovascular or all-cause mortality in the Italian Type 2 diabetic patients either in univariate or multivariate analyses. Age, duration of diabetes and glycated haemoglobin levels at entry were the primary determinants of premature mortality in the diabetic population. CONCLUSIONS: Apolipoprotein E polymorphisms are not markers for premature mortality in Italian Type 2 diabetic patients. The impact of apolipoprotein E mutations may be attenuated by environmental factors, notably a healthier diet, in Italian patients.