Search

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. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

Objective: Cardiovascular disease (CVD) is increased in patients with type 1 diabetes, but lipid and lipoprotein patterns remain favorable. In contrast, nephropathy is associated with an adverse distribution. We compared the associations and predictive power of lipid and lipoprotein disturbances with these complications.Research Design and Methods: A nested case-control study from the EURODIAB cohort of 140 case subjects with evidence of at least one complication and 84 control subjects with no complications were analyzed. Conventional and unconventional lipid and lipoprotein fractions, including apolipoprotein (apo)-A1, lipoprotein (Lp)-A1, LpA1/A2, apoB, and LDL particle size were measured centrally.Results: CVD was only associated with increased LDL cholesterol (3.6 vs. 3.0 mmol/l, P = 0.02). In contrast, albuminuria was associated with elevated cholesterol, triglyceride, LDL, and apoB and with diminished LDL particle size. No disturbances in HDL and related lipoproteins were noted. In normoalbuminuric patients, CVD was not associated with any significant changes in lipids. CVD in macroalbuminuric patients was associated with increased triglyceride level (2.37 vs. 1.07 mmol/l, P = 0.001; P = 0.02 for CVD/albuminuria interaction) and LDL cholesterol (5.4 vs. 3.3 mmol/l, P = 0.005; P = 0.004 for interaction). Independent associations were observed for total cholesterol and for LDL particle size and albuminuria.Conclusions: Abnormalities in lipid and lipoprotein disturbances are more closely related to albuminuria than to CVD in patients with type 1 diabetes. Measurement of conventional parameters provide sufficient risk information. ApoB and LDL particle size offer limited extra information. HDL metabolism remains undisturbed in the presence of complications. These changes reflect associations with glycemic control, which is the key to understanding lipid and lipoprotein disturbances. [ABSTRACT FROM AUTHOR]

Examines the mortality rates from coronary heart disease and stroke in relation to degree of glycemia. Risk for death from stroke; Difference in the age adjusted rates of mortality between diabetic men; Variables predictive of mortality from both stroke and coronary heart disease.

To monitor the progress of the improvement of diabetes care several methods are available such as clinical databases, epidemiological studies, and mortality and morbidity statistics. Developments in information technology have made clinical databases such as the DiabCare System a method of high potential because of high generalisability and the potential participation of many clinicians. Epidemiological studies utilize standardized methods to assess disease outcomes and to quantify risk factors. For example, the EURODIAB IDDM Complications Study indicated that life-style factors may have a direct influence on the risk of complications: 21% of 272 patients aged 15–19 years were smokers, rising to above 30% in those aged 20 and above (n = 1,193). This was associated with poor glycemic control in all age groups. Mortality and mortality statistics have the problem of under-ascertainment but they still provide evidence for substantial excess rates in young IDDM subjects with wide regional variations. Thus, for analysing the outcomes of improvements in the quality of care all available information sources have to be utilized, taking care to assess their accuracy and generalisibility. [ABSTRACT FROM AUTHOR]

Describes the complete sequences of the structural genes for both thecycothrome and flavoprotein components of a flavocytochrome. Features of PCHM flavoproteins; Mechanism action of PCHM; Indirect control of Pchc in E. coli by heme biosynthesis; Discrepancy in the value of PchF; Factors needed for covalent attachment.

A letter to the editor is presented in response to the article "Glycosylated hemoglobin and the risk of microalbuminuria in patients with insulin-dependent diabetes mellitus," by A.S. Krolewski, L.M.B. Laffel and colleagues in the May 11, 1995 issue.

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 casecontrol study, based in London, England. All diabetesrelated 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 100000 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. [ABSTRACT FROM AUTHOR]

Background: Altered regulation of extracellular matrix (ECM) composition by matrix metalloproteinases (MMPs) and tissue inhibitors of metalloproteinase (TIMPs) may contribute to arterial stiffening. We investigated associations between circulating MMP-1, -2, -3, -9, -10 and TIMP-1, and carotid-femoral pulse wave velocity (cfPWV) and pulse pressure (PP), as markers of arterial stiffness in type 1 diabetic patients. Methods: Individuals with type 1 diabetes from three different cohorts were included in this study: EURODIAB Prospective Complications study (n = 509), LEACE (n = 370) and PROFIL (n = 638). Linear regression analyses were used to investigate cross-sectional associations between circulating levels of MMP-1, -2, -3, -9, -10, and TIMP-1 and cfPWV (n = 614) as well as office PP (n = 1517). Data on 24-h brachial and 24-h central PP were available in 638 individuals from PROFIL. Analyses were adjusted for age, sex, duration of diabetes, HbA1c, mean arterial pressure (MAP), and eGFR, and additionally for other cardiovascular risk factors and presence of vascular complications. Results: After adjustment for potential confounders and presence of vascular complications, circulating MMP-3 was associated with cfPWV [β per 1 SD higher lnMMP3 0.29 m/s (0.02; 0.55)]. In addition, brachial and central 24-h PP measurements in PROFIL were significantly associated with MMP-2 [(1.40 (0.47:2.33) and 1.43 (0.63:2.23)]. Pooled data analysis showed significant associations of circulating levels of MMP-1 and MMP-2 with office PP [β per 1 SD higher lnMMP-1 and lnMMP-2 = - 0.83 mmHg (95% CI - 1.50; - 0.16) and = 1.33 mmHg (0.55; 2.10), respectively]. Conclusions: MMPs-1, -2, and -3 are independently associated with markers of arterial stiffening in patients with type 1 diabetes and may become therapeutic targets. [ABSTRACT FROM AUTHOR]

Background: Impaired regulation of extracellular matrix remodeling by matrix metalloproteinases (MMPs) and tissue inhibitor of metalloproteinase (TIMP) may contribute to vascular complications in patients with type 1 diabetes. We investigated associations between plasma MMP-1, -2, -3, -9, -10 and TIMP-1, and cardiovascular disease (CVD) or microvascular complications in type 1 diabetic patients. We also evaluated to which extent these associations could be explained by low-grade inflammation (LGI) or endothelial dysfunction (ED). Methods: 493 type 1 diabetes patients (39.5 ± 9.9 years old, 51% men) from the EURODIAB Prospective Complications Study were included. Linear regression analysis was applied to investigate differences in plasma levels of MMP-1, -2, -3, -9, -10, and TIMP-1 between patients with and without CVD, albuminuria or retinopathy. All analyses were adjusted for age, sex, duration of diabetes, Hba1c and additionally for other cardiovascular risk factors including LGI and ED. Results: Patients with CVD (n = 118) showed significantly higher levels of TIMP-1 [β = 0.32 SD (95%CI: 0.12; 0.52)], but not of MMPs, than patients without CVD (n = 375). Higher plasma levels of MMP-2, MMP-3, MMP-10 and TIMP-1 were associated with higher levels of albuminuria (p-trends were 0.028, 0.004, 0.005 and 0.001, respectively). Severity of retinopathy was significantly associated with higher levels of MMP-2 (p-trend = 0.017). These associations remained significant after further adjustment for markers of LGI and ED. Conclusions: These data support the hypothesis that impaired regulation of matrix remodeling by actions of MMP-2, -3 and-10 and TIMP-1 contributes to the pathogenesis of vascular complications in type 1 diabetes. [ABSTRACT FROM AUTHOR]

Background: Low circulating levels of total vitamin D [25(OH)D] and 25(OH)D3 have been associated with vascular complications in few studies on individuals with type 1 diabetes. However, these measures are affected by UV light exposure. Circulating 25(OH)D2, however, solely represents dietary intake of vitamin D2, but its association with complications of diabetes is currently unknown. We investigated the associations between 25(OH)D2 and 25(OH)D3 and the prevalence of albuminuria, retinopathy and cardiovascular disease (CVD) in individuals with type 1 diabetes. Methods: We measured circulating 25(OH)D2 and 25(OH)D3 in 532 individuals (40 ± 10 years old, 51 % men) with type 1 diabetes who participated in the EURODIAB Prospective Complications Study. Cross-sectional associations of 25(OH)D2 and 25(OH)D3 with albuminuria, retinopathy and CVD were assessed with multiple logistic regression analyses adjusted for age, sex, season, BMI, smoking, HbA1c, total-HDL-cholesterol-ratio, systolic blood pressure, antihypertensive medication, eGFR, physical activity, alcohol intake, albuminuria, retinopathy and CVD, as appropriate. Results: Fully adjusted models revealed that 1 nmol/L higher 25(OH)D2 and 10 nmol/L higher 25(OH)D3 were associated with lower prevalence of macroalbuminuria with ORs (95 % CI) of 0.56 (0.43;0.74) and 0.82 (0.72;0.94), respectively. These vitamin D species were not independently associated with microalbuminuria, non-proliferative and proliferative retinopathy or CVD. Conclusions: In individuals with type 1 diabetes, both higher 25(OH)D2 and 25(OH)D3 are associated with a lower prevalence of macroalbuminuria, but not of retinopathy and CVD. Prospective studies are needed to further examine the associations between 25(OH)D2 and 25(OH)D3 and the development of microvascular complications and CVD in type 1 diabetes. [ABSTRACT FROM AUTHOR]

Background: Impaired regulation of extracellular matrix remodeling by matrix metalloproteinases (MMPs) and tissue inhibitor of metalloproteinase (TIMP) may contribute to vascular complications in patients with type 1 diabetes. We investigated associations between plasma MMP-1, -2, -3, -9, -10 and TIMP-1, and cardiovascular disease (CVD) or microvascular complications in type 1 diabetic patients. We also evaluated to which extent these associations could be explained by low-grade inflammation (LGI) or endothelial dysfunction (ED). Methods: 493 type 1 diabetes patients (39.5 ± 9.9 years old, 51% men) from the EURODIAB Prospective Complications Study were included. Linear regression analysis was applied to investigate differences in plasma levels of MMP-1, -2, -3, -9, -10, and TIMP-1 between patients with and without CVD, albuminuria or retinopathy. All analyses were adjusted for age, sex, duration of diabetes, Hba1c and additionally for other cardiovascular risk factors including LGI and ED. Results: Patients with CVD (n = 118) showed significantly higher levels of TIMP-1 [β = 0.32 SD (95%CI: 0.12; 0.52)], but not of MMPs, than patients without CVD (n = 375). Higher plasma levels of MMP-2, MMP-3, MMP-10 and TIMP-1 were associated with higher levels of albuminuria (p-trends were 0.028, 0.004, 0.005 and 0.001, respectively). Severity of retinopathy was significantly associated with higher levels of MMP-2 (p-trend = 0.017). These associations remained significant after further adjustment for markers of LGI and ED. Conclusions: These data support the hypothesis that impaired regulation of matrix remodeling by actions of MMP-2, -3 and-10 and TIMP-1 contributes to the pathogenesis of vascular complications in type 1 diabetes. [ABSTRACT FROM AUTHOR]

OBJECTIVE Diabetes-associated autoantibodies can be detected in adult-onset diabetes, even when initially non-insulin requiring, i.e., with latent autoimmune diabetes. We aimed to identify adult-onset autoimmune diabetes in patients with established "type 2 diabetes" participating in the Collaborative Atorvastatin Diabetes Study (CARDS) to characterize their phenotype and clinical outcome. RESEARCH DESIGN AND METHODS We prospectively studied 2,425 European patients with presumed type 2 diabetes (mean age 62 years, diabetes duration 7.9 years) for outcomes at 3.9 years after randomization to either atorvastatin or placebo. Subjects were screened for autoantibodies to GAD (GADA), insulinoma-associated antigen-2 (IA-2A), and zinc-transporter 8 (ZnT8A). RESULTS A total of 173 patients (7.1%) had GADA, of whom 11 (0.5%) and 5 (0.2%) were also positive for IA-2A and ZnT8A, respectively. At baseline, 44% of GADA-positive patients were not on insulin. Fewer autoantibody-positive than autoantibody-negative patients had metabolic syndrome (64 vs. 80%), and more were on insulin (56 vs. 17%) (P < 0.0001 for each) without lower HbA1c (69 mmol/mol [8.5%] vs. 62 mmol/mol [7.8%]). The frequency of microvascular and macrovascular events was similar in both cohorts, independent of atorvastatin. CONCLUSIONS Adult-onset autoimmune diabetes was prevalent, even in patients with established diabetes presumed to have type 2 diabetes. After 11.8 years' diabetes duration, nearly half the patients with autoimmune diabetes were not on insulin treatment and almost two-thirds had metabolic syndrome. The type of diabetes, whether autoimmune diabetes or type 2 diabetes, did not impact the risk of microvascular disease. [ABSTRACT FROM AUTHOR]

OBJECTIVE--Circulating levels of NH2-terminal probrain natriuretic peptide (NTproBNP), a marker of acute heart failure, are associated with increased risk of cardiovascular disease (CVD) in the general population. However, there is little information on the potential role of NT-proBNP as a biomarker of vascular complications in type 1 diabetic patients. We investigated whether serum NT-proBNP levels were associated with micro- and macrovascular disease in type 1 diabetic subjects. RESEARCH DESIGN AND METHODS--A cross-sectional nested case-control study from the EURODIAB Prospective Complications Study of 507 type 1 diabetic patients was performed. Case subjects (n = 345) were defined as those with one or more complications of diabetes; control subjects (n = 162) were those with no evidence of any complication. We measured NT-proBNP levels by a two-site sandwich electrochemiluminescence immunoassay and investigated their associations with complications. RESULTS--Mean NT-proBNP levels were significantly higher in case than in control subjects. In logistic regression analyses, NT-proBNP values > 26.46 pg/mL were independently associated with a 2.56-fold increased risk of all complications. Odds ratios of CVD (3.95 [95% CI 1.26-- 12.35]), nephropathy (4.38 [1.30--14.76]), and distal symmetrical polyneuropathy (4.32 [1.41-- 13.23]) were significantly increased in patients with NT-proBNP values in the highest quartile (>84.71 pg/mL), independently of renal function and known risk factors. These associations were no longer significant after inclusion of TNF-α into the model. CONCLUSIONS--In this large cohort of type 1 diabetic subjects, we found an association between NT-proBNP and diabetic micro- and macrovascular complications. Our results suggest that the inflammatory cytokine TNF-a may be involved in this association. [ABSTRACT FROM AUTHOR]

Objective: Frequent episodes of severe hypoglycemia may increase the risk of cardiovascular disease (CVD) in people with diabetes. Our aim was to study the relationship between severe hypoglycemic episodes and CVD incidence in subjects with type 1 diabetes, and further, to assess if markers of inflammation/endothelial injury were enhanced in individuals who experienced hypoglycemic episodes.Research Design and Methods: The prospective study included 2,181 type 1 diabetic patients from the EURODIAB Prospective Complications Study. At baseline, frequency of self-reported severe hypoglycemia, defined as episodes serious enough to require the help of another person, was assessed based on responses to a patient questionnaire. Both fatal/nonfatal CVD was assessed 7.3 years after baseline examination. At the follow-up visit, data on both severe and nonsevere hypoglycemic episodes in the previous year were collected through a questionnaire and markers of inflammation/stress response/endothelial injury measured by enzyme-linked immunosorbent assays in the 531 subjects of the nested case-control study, including 363 case subjects with one or more complications of diabetes and 168 control subjects with no evidence of any complication.Results: During the follow-up period, 176 patients had incident CVD. Logistic regression analysis showed that severe hypoglycemia at the baseline examination was not associated with incidence of CVD (adjusted odds ratios [95% CI]: one to two episodes, 0.87 [0.55-1.37]; three or more episodes, 1.09 [0.68-1.75]). Furthermore, follow-up serum levels of markers of endothelial damage/inflammation were not cross-sectionally associated with the frequency of hypoglycemic episodes.Conclusions: Taken together our data do not support the hypothesis that in type 1 diabetes, severe hypoglycemia increases the risk of CVD. [ABSTRACT FROM AUTHOR]

OBJECTIVE--Frequent episodes of severe hypoglycemia may increase the risk of cardiovascular disease (CVD) in people with diabetes. Our aim was to study the relationship between severe hypoglycemic episodes and CVD incidence in subjects with type 1 diabetes, and further, to assess if markers of inflammation/endothelial injury were enhanced in individuals who experienced hypoglycemic episodes. RESEARCH DESIGN AND METHODS--The prospective study included 2,181 type 1 diabetic patients from the EURODIAB Prospective Complications Study. At baseline, frequency of self-reported severe hypoglycemia, defined as episodes serious enough to require the help of another person, was assessed based on responses to a patient questionnaire. Both fatal/nonfatal CVD was assessed 7.3 years after baseline examination. At the follow-up visit, data on both severe and nonsevere hypoglycemic episodes in the previous year were collected through a questionnaire and markers of inflammation/stress response/endothelial injury measured by enzyme-linked immunosorbent assays in the 531 subjects of the nested case-control study, including 363 case subjects with one or more complications of diabetes and 168 control subjects with no evidence of any complication. RESULTS--During the follow-up period, 176 patients had incident CVD. Logistic regression analysis showed that severe hypoglycemia at the baseline examination was not associated with incidence of CVD (adjusted odds ratios [95%CI]: one to two episodes, 0.87 [0.55--1.37]; three or more episodes, 1.09 [0.68--1.75]). Furthermore, follow-up serum levels of markers of endothelial damage/inflammation were not cross-sectionally associated with the frequency of hypoglycemic episodes. CONCLUSIONS--Taken together our data do not support the hypothesis that in type 1 diabetes, severe hypoglycemia increases the risk of CVD. [ABSTRACT FROM AUTHOR]

Context and objective: High-mobility group box-1 (HMGB1) is a pro-inflammatory cytokine that may contribute to the pathogenesis of micro-and macrovascular complications commonly observed in diabetes. We investigated whether HMGB1 is associated with: i) markers of low-grade inflammation (LGI) and endothelial dysfunction (ED) and pulse pressure (PP, a marker of arterial stiffness); ii) prevalent nephropathy, retinopathy and cardiovascular disease (CVD) in type 1 diabetes; and iii) the potential mediating roles of LGI, ED and PP therein. Design and methods: This was a cross-sectional nested case-control study of 463 patients (226 women; mean age 40±10 years) with type 1 diabetes from the EURODIAB Prospective Complications Study.We used linear and binary or multinomial logistic regression analyses adjusted for traditional risk factors. Results: Serum Ln-HMGB1 levels were positively associated with LGI and ED (standardised &bgr;=0.07 (95% confidence interval (CI): 0.02-0.12) and &bgr;=0.08 (95% CI: 0.02-0.14) respectively), but not with PP. Higher Ln-HMGB1 (per unit) was associated with greater odds of micro- and macroalbuminuria: odds ratio (OR)=1.24 (95% CI: 0.90-1.71) and OR=1.61 (95% CI: 1.15-2.25) respectively, P for trend=0.004. Further adjustments for LGI or ED did not attenuate these associations. No such associations were found between Ln-HMGB1 and estimated glomerular filtration rate (eGFR), retinopathy or CVD, however. Conclusions: In type 1 diabetes, higher serum HMGB1 levels are associated with greater prevalence and severity of albuminuria, though not with eGFR, retinopathy and CVD. Prospective studies are needed to clarify the causal role of HMGB1, if any, in the pathogenesis of vascular complications in type 1 diabetes. [ABSTRACT FROM AUTHOR]

OBJECTIVE--Circulating levels of soluble receptor for advanced glycation end products (sRAGE) likely comprise both a secreted isoform (esRAGE) and wild-type RAGE cleaved from the cell membrane. Both sRAGE , and esRAGE have been proposed as biomarkers of cardiovascular disease (CVD), but prospective data are limited. We examined the relationship of sRAGE mid esRAGE to incident coronary heart disease (CHD) and stroke in type 2 diabetic patients followed for 3.9 years in a trial of atorvastatin: the Collaborative Atorvastatin Diabetes Study (CARDS). RESEARCH DESIGN AND METHODS--We used a nested case-control design sampling all incident cases of CVD with available plasma and randomly selecting three control subjects, who were free of CVD throughout follow-up, per case. Analysis was by Cox regression with adjustment for treatment allocation and relevant covariates. RESULTS--sRAGE and esRAGE were strongly correlated (ρ = 0.88) and were both higher in those with lower BMI (P < 0.001), higher adiponectin (P < 0.001), lower estimated glomerular filtration rate (P = 0.009), and white ethnicity (P < 0.001). Both sRAGE mid esRAGE were associated with incident CHD events, independently of treatment allocation and the above factors; hazard ratio (HR) = 1.74 (95% CI 1.25-2.41; P = 0.002) for a doubling of the sRAGE level; HR = 1.45 ( 1.11-1.89; P = 0.006) for a doubling of the esRAGE level. There was no significant association with stroke; HR for sRAGE = 0.66 (0.38-1.14). Atorvastatin, 10 mg daily, did not alter sRAGE. CONCLUSIONS--Higher levels of sRAGE and esRAGE are associated with incident CHD but not stroke in type 2 diabetes. [ABSTRACT FROM AUTHOR]

Objective: Slow nerve conduction velocity and reduction in response amplitude are objective hallmarks of diabetic sensorimotor polyneuropathy. Because subjective or clinical indicators of neuropathy do not always match well with the presence of abnormal nerve physiology tests, we evaluated associations to nerve conduction in patients with type 1 diabetes.Research Design and Methods: Nerve conduction studies were performed in the distal sural and ulnar sensory nerves and the peroneal motor nerve in 456 individuals with type 1 diabetes who participated in the follow-up visit of the EURODIAB Prospective Complications Study (EPCS). We used multivariate regression models to describe associations to decreased nerve conduction measures.Results: In addition to an effect of duration of diabetes and A1C, which were both associated with low nerve conduction velocity and response amplitude, we found that the presence of nephropathy, retinopathy, or a clinical diagnosis of neuropathy was associated with low nerve conduction velocity and amplitude. In the case of nonproliferative retinopathy, the odds ratio (OR) for being in lowest tertile was 2.30 (95% CI 1.13-4.67) for nerve conduction velocity. A similar OR was found for each 2% difference in A1C (2.39 [1.68-3.41]).Conclusions: We show that the presence of other microvascular diabetes complications, together with diabetes duration and A1C, are associated with low nerve conduction velocity and amplitude response and that cardiovascular disease or risk factors do not seem to be associated with these measures. [ABSTRACT FROM AUTHOR]

OBJECTIVE-- Slow nerve conduction velocity and reduction in response amplitude are objective hallmarks of diabetic sensorimotor polyneuropathy. Because subjective or clinical indicators of neuropathy do not always match well with the presence of abnormal nerve physiology tests, we evaluated associations to nerve conduction in patients with type 1 diabetes. RESEARCH DESIGN AND METHODS-- Nerve conduction studies were performed in the distal sural and ulnar sensory nerves and the peroneal motor nerve in 456 individuals with type 1 diabetes who participated in the follow-up visit of the EURODIAB Prospective Complications Study (EPCS). We used multivariate regression models to describe associations to decreased nerve conduction measures. RESULTS-- In addition to an effect of duration of diabetes and A1C, which were both associated with low nerve conduction velocity and response amplitude, we found that the presence of nephropathy, retinopathy, or a clinical diagnosis of neuropathy was associated with low nerve conduction velocity and amplitude. In the case of nonproliferative retinopathy, the odds ratio (OR) for being in lowest tertile was 2.30 (95% CI 1.13- 4.67) for nerve conduction velocity. A similar OR was found for each 2% difference in A1C (2.39 [1.68 -3.41]). CONCLUSIONS-- We show that the presence of other microvascular diabetes complications, together with diabetes duration and A1C, are associated with low nerve conduction velocity and amplitude response and that cardiovascular disease or risk factors do not seem to be associated with these measures. [ABSTRACT FROM AUTHOR]

A response by Solomon Tesfaye, Daniel R. Witte and John H. Fuller to several letters to the editor about their article "Vascular Risk Factors and Diabetic Neuropathy" in the January 27, 2005 issue is presented.

OBJECTIVE -- Diabetic large-nerve fiber dysfunction, as measured by vibration perception threshold (VPT), predicts foot ulceration, amputation, and mortality. Thus, determination of modifiable risk factors is of great clinical importance. RESEARCH DESIGN AND METHODS -- We assessed 1,407 patients with type 1 diabetes and a normal VPT participating in the EURODIAB Prospective Complications Study, at baseline mean ± SD age of 32.7 ± 10.2 years with diabetes duration of 14.7 ± 9.3 years and follow-up of 7.3 ± 0.6 years. VPT was measured using biothesiometry on the right big toe and medial malleolus. An abnormal result was defined as >2 SD from the predicted mean for the patient's age. RESULTS -- An abnormal VPT was associated with an increased incidence of gangrene, amputation, foot ulceration, leg bypass or angioplasty, and mortality (P ≤ 0.02). The incidence of abnormal VPT was 24% over the 7.3-year follow-up. Duration of diabetes and A1C significantly influenced the incidence of abnormal VPT (P < 0.0001). After correction for these, established risk factors for cardiovascular disease (CVD), including male sex (P = 0.0004), hypertension (P < 0.0001), total cholesterol (P = 0.002), LDL cholesterol (P = 0.01), smoking (P < 0.0001), weight (P < 0.0001), and diabetes complications (retinopathy [P = 0.0001], nephropathy [P = 0.01], and autonomic neuropathy [P = 0.001]), were all found to be significant risk factors. A previous history of CVD doubled the incidence of abnormal VPT. CONCLUSIONS -- This prospective study indicates that cardiovascular risk factors predict development of large-fiber dysfunction, which may account for the high mortality rate in patients with an abnormal VPT, and emphasizes the importance of early determination of VPT to detect subclinical neuropathy and to address cardiovascular risk factors. [ABSTRACT FROM AUTHOR]

Objective: The purpose of this study was to examine risk factors for mortality in patients with type 1 diabetes.Research Design and Methods: Baseline risk factors were measured in the EURODIAB Prospective Cohort Study with 2,787 type 1 diabetic patients (51% men and 49% women) recruited from 16 European countries. Mortality data were collected during a 7-year follow-up.Results: There was an annual mortality rate of 5 per 1,000 person-years in patients with type 1 diabetes (mean age at baseline 33 years, range 15-61 years); of the total 2,787 subjects, 102 died. The final multivariable model contained age at baseline (standardized hazard ratio 1.78 [95% CI 1.44-2.20]), A1C (1.18 [0.95-1.46]), waist-to-hip ratio (WHR) (1.32 [1.14-1.52]), pulse pressure (1.33 [1.13-1.58]), and non-HDL cholesterol (1.33 [1.12-1.60]) as risk factors for all-cause mortality. Macroalbuminuria (2.39 [1.19-4.78]) and peripheral (1.88 [1.06-3.35]) and autonomic neuropathy (2.40 [1.32-4.36]) were the most important risk markers for mortality. Similar risk factors were found for all-cause, non-cardiovascular disease (CVD), unknown-cause, and CVD mortality.Conclusions: Important risk factors for the increased total and non-CVD mortality in type 1 diabetic patients are age, WHR, pulse pressure, and non-HDL cholesterol. Microvascular complications from macroalbuminuria and peripheral and autonomic neuropathy are strong risk markers for future mortality exceeding the effect of the traditional risk factors. [ABSTRACT FROM AUTHOR]

OBJECTIVE -- The purpose of this study was to examine risk factors for mortality in patients with type 1 diabetes. RESEARCH DESIGN AND METHODS -- Baseline risk factors were measured in the EURODIAB Prospective Cohort Study with 2,787 type 1 diabetic patients (51% men and 49% women) recruited from 16 European countries. Mortality data were collected during a 7-year follow-up. RESULTS -- There was an annual mortality rate of 5 per 1,000 person-years in patients with type 1 diabetes (mean age at baseline 33 years, range 15-61 years); of the total 2,787 subjects, 102 died. The final multivariable model contained age at baseline (standardized hazard ratio 1.78 [95% CI 1.44-2.20]), A1C (1.18 [0.95-1.46]), waist-to-hip ratio (WHR) (1.32 [1.14-1.52]), pulse pressure (1.33 [1.13-1.58]), and non-HDL cholesterol (1.33 [1.12-1.60]) as risk factors for all-cause mortality. Macroalbuminuria (2.39 [1.19-4.78]) and peripheral (1.88 [1.06-3.35]) and autonomic neuropathy (2.40 [1.32-4.36]) were the most important risk markers for mortality. Similar risk factors were found for all-cause, non-cardiovascular disease (CVD), unknown-cause, and CVD mortality. CONCLUSIONS -- Important risk factors for the increased total and non-CVD mortality in type 1 diabetic patients are age, WHR, pulse pressure, and non-HDL cholesterol. Microvascular complications from macroalbuminuria and peripheral and autonomic neuropathy are strong risk markers for future mortality exceeding the effect of the traditional risk factors. [ABSTRACT FROM AUTHOR]

Objective: Heat shock protein 27 (HSP27) is a member of the small heat shock protein family of proteins. HSP27 expression is enhanced in target tissues of diabetic microvascular complications, and changes in circulating serum HSP27 levels (sHSP27) have been reported in patients with macrovascular disease. We investigated whether sHSP27 levels were associated with micro- and macrovascular complications in type 1 diabetic patients.Research Design and Methods: A cross-sectional, nested, case-control study from the EURODIAB Prospective Complications Study of 531 type 1 diabetic patients was performed. Case subjects (n = 363) were defined as those with one or more complications of diabetes; control subjects (n = 168) were defined as those with no evidence of any complication. We measured sHSP27 levels and investigated their associations with diabetes complications.Results: Mean sHSP27 levels were significantly higher in case subjects with distal symmetrical polyneuropathy (DSP) than in control subjects, even after adjustment for age and albumin excretion rate (AER) (785.9 vs. 574.7 pg/ml, P = 0.03). In logistic regression analysis, sHSP27 levels in the upper quartile were associated with a twofold increased odds ratio (OR) of DSP, independently of conventional risk factors, markers of inflammation, and AER (OR 2.41 [95% CI 1.11-5.24]).Conclusions: In this large cohort of type 1 diabetic subjects, we found an independent association between sHSP27 and DSP. This suggests that sHSP27 levels may be a novel marker for diabetic neuropathy. [ABSTRACT FROM AUTHOR]

OBJECTIVE--Heat shock protein 27 (HSP27) is a member of the small heat shock protein family of proteins. HSP27 expression is enhanced in target tissues of diabetic microvascular complications, and changes in circulating serum HSP27 levels (sHSP27) have been reported in patients with macrovascular disease. We investigated whether sHSP27 levels were associated with micro- and macrovascular complications in type 1 diabetic patients. RESEARCH DESIGN AND METHODS--A cross-sectional, nested, case-control study from the EURODIAB Prospective Complications Study of 531 type 1 diabetic patients was performed. Case subjects (n = 363) were defined as those with one or more complications of diabetes; control subjects (n = 168) were defined as those with no evidence of any complication. We measured sHSP27 levels and investigated their associations with diabetes complications. RESULTS--Mean sHSP27 levels were significantly higher in case subjects with distal symmetrical polyneuropathy (DSP) than in control subjects, even after adjustment for age and albumin excretion rate (AER) (785.9 vs. 574.7 pg/ml, P = 0.03). In logistic regression analysis, sHSP27 levels in the upper quartile were associated with a twofold increased odds ratio (OR) of DSP, independently of conventional risk factors, markers of inflammation, and AER (OR 2.41 [95% CI 1.11-5.24]). CONCLUSIONS--In this large cohort of type 1 diabetic subjects, we found an independent association between sHSP27 and DSP. This suggests that sHSP27 levels may be a novel marker for diabetic neuropathy. Diabetes 57:1966-1970, 2008 [ABSTRACT FROM AUTHOR]

OBJECTIVE -- Corrected QT (QTc) prolongation is predictive of cardiovascular mortality in both the general and diabetic populations. As part of the EURODIAB Prospective Complication Study, we have assessed the 7-year incidence and risk factors of prolonged QTc in people with type 1 diabetes. RESEARCH DESIGN AND METHODS -- A total of 1,415 type 1 diabetic subjects, who had normal QTc at baseline, were reanalyzed after the 7-year follow-up period. QTc >0.44s was considered abnormally prolonged. RESULTS -- Cumulative incidence of prolonged QTc was 18.7%, which is twofold higher in women than in men (24.5 vs. 13.9%, P < 0.0001). At the baseline examination, incident cases were older and less physically active than nonincident cases, had higher mean values of systolic blood pressure and HDL cholesterol, and had higher frequencies of hypertension, coronary heart disease, and distal symmetrical polyneuropathy. In multivariate logistic regression analyses, female sex and higher values of A1C and systolic blood pressure were associated with the risk of prolonged QTc, whereas physical activity and BMI within the range of 21.5-23.2 kg/m² were protective factors. In women, association with modifiable factors, particularly BMI, was stronger than in men. CONCLUSIONS-- In type 1 diabetic subjects from the EURODIAB cohort, female sex, A1C, and systolic blood pressure are predictive of prolonged QTc, whereas physical activity and BMI within the range of 21.5-23.2 kg/m² play a protective role. These findings are clinically relevant, as they may help to identify subjects at higher risk for prolonged QTc, as well as provide potential targets for risk-lowering strategies. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

Abstract: 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. [Copyright &y& Elsevier]

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. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

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° 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 (HIEs) 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. [ABSTRACT FROM AUTHOR]

Background Type 2 diabetes is associated with a substantially increased risk of cardiovascular disease, but the role of lipid-lowering therapy with statins for the primary prevention of cardiovascular disease in diabetes is inadequately defined. We aimed to assess the effectiveness of atorvastatin 10mg daily for primary prevention of major cardiovascular events in patients with type 2 diabetes without high concentrations of LDL-cholesterol. Methods 2838 patients aged 40-75 years in 132 centres in the UK and Ireland were randomised to placebo (n=1410) or atorvastatin 10 mg daily (n=1428). Study entrants had no documented previous history of cardiovascular disease, an LDL-cholesterol concentration of 4.14 mmol/L or lower, a fasting triglyceride amount of 6.78 mmol/L or less, and at least one of the following: retinopathy, albuminuria, current smoking, or hypertension. The primary endpoint was time to first occurrence of the following: acute coronary heart disease events, coronary revascularisation, or stroke. Analysis was by intention to treat. Findings The trial was terminated 2 years earlier than expected because the prespecified early stopping rule for efficacy had been met. Median duration of follow-up was 3.9 years (IQR 3.0--4.7). 127 patients allocated placebo (2.46 per 100 person-years at risk) and 83 allocated atorvastatin (1.54 per 100 person-years at risk) had at least one major cardiovascular event (rate reduction 37% [95% CI -52 to -17], p=0.001). Treatment would be expected to prevent at least 37 major vascular events per 1000 such people treated for 4 years. Assessed separately, acute coronary heart disease events were reduced by 36% (-55 to -9), coronary revascularisations by 31% (-59 to 16), and rate of stroke by 48% (-69 to -11). Atorvastatin reduced the death rate by 27% (-48 to 1, p=0.059). No excess of adverse events was noted in the atorvastatin group. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

OBJECTIVE -- Transforming growth factor (TGF)-β1 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-β1 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-β1 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-β1) and 1.67 (1.34-2.07, P = 0.001 for Amadori albumin). The SRE for urinary TGF-β1 remained statistically significant when adjusted for HbA[sub1c], Amadori albumin, and blood pressure. Circulating TGF-β1 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[sub1c]. CONCLUSIONS -- Elevated levels of urinary TGF-β1 in macroalbuminuria were associated with elevations in Amadori albumin and HbA[sub1c] and also in blood pressure. In contrast, only circulating TGF-β1 was related to proliferative retinopathy, and HbA[sub1c] largely accounted for this. These findings may indicate novel pathways for understanding mechanisms and therapeutic interventions. [ABSTRACT FROM AUTHOR]

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 NG 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. [Copyright &y& Elsevier]

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 2effect 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. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

Determines the activation of Wnt/beta-catenin pathway in human colon cancers. Effect of beta-catenin antisense oligodeoxynucleotides on the level of axin2 and human naked cuticle (hnkd) mRNA; Expression of axin2 and hnkd in colon cancer cell lines; Correlation of the increased expression of axin2 and hnkd with truncations in polyposis coli.

Microalbuminuria in type 1 diabetes: Rates, risk factors and glycemic threshold. Background. The occurrence of microalbuminuria in type 1 diabetes is strongly predictive of renal and cardiovascular disease and is still likely to occur despite improvements in glycemic control. A better understanding of microalbuminuria is required to inform new interventions. We determined the incidence and risk factors for microalbuminuria [albumin excretion rate (AER) 20 to 200 μg/min] in the EURODIAB Prospective Complications Study. Methods. This is a seven-year follow-up (between 1988 and 1991) of 1134 normoalbuminuric men and women (aged 15 to 60) with type 1 diabetes from 31 European centers. Risk factors and AER were measured centrally. Results. The incidence of microalbuminuria was 12.6% over 7.3 years. Independent baseline risk factors were HbA1c (7.1 vs. 6.2%, P = 0.0001) and AER (9.6 vs. 7.8 μg/min, P = 0.0001) and, independent of these, fasting triglyceride (0.99 vs. 0.88 mmol/L, P = 0.01), low-density lipoprotein cholesterol (3.5 vs. 3.2 mmol/L, P = 0.02), body mass index (24.0 vs. 23.4 kg/m2, P = 0.01), and waist to hip ratio (WHR; 0.85 vs. 0.83, P = 0.009). Triglyceride and WHR risk factors were nearly as strong as AER in predicting microalbuminuria (standardized regression effects of 1.3 for triglyceride and WHR and 1.5 for AER). Blood pressure at follow-up, but not at baseline, was also raised in those who progressed. There was no evidence of a threshold of HbA1c on microalbuminuria risk. Conclusions. The incidence of microalbuminuria in patients with type 1 diabetes remains high, and there is no apparent glycemic threshold for it. Markers of insulin resistance, such as triglyceride and WHR, are strong risk factors. Systemic blood pressure is not raised prior to the onset of microalbuminuria. [ABSTRACT FROM AUTHOR]

Objective: To examine the association of heart-rate variability with cardiovascular risk factors and coronary calcification in type 1 diabetic and nondiabetic subjects without a history of cardiovascular disease. Reduced heart-rate variability is associated with increased risk of coronary events. Whether it is associated with coronary atherosclerosis is unknown.Research Design and Methods: Power spectral analysis was used to define heart-rate variability in a cross-sectional study of 160 type 1 diabetic patients and 163 randomly selected nondiabetic adults from the general population aged 30-55 years. Coronary artery calcification was measured using electron beam-computed tomography.Results: Reduced heart-rate variability was associated with similar risk factors in the diabetic and nondiabetic subjects, namely higher HbA(1c), triglycerides, systolic blood pressure, BMI, and albumin excretion rate. Reduced heart-rate variability was significantly associated with coronary artery calcification in all subjects (odds ratio per tertile lower total power = 1.5, P = 0.01). This association was not independent of blood pressure or BMI (odds ratio on adjustment = 1.3, P = 0.1).Conclusions: Reduced heart-rate variability clusters with other cardiovascular disease risk factors, especially those that are more common in the insulin resistance syndrome, and is associated with increased coronary calcification in asymptomatic young adults. Whether reduced heart-rate variability leads to other risk factor disturbances or mediates the effects of other risk factors on atherosclerosis deserves further study. [ABSTRACT FROM AUTHOR]

Objective: To test the hypothesis that an increased plasma concentration of sialic acid, a marker of the acute-phase response, is related to the presence of diabetic micro- and macrovascular complications in type 1 diabetes.Research Design and Methods: We investigated the relationship between plasma sialic acid concentration and nephropathy, retinopathy, neuropathy, and coronary heart disease (CHD) in a cross-sectional survey of 1,369 people with type 1 diabetes. Subjects were participants in the EURODIAB IDDM Complications Study, which involved 31 centers in 16 European countries.Results: There was a significantly increasing trend of plasma sialic acid with severity of retinopathy (P < 0.001 in men) and with degree of urinary albumin excretion (P < 0.001 men, P < 0.01 women). Plasma sialic acid correlated with increasing plasma creatinine concentration (P < 0.009 men, P < 0.0002 women), and men with neuropathy had a higher plasma sialic acid concentration than those without (P < 0.006). There was no significant correlation between plasma sialic acid and CHD in either sex. Elevated plasma sialic acid concentrations were also associated with several risk factors for diabetic vascular disease: diabetes duration, HbA1c, plasma triglyceride and cholesterol concentrations, waist-to-hip ratio, hypertension and smoking (in men), and low physical exercise (in women). In multiple logistic regression analysis, plasma sialic acid was independently related to proliferative retinopathy and urinary albumin excretion rate in men.Conclusions: We conclude that an elevated plasma sialic concentration is strongly related to the presence of microvascular complications in type 1 diabetes, especially retinopathy and nephropathy. Further study of acute-phase response markers and mediators as indicators or predictors of diabetic microvascular complications is therefore justified. [ABSTRACT FROM AUTHOR]

Objective: To determine the incidence of retinopathy and the relative importance of its risk factors in type 1 diabetes.Research Design and Methods: This is a 7.3-year follow-up of 764 of 1,215 (63%) people with type 1 diabetes across Europe, aged 15-60 years at baseline with no retinopathy (the EURODIAB Prospective Complications Study). Retinal photographs were taken at baseline and follow-up and risk factors were assessed to a standard protocol.Results: Retinopathy incidence was 56% (429/764, 95% CI 52-59%). Key risk factors included diabetes duration and glycemic control. We found no evidence of a threshold effect for HbA1c on retinopathy incidence. Univariate associations were observed between incidence and albumin excretion rate, cholesterol, triglyceride, fibrinogen, von Willebrand factor, gamma-glutamyltransferase, waist-to-hip ratio, and insulin dose. No associations were observed for blood pressure, cardiovascular disease, or smoking. Independent risk factors, as assessed by standardized regression effects, were HbA1C (1.93, P = 0.0001), duration (1.32, P = 0.008), waist-to-hip ratio (1.32, P = 0.01), and fasting triglyceride (1.24, P = 0.04).Conclusions: Retinopathy incidence in type 1 diabetes remains high. Key risk factors include diabetes duration and glycemic control, with no evidence of a threshold for the latter. Other independent risk factors, such as waist-to-hip ratio and triglyceride levels, both markers of insulin resistance, were strongly related to incidence. [ABSTRACT FROM AUTHOR]

We examined whether the ACE gene insertion/deletion (I/D) polymorphism modulates renal disease progression in IDDM and how ACE inhibitors influence this relationship. The EURODIAB Controlled Trial of Lisinopril in IDDM is a multicenter randomized placebo-controlled trial in 530 nonhypertensive, mainly normoalbuminuric IDDM patients aged 20-59 years. Albumin excretion rate (AER) was measured every 6 months for 2 years. Genotype distribution was 15% II, 58% ID, and 27% DD. Between genotypes, there were no differences in baseline characteristics or in changes in blood pressure and glycemic control throughout the trial. There was a significant interaction between the II and DD genotype groups and treatment on change in AER (P = 0.05). Patients with the II genotype showed the fastest rate of AER progression on placebo but had an enhanced response to lisinopril. AER at 2 years (adjusted for baseline AER) was 51.3% lower on lisinopril than placebo in the II genotype patients (95% CI, 15.7 to 71.8; P = 0.01), 14.8% in the ID group (-7.8 to 32.7; P = 0.2), and 7.7% in the DD group (-36.6 to 37.6; P = 0.7). Absolute differences in AER between placebo and lisinopril at 2 years were 8.1, 1.7, and 0.8 microg/min in the II, ID, and DD groups, respectively. The significant beneficial effect of lisinopril on AER in the II group persisted when adjusted for center, blood pressure, and glycemic control, and also for diastolic blood pressure at 1 month into the study. Progression from normoalbuminuria to microalbuminuria (lisinopril versus placebo) was 0.27 (0.03-2.26; P = 0.2) in the II group, and 1.30 (0.33-5.17; P = 0.7) in the DD group (P = 0.6 for interaction). Knowledge of ACE genotype may be of value in determining the likely impact of ACE inhibitor treatment. [ABSTRACT FROM AUTHOR]

Presents a study assessing the persistence of the inverse socioeconomic mortality gradient observed in the general population on diabetic people. Discussion on the Whitehall cohort study and the London cohort of the World Health Organization (WHO) multinational study of vascular disease in diabetes; Subjects of the study; Comparison of the result of the study with the Finnish study. INSET: Key messages.

Examines the role of nutritional factors in the genesis of diabetes. Estimation of blood sugar concentrations, food intake and adiposity; Inverse correlations between food energy intake and adiposity; Effects of age on the interactions of blood sugar, nutrient intake, and adiposity.

Reports issues related to medicine in Great Britain. Frequency of migraine in childhood; Interrelated factors in hypertensive patients; Treatment of tuberculosis.