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Biomedical subjects

John H Fuller

Publications and source records attributed to John H Fuller.

At least 19 recordsLinked to original sources
PubMed2006

Analysis of efficacy and safety in patients aged 65-75 years at randomization: Collaborative Atorvastatin Diabetes Study (CARDS).

OBJECTIVE: Rates of cardiovascular disease are highest in the elderly. Lipid-lowering statin therapy reduces the proportional risk as effectively in older patients as in younger individuals; however, limited data are available for elderly patients with type 2 diabetes. We conducted a post hoc analysis to compare the efficacy and safety of atorvastatin among 1,129 patients aged 65-75 years at randomization with 1,709 younger patients in the Collaborative Atorvastatin Diabetes Study (CARDS). RESEARCH DESIGN AND METHODS: CARDS was a randomized placebo-controlled trial of 10 mg/day atorvastatin for primary prevention of cardiovascular disease in patients aged 40-75 years with LDL cholesterol concentrations </=4.14 mmol/l followed for a median of 3.9 years. The primary end point was time to first occurrence of acute coronary heart disease events, coronary revascularizations, or stroke. RESULTS: Atorvastatin treatment resulted in a 38% reduction in relative risk ([95% CI -58 to -8], P = 0.017) of first major cardiovascular events in older patients and a 37% reduction ([-57 to -7], P = 0.019) in younger patients. Corresponding absolute risk reductions were 3.9 and 2.7%, respectively (difference 1.2% [95% CI -2.8 to 5.3], P = 0.546); numbers needed to treat for 4 years to avoid one event were 21 and 33, respectively. All-cause mortality was reduced nonsignificantly by 22% ([-49 to 18], P = 0.245) and 37% ([-64 to 9], P = 0.98), respectively. The overall safety profile of atorvastatin was similar between age-groups. CONCLUSIONS: Absolute and relative benefits of statin therapy in older patients with type 2 diabetes are substantial, and all patients warrant treatment unless specifically contraindicated.

Adult↗
PubMed2006

Relation between blood glucose and coronary mortality over 33 years in the Whitehall Study.

OBJECTIVE: Glucose intolerance is a risk factor for coronary disease, but there is uncertainty about the shape of the dose-response relationship between glucose level and risk of coronary mortality. We examined the prospective relation of 2-h postload blood glucose (2hBG) with coronary and other major causes of mortality over 33 years. RESEARCH DESIGN AND METHODS: A 50-g oral glucose tolerance test (OGTT) was performed at baseline (1967-1969) in 17,869 male civil servants aged 40-64 years. RESULTS: There were 3,561 coronary deaths during 451,787 person-years of observation. All-cause, cardiovascular, and respiratory mortality were elevated among participants with glucose intolerance. The hazard of coronary mortality rose from 2hBG = 4.6 mmol/l (83 mg/dl [95% CI 4.2-5.3]). The dose-response relation was best fitted by a single slope above this level, with no evidence of nonlinearity, compared with Cox models using other threshold levels, and those containing log 2hBG terms. There was no evidence for a dose-response relationship below 2hBG = 4.6 mmol/l. Between this level and 11.1 mmol/l (200 mg/dl), the age-adjusted hazard ratio was 3.62 (95% CI 2.3-5.6). The graded relationship was attenuated by 45% after adjustment for baseline coronary heart disease (CHD), BMI, systolic blood pressure, blood cholesterol, smoking, physical activity, lung function, and employment grade. CONCLUSIONS: A threshold model with linear slope best described the dose-response relationship between postload blood glucose and CHD mortality risk.

Adult↗
PubMed2006

High risk of cardiovascular disease in patients with type 1 diabetes in the U.K.: a cohort study using the general practice research database.

OBJECTIVE: To estimate the absolute and relative risk of cardiovascular disease (CVD) in patients with type 1 diabetes in the U.K. RESEARCH DESIGN AND METHODS: Subjects with type 1 diabetes (n = 7,479) and five age- and sex-matched subjects without diabetes (n = 38,116) and free of CVD at baseline were selected from the General Practice Research Database (GPRD), a large primary care database representative of the U.K. population. Incident major CVD events, comprising myocardial infarction, acute coronary heart disease death, coronary revascularizations, or stroke, were captured for the period 1992-1999. RESULTS: The hazard ratio (HR) for major CVD was 3.6 (95% CI 2.9-4.5) in type 1 diabetic men compared with those without diabetes and 7.7 (5.5-10.7) in women. Increased HRs were found for acute coronary events (3.0 and 7.6 in type 1 diabetic men and women, respectively, versus nondiabetic subjects), coronary revascularizations (5.0 in men, 16.8 in women), and for stroke (3.7 in men, 4.8 in women). Type 1 diabetic men aged 45-55 years had an absolute CVD risk similar to that of men in the general population 10-15 years older, with an even greater difference in women. CONCLUSIONS: Despite advances in care, these data show that absolute and relative risks of CVD remain extremely high in patients with type 1 diabetes. Women with type 1 diabetes continue to experience greater relative risks of CVD than men compared with those without diabetes.

Adult↗
PubMed2005

Adiponectin is inversely associated with renal function in type 1 diabetic patients.

OBJECTIVE: Adipose tissue is a source of several adipocytokines that may contribute to vascular complications. We examined the relation of adiponectin with several cardiovascular risk factors and with micro- and macrovascular outcomes in type 1 diabetic patients. DESIGN: Cross-sectional data on 543 type 1 diabetic patients from the EURODIAB Prospective Complications Study were analyzed. We determined adiponectin, TNF-alpha, IL-6, C-reactive protein, soluble vascular cell adhesion molecule (sVCAM-1), and sE-selectin by ELISA. RESULTS: We found that adiponectin was negatively correlated with body mass index, waist to hip ratio, insulin, and fasting triglyceride, and positively with high-density lipoprotein, low-density lipoprotein, and total cholesterol, TNF-alpha, and sVCAM-1, but was not related to C-reactive protein, IL-6, and sE-selectin. Surprisingly, significantly raised concentrations of adiponectin were found with albuminuria, retinopathy, and cardiovascular diseases (for all, P < 0.0001). Adiponectin levels were inversely associated with glomerular filtration rate (GFR) (P < 0.0001). Multivariate regression models showed that the associations of adiponectin with albuminuria and GFR were independent of established risk factors. The association between adiponectin and albuminuria was attenuated by GFR, whereas the association of adiponectin with retinopathy and cardiovascular disease disappeared after adjustments for established risk factors. The association of adiponectin with sVCAM-1 was independent of established risk factors. CONCLUSION: We conclude that in type 1 diabetic patients, adiponectin is associated with impaired renal function. Adiponectin may be enhanced in type 1 diabetic patients as a physiological counterregulatory response to mitigate endothelial damage and vascular damage.

Adiponectin↗
PubMed2005

Advanced glycation end products are associated with pulse pressure in type 1 diabetes: the EURODIAB Prospective Complications Study.

We investigated the associations of pulse pressure (a measure of arterial stiffness) with the early glycation products hemoglobin A1c (HbA1c) and Amadori albumin and the advanced glycation end products pentosidine, Nepsilon-(carboxymethyl)lysine and Nepsilon-(carboxyethyl)lysine in a large group of type 1 diabetic individuals of the EURODIAB Prospective Complications Study. We did a cross-sectional nested case-control study from the EURODIAB Prospective Complications Study of 543 (278 men) European individuals with type 1 diabetes diagnosed at <36 years of age. We used linear regression analyses to investigate the association of pulse pressure with glycation products. Pulse pressure was significantly associated with plasma levels of Nepsilon-(carboxymethyl)lysine and Nepsilon-(carboxyethyl)lysine but not with HbA1c, Amadori albumin, and urinary levels of pentosidine. Regression coefficients adjusted for age, sex, mean arterial pressure, and duration of diabetes were 0.09 mm Hg (P=0.003) per 1 microM/M lysine Nepsilon-(carboxymethyl)lysine; 0.24 mm Hg (P=0.001) and -0.03 mm Hg (P=0.62) per 1 microM/M lysine Nepsilon-(carboxyethyl)lysine (in individuals with and without complications, respectively; P interaction=0.002); and 0.50 mm Hg (P=0.16) per 1% HbA1c; 0.07 mm Hg (P=0.12) per 1 U/mL Amadori albumin; and 0.77 mm Hg (P=0.48) per 1 nmol/mmol creatinine pentosidine. In young type 1 diabetic individuals, arterial stiffness is strongly associated with the advanced glycation end products Nepsilon-(carboxymethyl)lysine and Nepsilon-(carboxyethyl)lysine. These findings suggest that the formation of advanced glycation end products is an important pathway in the development of arterial stiffness in young type 1 diabetic individuals.

Adult↗
PubMed2005

Vascular risk factors and diabetic neuropathy.

BACKGROUND: Other than glycemic control, there are no treatments for diabetic neuropathy. Thus, identifying potentially modifiable risk factors for neuropathy is crucial. We studied risk factors for the development of distal symmetric neuropathy in 1172 patients with type 1 diabetes mellitus from 31 centers participating in the European Diabetes (EURODIAB) Prospective Complications Study. METHODS: Neuropathy was assessed at baseline (1989 to 1991) and at follow-up (1997 to 1999), with a mean (+/-SD) follow-up of 7.3+/-0.6 years. A standardized protocol included clinical evaluation, quantitative sensory testing, and autonomic-function tests. Serum lipids and lipoproteins, glycosylated hemoglobin, and the urinary albumin excretion rate were measured in a central laboratory. RESULTS: At follow-up, neuropathy had developed in 276 of 1172 patients without neuropathy at baseline (23.5 percent). The cumulative incidence of neuropathy was related to the glycosylated hemoglobin value and the duration of diabetes. After adjustment for these factors, we found that higher levels of total and low-density lipoprotein cholesterol and triglycerides, a higher body-mass index, higher von Willebrand factor levels and urinary albumin excretion rate, hypertension, and smoking were all significantly associated with the cumulative incidence of neuropathy. After adjustment for other risk factors and diabetic complications, we found that duration of diabetes, current glycosylated hemoglobin value, change in glycosylated hemoglobin value during the follow-up period, body-mass index, and smoking remained independently associated with the incidence of neuropathy. Cardiovascular disease at baseline was associated with double the risk of neuropathy, independent of cardiovascular risk factors. CONCLUSIONS: This prospective study indicates that, apart from glycemic control, the incidence of neuropathy is associated with potentially modifiable cardiovascular risk factors, including a raised triglyceride level, body-mass index, smoking, and hypertension.

Adult↗
PubMed2005

Diabetic retinopathy is associated with mortality and cardiovascular disease incidence: the EURODIAB prospective complications study.

OBJECTIVE: To study the relationship of nonproliferative and proliferative retinopathy with all-cause mortality and cardiovascular disease (CVD) incidence in type 1 diabetic patients and, additionally, the role of cardiovascular risk factors in these associations. RESEARCH DESIGN AND METHODS: This prospective study included 2,237 type 1 diabetic patients from 31 centers in 16 European countries at baseline, aged 15-60 years, who were examined for retinopathy by taking two-field 45 degrees fundus photographs, which were centrally graded. Mortality and cardiovascular morbidity follow-up was assessed 6-8 years after baseline examination according to a standardized protocol. RESULTS: After 7.9 years of follow-up, 64 patients had died and 128 patients had incident CVD. The age- and sex-adjusted hazard ratios (HRs) of all-cause mortality were 1.45 (95% CI 0.71-2.96) and 4.16 (1.96-8.84) in patients with nonproliferative and proliferative retinopathy at baseline, respectively. Adjustments for cardiovascular risk factors completely obliterated the association with nonproliferative retinopathy, whereas the association with proliferative retinopathy remained twofold increased, although nonsignificant. The age- and sex-adjusted HRs of incident CVD were 1.73 (1.15-2.60) and 2.05 (1.22-3.45) in patients with nonproliferative and proliferative retinopathy, respectively. After adjustments for cardiovascular risk factors, both associations were attenuated and lost statistical significance. CONCLUSIONS: This study shows that type 1 diabetic patients with nonproliferative or proliferative retinopathy have an increased risk for all-cause mortality and incident CVD. The presence of cardiovascular risk factors explained the associations to a large extent, except for the associations with proliferative retinopathy, which suggests that other shared mechanisms may be involved.

Adolescent↗
PubMed2004

Risk factors for coronary heart disease in type 1 diabetic patients in Europe: the EURODIAB Prospective Complications Study.

OBJECTIVE: The goal of the study was to examine risk factors in the prediction of coronary heart disease (CHD) and differences in men and women in the EURODIAB Prospective Complications Study. RESEARCH DESIGN AND METHODS: Baseline risk factors and CHD at follow-up were assessed in 2,329 type 1 diabetic patients without prior CHD. CHD was defined as physician-diagnosed myocardial infarction, angina pectoris, coronary artery bypass graft surgery, and/or Minnesota-coded ischemic electrocardiograms or fatal CHD. RESULTS: There were 151 patients who developed CHD, and the 7-year incidence rate was 8.0 (per 1,000 person-years) in men and 10.2 in women. After adjustment for age and/or duration of diabetes, the following risk factors were related to CHD in men: age, GHb, waist-to-hip ratio (WHR), HDL cholesterol, smoking, albumin excretion rate (AER), and autonomic neuropathy. The following risk factors were related to CHD in women: age, systolic blood pressure (BP), fasting triglycerides, AER, and retinopathy. Multivariate standardized Cox proportional hazards models showed that age (hazard ratio 1.5), AER (1.3 in men and 1.6 in women), WHR (1.3 in men), smoking (1.5 in men), fasting triglycerides (1.3 in women) or HDL cholesterol (0.74 in women), and systolic BP (1.3 in women) were predictors of CHD. CONCLUSIONS: This study supports the evidence for a strong predictive role of baseline albuminuria in the pathogenesis of CHD in type 1 diabetes. Furthermore, sex-specific risk factors such as systolic BP, fasting triglycerides (or HDL cholesterol), and WHR were found to be important in the development of CHD.

Adult↗
PubMed2003

beta-Catenin regulates vascular endothelial growth factor expression in colon cancer.

To evaluate whether beta-catenin signaling has a role in the regulation of angiogenesis in colon cancer, a series of angiogenesis-related gene promoters was analyzed for beta-catenin/TCF binding sites. Strikingly, the gene promoter of human vascular endothelial growth factor (VEGF, or VEGF-A) contains seven consensus binding sites for beta-catenin/TCF. Analysis of laser capture microdissected human colon cancer tissue indicated a direct correlation between up-regulation of VEGF-A expression and adenomatous polyposis coli (APC) mutational status (activation of beta-catenin signaling) in primary tumors. In metastases, this correlation was not observed. Analysis by immunohistochemistry of intestinal polyps in mice heterozygous for the multiple intestinal neoplasia gene (Min/+) at 5 months revealed an increase and redistribution of VEGF-A in proximity to those cells expressing nuclear beta-catenin with a corresponding increase in vessel density. Transfection of normal colon epithelial cells with activated beta-catenin up-regulated levels of VEGF-A mRNA and protein by 250-300%. When colon cancer cells with elevated beta-catenin levels were treated with beta-catenin antisense oligodeoxynucleotides, VEGF-A expression was reduced by more than 50%. Taken together, our observations indicate a close link between beta-catenin signaling and the regulation of VEGF-A expression in colon cancer.

Adenocarcinoma↗
PubMed2003

Pulse pressure is associated with age and cardiovascular disease in type 1 diabetes: the Eurodiab Prospective Complications Study.

OBJECTIVE: Type 1 diabetic individuals are thought to have increased arterial stiffness, and are at high risk for cardiovascular disease. However, it is not known whether increased arterial stiffness in type 1 diabetes causes cardiovascular disease. To explore this issue, the present study investigated the association, in type 1 diabetes, of age and pulse pressure, an estimate of arterial stiffness, and the influence of the presence of microvascular complications on this association. In addition, we determined the association of mean arterial pressure and pulse pressure with incident cardiovascular disease. METHODS: We studied a cohort of 3250 type 1 diabetic individuals of the EURODIAB Prospective Complications Study. Mean age and median follow-up were 33 and 7.4 years. One hundred and sixty-three individuals developed a first manifestation of cardiovascular disease during follow-up. Linear regression analysis was used to determine the association of age with pulse pressure. Relative risks of cardiovascular disease were estimated by Cox regression analyses adjusted for age, sex and mean arterial pressure or pulse pressure.RESULTS In cross-sectional analyses, age was associated with pulse pressure (P < 0.001) and this association was stronger in the presence of micro- or macroalbuminuria or retinopathy than in their absence (interaction for albuminuria, P < 0.001; interaction for retinopathy, P < 0.001). In prospective analyses, both mean arterial pressure and pulse pressure were associated with cardiovascular disease [adjusted relative risks and (95% confidence interval) per 10 mmHg increase were 1.08 (0.94-1.24) and 1.09 (0.98-1.21)]. CONCLUSIONS: This study shows an association of age with pulse pressure in young type 1 diabetic individuals, which is stronger in the presence of microvascular complications. In addition, both mean arterial pressure and pulse pressure are associated with incident cardiovascular disease. These findings support the concept of early vascular ageing in type 1 diabetes, especially in the presence of microvascular complications.

Adolescent↗
PubMed2003

Vascular risk factors and markers of endothelial function as determinants of inflammatory markers in type 1 diabetes: the EURODIAB Prospective Complications Study.

OBJECTIVE: Inflammatory activity is increased in type 1 diabetes and may predispose to vascular disease. Its origin is not clear. We therefore investigated determinants of inflammation in type 1 diabetes. RESEARCH DESIGN AND METHODS: We performed a nested case-control study from the EURODIAB Prospective Complications Study of 543 European individuals having type 1 diabetes (278 men), diagnosed at <36 years of age. Case subjects (n = 348) were those with one or more complications of diabetes; control subjects (n = 195) were all those with no evidence of any complication. We determined levels of C-reactive protein, interleukin-6, and tumor necrosis factor-alpha, combined them in a "general score of inflammatory markers," and investigated their associations with vascular risk factors and markers of endothelial dysfunction by use of multiple linear regression analysis. RESULTS: Measures of inflammation were associated with sex, diabetes duration, glycemic control, the advanced glycation end product pentosidine, BMI, HDL cholesterol, triglycerides, and systolic blood pressure (standardized betas with the general score of inflammatory markers 0.15 [P = 0.002], 0.15 [P = 0.006], 0.18 [P < 0.0001], 0.12 [P = 0.005], 0.10 [P = 0.057], -0.15 [P = 0.001], 0.16 [P < 0.0001], and 0.09 [P = 0.042], respectively). In addition, measures of inflammation were strongly associated with markers of endothelial dysfunction, soluble vascular cell adhesion molecule-1, and soluble E-selectin (standardized betas with the general score of inflammatory markers 0.28 [P < 0.0001] and 0.19 [P < 0.0001]). CONCLUSIONS: We have shown that conventional risk factors for vascular disease and endothelial adhesion molecules are important determinants of inflammation in type 1 diabetic individuals, suggesting that strategies to decrease inflammatory activity in type 1 diabetes should focus not only on control of conventional risk factors, but also on improvement of endothelial function.

Adult↗
PubMed2002

Ethnicity and risk of diabetes-related lower extremity amputation: a population-based, case-control study of African Caribbeans and Europeans in the United kingdom.

BACKGROUND: In the United States, people of black African descent with diabetes have 2 to 3 times the amputation risk of whites. This may be due to differences in care or pathophysiological characteristics. We therefore determined diabetes-related amputation rates in African Caribbeans vs Europeans in the United Kingdom, where care delivery is more equitable. METHODS: We conducted an incidence and case-control study, based in London, England. All diabetes-related amputations performed between 1992 and 1997 were identified. Controls, those with diabetes but no amputation, were sampled from family practitioners. Risk factor data were abstracted from medical records. RESULTS: Incident diabetes-related amputation occurred in 67 Europeans and 19 African Caribbeans. Amputation rates, age standardized to the diabetic population, were 147 per 100 000 and 219 per 100 000 in African Caribbeans and Europeans, respectively (relative risk, 0.67; 95% confidence interval [CI], 0.32-1.40; P =.2). Case-control analyses were performed on 178 cases and 350 controls. The ethnic difference in amputation risk differed significantly by sex (P =.009 for interaction). The unadjusted odds ratio comparing African Caribbeans with Europeans in men was 0.31 (95% CI, 0.17-0.57; P<.001), and in women was 0.97 (95% CI, 0.49-1.85; P =.9). Adjustment for smoking attenuated the odds ratio in men to 0.45 (95% CI, 0.23-0.89, P =.02); adding neuropathy, peripheral vascular disease, and age attenuated the odds ratio further to 0.97 (95% CI, 0.34-2.73; P =.9). CONCLUSIONS: In contrast to the United States, we find no ethnic difference in diabetes-related amputation in women in the United Kingdom, but in men, amputation risk in African Caribbeans is one third that of Europeans. This was wholly accounted for by low smoking, neuropathy, and peripheral vascular disease rates.

Africa↗
PubMed2002

Activated factor XII levels and factor XII 46C>T genotype in relation to coronary artery calcification in patients with type 1 diabetes and healthy subjects.

The relationship of activated factor XII (FXIIa) and FXII 46C>T genotype to coronary atherosclerosis and endothelial function was examined in 192 randomly sampled subjects from the general population and 190 type 1 diabetic subjects (mean age 38+/-4 years). Coronary artery calcification (CAC) was measured using Electron beam CT. von Willebrand factor (vWF), a marker of endothelial function, and FXIIa were measured by ELISA. Endothelial nitric oxide production was quantified as the forearm blood flow response to intra-brachial infusion of bradykinin and N(G) monomethyl-L-arginine (L-NMMA). A higher FXIIa was independently associated with higher triglycerides (P<0.001), BMI (P=0.001), alcohol consumption (P=0.003) and vWF (P<0.001) in non-diabetic subjects and with insulin dose (P=0.009), total cholesterol (P=0.02) and alcohol (P<0.001) in diabetic subjects. Diabetic subjects had lower FXIIa (1.55 ng/ml) than non-diabetic subjects (1.92 ng/ml, P<0.001). Higher FXIIa was associated with lower response to bradykinin (P=0.048) and to L-NMMA (P=0.029). FXIIa was positively associated with CAC (odds ratio=1.57 for every 1 ng/ml higher FXIIa, P=0.005) but not independently of other risk factors (odds ratio=1.1 on adjustment). 46C>T genotype explained 18% of the variance in FXIIa (P<0.001) but was not associated with CAC (P=0.6). We conclude that plasma FXIIa is under strong genetic control but also reflects plasma triglycerides and endothelial activation or dysfunction. FXIIa appears unlikely to be directly atherogenic but may be a useful marker of coronary atherosclerosis because of its association with these other factors. Type 1 diabetes is associated with lower levels of FXIIa despite a greater prevalence of atherosclerosis.

Adult↗
PubMed2002

Lipoprotein subclasses and particle sizes and their relationship with coronary artery calcification in men and women with and without type 1 diabetes.

Type 1 diabetes is associated with increased coronary atherosclerosis, especially in women, even though such patients often have an apparently normal lipid profile. We examined whether lipoprotein particle sizes and subclasses differed between type 1 diabetic subjects (n = 194, age 30-55 years) and age- and sex-matched control subjects (n = 195). We examined whether any abnormalities were of similar magnitude in men and women. The relationship of particle size to electron beam computer tomography-defined coronary artery calcification, a measure of atherosclerosis, was also examined. Proton nuclear magnetic resonance (NMR) spectroscopy was used to quantify VLDL, LDL, and HDL subclass levels and average particle size on fasting samples. LDL size and subclass were similar in diabetic and nondiabetic men. In contrast, in women diabetes was associated with less large and more small LDL and a reduced LDL size (mean difference 0.2 nm; P = 0.0009). This greater effect of diabetes on LDL size in women compared with men was significant (P = 0.007). Diabetes was associated with more large and less small HDL and, to a similar degree in both sexes, a higher HDL size (difference of 0.4 nm in men and 0.3 nm in women; both P < 0.0001). There were no definitive abnormalities in VLDL size. In nondiabetic subjects, lower average HDL particle size, lower LDL size, and higher VLDL size were significantly associated with coronary calcification (P = 0.001, 0.02, and 0.04, respectively). Thus the HDL size differences with diabetes would be expected to be antiatherogenic and the LDL size differences pro-atherogenic. However, there was no clear relationship between particle size and calcification in diabetic subjects. We conclude that in the general population NMR spectroscopy-derived particle size reveals important information about the atherogenicity of lipoprotein profile. Type 1 diabetes is associated with differences in NMR-derived particle size, but their pathogenic significance is unclear.

Adult↗
PubMed2002

Circulating and urinary transforming growth factor beta1, Amadori albumin, and complications of type 1 diabetes: the EURODIAB prospective complications study.

OBJECTIVE: Transforming growth factor (TGF)-beta1 is overexpressed in diabetes as a consequence of hyperglycemia and the creation of early glycated end products and may be responsible for the characteristic structural renal changes associated with diabetes. We sought to examine the role of both urinary and circulating TGF-beta1 and its promoter Amadori albumin in the vascular complications of type 1 diabetes. RESEARCH DESIGN AND METHODS: The present article reports on a nested case-control study from the EURODIAB Prospective Complications Study of Europeans with type 1 diabetes. Case subjects (n = 356) were all individuals with one or more complications of diabetes; control subjects (n = 185) were all individuals with no evidence of complications. RESULTS: Urinary TGF-beta1 and Amadori albumin were elevated in patients with micro- or macroalbuminuria. Standardized regression effects (SREs) for macroalbuminuria versus normoalbuminuria were 2.45 (95% CI 1.88-3.18, P = 0.0001 for urinary TGF-beta1) and 1.67 (1.34-2.07, P = 0.001 for Amadori albumin). The SRE for urinary TGF-beta1 remained statistically significant when adjusted for HbA(1c), Amadori albumin, and blood pressure. Circulating TGF-beta1 was elevated in individuals with proliferative retinopathy compared with individuals without retinopathy (SRE 1.29 [1.07-1.550], P = 0.007). This result was attenuated to 1.16 (0.95-1.43, P = 0.2) in the multivariate model, largely because of HbA(1c). CONCLUSIONS: Elevated levels of urinary TGF-beta1 in macroalbuminuria were associated with elevations in Amadori albumin and HbA(1c) and also in blood pressure. In contrast, only circulating TGF-beta1 was related to proliferative retinopathy, and HbA(1c) largely accounted for this. These findings may indicate novel pathways for understanding mechanisms and therapeutic interventions.

Adult↗
PubMed2002

Prevalence of Q-T interval dispersion in type 1 diabetes and its relation with cardiac ischemia : the EURODIAB IDDM Complications Study Group.

OBJECTIVE: The interlead variation in duration of the Q-T interval on the surface electrocardiogram (Q-T interval dispersion [QTd]) has been shown to predict mortality in type 2 diabetic patients. We evaluated the prevalence of QTd prolongation in the EURODIAB population and its relation to corrected Q-T interval (QTc), sex, age, duration of diabetes, blood glucose control, and complications. RESEARCH DESIGN AND METHODS; A total of 3,042 type 1 diabetic patients were studied. QTc was calculated according to the Bazett's formula; QTc > 0.44 s was considered abnormally prolonged. QTd was calculated using the difference between the maximum and the minimum QTc in any thoracic lead. QTd >0.080 s was considered abnormally prolonged. RESULTS: The prevalence of an increased QTd was 7%. A significant relation was observed between QTd prolongation and diastolic blood pressure (P < 0.05). A higher prevalence of QTd prolongation was observed in patients with ischemic heart disease (P = 0.004), whereas no relationship was observed with retinopathy, albumin excretion rate, or measures of somatic and autonomic neuropathy. QTc and QTd were significantly related (P = 0.001); however, a proportion of patients with normal QTd showed a prolonged QTc (>0.44 s). CONCLUSIONS: In patients with type 1 diabetes, QTd is associated with ischemic heart disease and diastolic blood pressure but not neuropathy. Although QTd is statistically related to duration of QTc, increased QTd and increased QTc identify different patients, and their predictive value deserves prospective evaluation.

Adult↗
PubMedDate not supplied

Soluble vascular cell adhesion molecule-1 and soluble E-selectin are associated with micro- and macrovascular complications in Type 1 diabetic patients.

OBJECTIVE: There are no large studies in Type 1 diabetic patients that have examined the relation between soluble adhesion molecules and micro- and macrovascular outcomes, although the risks of such complications are high. Therefore, the main objective is to examine the relationship between soluble (s) vascular cell adhesion molecule-1 (sVCAM-1) and sE-selectin and retinopathy, albuminuria, and cardiovascular disease (CVD) in Type 1 diabetic patients. METHODS: Cross-sectional data on 540 Type 1 diabetic patients, with a mean age of 40 years and diabetes duration of 22 years, from the EURODIAB Prospective Complications Study (PCS) were analysed. Retinopathy was assessed by centrally graded retinal photographs. Albumin excretion rate (AER) was used to define micro- and macroalbuminuria. CVD was defined as having physician diagnosed myocardial infarction (MI), stroke, coronary artery bypass graft (CABG) or angina, or Minnesota coded ischaemic electrocardiograms (ECGs). RESULTS: Unadjusted, there was a positive relationship between sVCAM-1 and sE-selectin with nonproliferative and proliferative retinopathy, micro- and macroalbuminuria, and CVD. After adjustment for age, sex, duration of diabetes, systolic blood pressure (BP), LDL-cholesterol, fasting triglycerides (TGs), smoking, body mass index (BMI), and glycated haemoglobin, as well as other complications, the strongest significant associations were shown between sVCAM-1 and macroalbuminuria, with an odds ratio of 1.83 (1.33-2.53) for every 100 ng/ml increase in sVCAM-1. CONCLUSIONS: In this large sample of Type 1 diabetic patients, it was shown that sVCAM-1 and sE-selectin have positive associations with retinopathy, albuminuria, and CVD. This suggests that adhesion molecules are important in the pathogenesis of vascular complications in Type 1 diabetes.

Adult↗