Effects of self-monitoring of glucose on distress and self-efficacy in people with non-insulin-treated Type 2 diabetes: a randomized controlled trial.

AIMS: To investigate the effects of self-monitoring of glucose in blood or urine, on diabetes-specific distress and self-efficacy, compared with usual care in people with non-insulin-treated Type 2 diabetes mellitus. METHODS: One hundred and eighty-one participants with non-insulin-treated Type 2 diabetes mellitus [diabetes duration ≥ 1 year, age 45-75 years, HbA1c ≥ 53.0 mmol/mol (7.0%), self-monitoring frequency < 3 times in the previous year] were randomly assigned to blood self-monitoring (n = 60), urine self-monitoring (n = 59) or usual care (n = 62). Primary outcomes were between-group differences in diabetes-specific distress [Problem Areas in Diabetes scale (PAID)] and self-efficacy [Confidence in Diabetes Self-Care questionnaire (CIDS-2)] after 12 months. Secondary outcomes included changes in HbA1c , treatment satisfaction and depressive symptoms. RESULTS: There were no statistically significant between-group differences in changes in PAID and CIDS-2 after 12 months. Mean difference in PAID between blood monitoring and control was -2.2 [95% confidence interval (CI) -7.1 to 2.7], between urine monitoring and control was -0.9 (95% CI -4.4 to 2.5) and between blood monitoring and urine monitoring was -2.0 (95% CI -4.1 to 0.1). Mean difference in CIDS-2 between blood monitoring and control was 0.6 [95% CI (-2.0 to 2.1), between urine monitoring and control was 2.8 (95% CI -2.3 to 7.9)] and between blood monitoring and urine monitoring was -3.3 (95% CI -7.9 to 1.3). No statistically significant between-group differences in change in any of the secondary outcome measures were found. CONCLUSIONS: This study did not find statistical or clinical evidence for a long-term effect of self-monitoring of glucose in blood or urine on diabetes-specific distress and self-efficacy in people with moderately controlled non-insulin-treated Type 2 diabetes mellitus. (Current Controlled Trials ISRCTN84568563).

Does low-molecular-weight heparin influence fetal growth or uterine and umbilical arterial Doppler in women with a history of early-onset uteroplacental insufficiency and an inheritable thrombophilia? Secondary randomised controlled trial results.

OBJECTIVE: Does low-molecular-weight heparin (LMWH) added to low-dose aspirin influence fetal growth and flow velocity in uterine and umbilical arteries in women with an inheritable thrombophilia and previous early-onset uteroplacental insufficiency? DESIGN: Secondary outcomes of the FRUIT-RCT. SETTING: Multicentre, international. POPULATION: The FRUIT-RCT included 139 women with inheritable thrombophilia before 12 weeks of gestation. Inclusion criteria were previous delivery before 34 weeks of gestation with a hypertensive disorder of pregnancy and/or small-for-gestational-age infant and an inheritable thrombophilia. METHODS: After randomisation to either daily LMWH with aspirin, or aspirin only, ultrasound measurements were performed at 22-24, 28-30 and 34-36 weeks of gestation. Development during gestation of growth, birthweight and flow velocity of the umbilical artery was examined using the linear mixed model. Uterine artery flow velocity at a single time-point (22-24 weeks) was examined using a chi-square test. MAIN OUTCOME MEASURES: Fetal growth over time including birthweight, using Scandinavian, Dutch and customised growth curves; and flow velocity within the uterine and umbilical arteries. RESULTS: No difference of fetal growth over time could be demonstrated between the study arms, regardless of which reference criteria were used. The flow velocity within the uterine artery and umbilical artery did not differ between study arms. CONCLUSION: The addition of LMWH to aspirin did not influence fetal growth or umbilical artery flow velocity over time; nor did it influence uterine artery flow velocity. TWEETABLE ABSTRACT: LMWH does not influence fetal growth or uterine or umbilical flow velocities.

Determining the genome-wide kinship coefficient seems unhelpful in distinguishing consanguineous couples with a high versus low risk for adverse reproductive outcome.

BACKGROUND: Offspring of consanguineous couples are at increased risk of congenital disorders. The risk increases as parents are more closely related. Individuals that have the same degree of relatedness according to their pedigree, show variable genomic kinship coefficients. To investigate whether we can differentiate between couples with high- and low risk for offspring with congenital disorders, we have compared the genomic kinship coefficient of consanguineous parents with a child affected with an autosomal recessive disorder with that of consanguineous parents with only healthy children, corrected for the degree of pedigree relatedness. METHODS: 151 consanguineous couples (73 cases and 78 controls) from 10 different ethnic backgrounds were genotyped on the Affymetrix platform and passed quality control checks. After pruning SNPs in linkage disequilibrium, 57,358 SNPs remained. Kinship coefficients were calculated using three different toolsets: PLINK, King and IBDelphi, yielding five different estimates (IBDelphi, PLINK (all), PLINK (by population), King robust (all) and King homo (by population)). We performed a one-sided Mann Whitney test to investigate whether the median relative difference regarding observed and expected kinship coefficients is bigger for cases than for controls. Furthermore, we fitted a mixed effects linear model to correct for a possible population effect. RESULTS: Although the estimated degrees of genomic relatedness with the different toolsets show substantial variability, correlation measures between the different estimators demonstrated moderate to strong correlations. Controls have higher point estimates for genomic kinship coefficients. The one-sided Mann Whitney test did not show any evidence for a higher median relative difference for cases compared to controls. Neither did the regression analysis exhibit a positive association between case-control status and genomic kinship coefficient. CONCLUSIONS: In this case-control setting, in which we compared consanguineous couples corrected for degree of pedigree relatedness, a higher degree of genomic relatedness was not significantly associated with a higher likelihood of having an affected child. Further translational research should focus on which parts of the genome and which pathogenic mutations couples are sharing. Looking at relatedness coefficients by determining genome-wide SNPs does not seem to be an effective measure for prospective risk assessment in consanguineous parents.

Experience of hypoglycaemia is associated with changes in beliefs about diabetes in patients with type 2 diabetes.

AIM: Hypoglycaemia may have a detrimental impact on quality of life for patients with Type 2 diabetes. There are few clinical studies exploring the impact of experiencing hypoglycaemia on beliefs about diabetes and health status. The aim of this study was to explore associations between experience of hypoglycaemia and changes in diabetes beliefs and self-reported health status in patients with non-insulin-treated Type 2 diabetes using a blood glucose meter. METHODS: One-year prospective cohort analysis of 226 patients recruited to a randomized trial evaluating the impact of self-monitoring of blood glucose. Self-reported hypoglycaemia over 1 year was categorized into three groups: (1) no experience of hypoglycaemia; (2) blood glucose measurements < 4 mmol/l with no associated symptoms of hypoglycaemia (grade 1); and (3) symptomatic hypoglycaemia (grade 2 and 3). Measures of beliefs about diabetes (Revised Illness Perception Questionnaire) and health status (EuroQol-5D) were assessed at baseline and 1 year. Differences in mean changes over 1 year were explored with analyses of covariance. RESULTS: There was a significant increase in mean score in beliefs about personal control (1.14; 95%CI 0.14-2.14) among those experiencing grade 1 hypoglycaemia compared with those not experiencing hypoglycaemia. There were no significant differences in changes in health status between groups, with small overall changes that were inconsistent between groups. CONCLUSIONS: This study does not provide support for a long-term adverse impact on beliefs about diabetes or health status from the experience of mild symptomatic hypoglycaemia, in well-controlled, non-insulin-treated patients with Type 2 diabetes using self-monitoring of blood glucose.

Efficacy of serology driven "test and treat strategy" for eradication of H. pylori in patients with rheumatic disease in the Netherlands.

The treatment of choice of H. pylori infections is a 7-day triple-therapy with a proton pump inhibitor (PPI) plus amoxicillin and either clarithromycin or metronidazole, depending on local antibiotic resistance rates. The data on efficacy of eradication therapy in a group of rheumatology patients on long-term NSAID therapy are reported here. This study was part of a nationwide, multicenter RCT that took place in 2000-2002 in the Netherlands. Patients who tested positive for H. pylori IgG antibodies were included and randomly assigned to either eradication PPI-triple therapy or placebo. After completion, follow-up at 3 months was done by endoscopy and biopsies were sent for culture and histology. In the eradication group 13% (20/152, 95% CI 9-20%) and in the placebo group 79% (123/155, 95% CI 72-85%) of the patients were H. pylori positive by histology or culture. H. pylori was successfully eradicated in 91% of the patients who were fully compliant to therapy, compared to 50% of those who were not (difference of 41%; 95% CI 18-63%). Resistance percentages found in isolates of the placebo group were: 4% to clarithromycin, 19% to metronidazole, 1% to amoxicillin and 2% to tetracycline.

Plasma adiponectin concentration has an inverse and a non linear association with estimated glomerular filtration rate in patients with K/DOQI 3 - 5 chronic kidney disease.

BACKGROUND: Chronic kidney disease (CKD) is associated with an increased incidence of cardiovascular disease (CVD). A few studies have demonstrated elevated plasma adiponectin and leptin levels in CKD. The aims of this study were to assess whether 1) estimated glomerular filtration rate (eGFR) is associated with plasma leptin and adiponectin; and 2) adiponectin and leptin (partly) explain associations of CKD with endothelial dysfunction, insulin resistance, and low-grade inflammation in patients with K/DOQI Stage 3 - 5 CKD. METHODS: Baseline data from 91 patients with Stage 3 - 4 CKD in the anti-oxidant therapy in chronic renal insufficiency study, a randomized, double-blind, placebo-controlled trial, in which the effects of oxidative stress-lowering treatment on vascular function and structure were studied, and from 50 dialysis naïve patients, who took part in an open-label, randomized study that compared two peritoneal dialysis regimens, used in the analysis. All subjects for both the studies were recruited in the same centres. RESULTS: The association between eGFR and adiponectin was non-linear. In multivariate analysis, log-eGFR (unstandardized beta = 8.303 microg/ml, p < 0.0001) was the strongest determinant of adiponectin, and body mass index the strongest determinant of leptin (beta = 2.477 ng/ml, p < 0.0001). Plasma adiponectin and leptin did not modify the associations between eGFR and plasma von Willebrand factor or soluble vascular adhesion molecule-1. Plasma leptin had the strongest association with the homeostatic model assessment (HOMA-IR) index. Plasma C-reactive protein had no association with adiponectin or leptin. CONCLUSIONS: In patients with K/DOQI Stage 3 - 5 CKD, renal function had a significant non-linear inverse association with and was the strongest predictor of adiponectin. BMI was the strongest predictor of plasma leptin. Plasma adiponectin and leptin did not explain, and thus presumably are not involved in, the association between eGFR and some markers of endothelial dysfunction.

Absence of an acute insulin response predicts onset of type 2 diabetes in a Caucasian population with impaired glucose tolerance.

CONTEXT: In persons with impaired glucose tolerance (IGT), both impaired insulin secretion and insulin resistance contribute to the conversion to type 2 diabetes mellitus (T2DM). However, few studies have used criterion standard measures to asses the predictive value of impaired insulin secretion and insulin resistance for the conversion to T2DM in a Caucasian IGT population. OBJECTIVES: The objective of the study was to determine the predictive value of measures of insulin secretion and insulin resistance derived from a hyperglycemic clamp, including the disposition index, for the development of T2DM in a Caucasian IGT population. DESIGN, SETTING, AND PARTICIPANTS: The population-based Hoorn IGT study consisted of 101 Dutch IGT subjects (aged < 75 yr), with mean 2-h plasma glucose values, of two separate oral glucose tolerance tests, between 8.6 and 11.1 mmol/liter. A hyperglycemic clamp at baseline was performed to assess first-phase and second-phase insulin secretion and insulin sensitivity. During follow-up, conversion to T2DM was assessed by means of 6-monthly fasting glucose levels and yearly oral glucose tolerance tests. RESULTS: The cumulative incidence of T2DM was 34.7%. Hazard ratio for T2DM development adjusted for age, sex, and body mass index was 5.74 [95% confidence interval (CI) 2.60-12.67] for absence of first insulin peak, 1.58 (95% CI 0.60-4.17) for lowest vs. highest tertile of insulin sensitivity, and 1.78 (95% CI 0.65-4.88) for lowest vs. highest tertile of the disposition index. CONCLUSIONS: In these Caucasian persons with IGT, the absence of the first insulin peak was the strongest predictor of T2DM.

Evaluation of the one-minute exercise test to detect peripheral arterial disease.

BACKGROUND: Asymptomatic peripheral arterial disease (PAD) is common amongst the elderly and is a risk factor for cardiovascular morbidity and mortality. PAD can be assessed by non-invasive tests such as the ankle/brachial pressure index (ABPI) at rest and Doppler flow velocity (DFV) scanning, but these tests may underestimate the prevalence of PAD. The aim of this study was to estimate the added value, for the detection of PAD, of the one-minute exercise test, defined as positive if the drop of the ankle systolic pressure was more than 30 mmHg. We also investigated whether the combination of the ABPI at rest and the one-minute exercise test could replace DFV scanning. MATERIALS AND METHODS: We studied this in a random sample (n = 631) of a 50- to 75-year-old population. RESULTS: Of these subjects 11% (66/631) had an abnormal ABPI (< 0.9) and 16% (102/631) had an abnormal DFV curve. Of this sample 72% of the subjects performed a one-minute exercise test. Of all subjects 6% (27/451) had an abnormal ABPI (< 0.9) and 12% (54/451) had an abnormal DFV curve. The one-minute exercise test revealed seven cases of PAD (beyond the 67 already identified) which were not detected by an abnormal ABPI at rest and/or DFV scanning. As a result the prevalence of PAD increased by 2%. All patients with an aortoiliac or femoropopliteal obstruction had an ABPI at rest < 0.9. The sensitivity of the combination of the ABPI at rest and the one-minute exercise test to detect abnormal DFV curves was low for crural obstructions. CONCLUSION: The one-minute exercise test slightly improves the detection of peripheral arterial disease in the general population.

Deteriorating glucose tolerance status is associated with left ventricular dysfunction--the Hoorn Study.

BACKGROUND: Type 2 diabetes (DM2) is associated with a greater risk of heart failure. The mechanisms underlying this association remain controversial and include diabetes-associated hypertension and obesity, impaired small and large artery function, and a distinct metabolic cardiomyopathy related to hyperglycaemia/ hyperinsulinaemia. The proximate causes of heart failure are left ventricular (LV) systolic dysfunction (SDF) and diastolic dysfunction (DDF). We investigated, in a population-based cohort (n=746), the association between glucose tolerance status and SDF and DDF . METHODS AND RESULTS: The study population consisted of 274 individuals with normal glucose metabolism (NGM), 174 with impaired glucose metabolism (IGM) and 298 with DM2 (mean age 68.5 years). All participants underwent an LV echocardiogram. SDF was defined as ejection fraction <55%. DDF was determined by a sum score of peak A velocity (abnormal, >or =97 cm/s), the difference between Apv and Amv duration (> or =41 ms), and left atrial volume (> or =57 ml), where cut-off values were based upon the 90th percentile in NGM. In addition, we analysed the ratio of early to late diastolic filling (E/A ratio) on a continuous scale using linear regression analyses. The age- and sex-standardised prevalences in NGM, IGM and DM2 were 13, 14 and 30% for SDF , and 26, 36 and 47% for DDF (P trend for both <0.001). After adjustment for sex, age, hypertension, body mass index, prior cardiovascular disease and (micro) albuminuria, DM2 was significantly associated with both SDF (odds ratio (95% CI) 2.04 (1.24 to 3.36)) and DDF (2.42 (1.63 to 3.60)) (90th percentile definition). This was also true for the analyses with the E/A ratio on a continuous scale (regression coefficient b (95% CI) -0.05 (-0.09 to -0.01). After adjustment for sex, age, hypertension, body mass index, prior cardiovascular disease and (micro) albuminuria IGM was not significantly associated with SDF (odds ratio (95% CI) 1.04 (0.58 to 1.88)) or DDF (1.33 (0.86 to 2.06)) using the definition based upon the 90th percentile. However, IGM was significantly associated with DDF if the E/A ratio was analysed on a continuous scale (regression coefficient beta (95% CI) -0.05 (-0.10 to -0.01). Additional adjustment for brachial artery flow-mediated vasodilation or arterial stiffness, as measures of large artery function, did not materially alter the results. Hyperglycaemia and hyperinsulinaemia together explained approximately 30% of the association of DM2 with SDF and approximately 40% of that with DDF . CONCLUSION: DM2 is independently associated with a 2.0-fold greater risk of SDF and a 2.4-fold greater risk of DDF . IGM was not associated with SDF , and the association with DDF was limited to the E/A ratio. These observations may therefore explain the increased risk of systolic and diastolic heart failure in elderly individuals with DM2.

S-adenosylmethionine and 5-methyltetrahydrofolate are associated with endothelial function after controlling for confounding by homocysteine: the Hoorn Study.

OBJECTIVE: To explore to what extent homocysteine, S-adenosylmethionine (SAM), S-adenosylhomocysteine, total folate, 5-methyltetrahydrofolate (5-MTHF), vitamin B12, and vitamin B6 are associated with endothelium-dependent, flow-mediated vasodilation (FMD), and whether these associations are stronger in individuals with diabetes or other cardiovascular risk factors. METHODS AND RESULTS: In this population-based study of 608 elderly people, FMD and endothelium-independent nitroglycerin-mediated dilation (NMD) were ultrasonically estimated from the brachial artery (absolute change in diameter [mum]). High SAM and low 5-MTHF were significantly associated with high and low FMD, respectively (linear regression coefficient, [95% confidence interval]): 48.57 microm (21.16; 75.98) and -32.15 microm (-59.09; -5.20), but high homocysteine was not (-15.11 microm (-42.99; 12.78). High SAM and low 5-MTHF were also significantly associated with high and low NMD, respectively. NMD explained the association of 5-MTHF with FMD but not of SAM. No interactions were observed for diabetes or cardiovascular risk factors. CONCLUSIONS: In this elderly population, both SAM and 5-MTHF are associated with endothelial and smooth muscle cell function. The effect of homocysteine on endothelial function is relatively small compared with SAM and 5-MTHF. The relative impact of SAM, 5-MTHF, and homocysteine, and the mechanisms through which these moieties may affect endothelial and smooth muscle cell function need clarification.

Hyperhomocysteinemia increases risk of death, especially in type 2 diabetes : 5-year follow-up of the Hoorn Study.

BACKGROUND: A high serum total homocysteine (tHcy) concentration is a risk factor for death, but the strength of the relation in patients with type 2 (non-insulin-dependent) diabetes mellitus compared with nondiabetic subjects is not known. A cross-sectional study suggested that the association between tHcy and cardiovascular disease is stronger in diabetic than in nondiabetic subjects. We therefore prospectively investigated the combined effect of hyperhomocysteinemia and type 2 diabetes on mortality. METHODS AND RESULTS: Between October 1, 1989, and December 31, 1991, serum was saved from 2484 men and women, 50 to 75 years of age, who were randomly selected from the town of Hoorn, The Netherlands. Fasting serum tHcy concentration was measured in 171 subjects who died (cases; 76 of cardiovascular disease) and in a stratified random sample of 640 survivors (control subjects). Mortality risks were calculated over 5 years of follow-up by means of logistic regression. The prevalence of hyperhomocysteinemia (tHcy >14 micromol/L) was 25. 8%. After adjustment for major cardiovascular risk factors, serum albumin, and HbA(1c), the odds ratio (95% CI) for 5-year mortality was 1.56 (1.07 to 2.30) for hyperhomocysteinemia and 1.26 (1.02 to 1. 55) per 5-micromol/L increment of tHcy. The odds ratio for 5-year mortality for hyperhomocysteinemia was 1.34 (0.87 to 2.06) in nondiabetic subjects and 2.51 (1.07 to 5.91) in diabetic subjects (P=0.08 for interaction). CONCLUSIONS: Hyperhomocysteinemia is related to 5-year mortality independent of other major risk factors and appears to be a stronger (1.9-fold) risk factor for mortality in type 2 diabetic patients than in nondiabetic subjects.

Effect of chemotherapy on survival of craniofacial osteosarcoma: a systematic review of 201 patients.

PURPOSE: To evaluate the possible value of chemotherapy in the treatment of craniofacial osteosarcoma (CFOS). DESIGN: In a systematic review, data of 201 patients (age, 36.6 +/- 19.0 years [mean +/- SD]) from 20 uncontrolled series on CFOS indexed in Medline and Excerpta Medica between 1974 and 1994 were pooled; 180 patients had undergone surgery. Various chemotherapy regimens had been given to 71 patients. Radiotherapy was used in 69 patients. All patients had data for overall survival, and 182 had data for disease-free survival analysis. Cumulative survival distributions were estimated by the product-limit method, and a multiple regression analysis was performed. RESULTS: Patients' overall and disease-free survival rates were significantly improved by treatment with chemotherapy. This was confirmed for patients with complete surgical removal, as well as for those with incomplete removal of tumor. In a proportional hazards model, complete surgical removal and chemotherapy were independent significant factors for overall and disease-free survival. The effect of radiotherapy was insignificant. No prognostic factors could be identified among age groups, sex, and subsites. CONCLUSION: Evidence exists that chemotherapy improves survival in CFOS. We advocate the adoption of the chemotherapy protocols used for OS of the long bones for CFOS.

Increased levels of soluble vascular cell adhesion molecule 1 are associated with risk of cardiovascular mortality in type 2 diabetes: the Hoorn study.

Membrane-bound vascular cell adhesion molecule 1 (VCAM-1) allows the tethering and rolling of monocytes and lymphocytes as well as firm attachment and transendothelial migration of leukocytes. Soluble forms of VCAM (sVCAM-1) may serve as monitors of increased expression of membrane-bound VCAM-1 and thus may reflect progressive formation of atherosclerotic lesions. Levels of sVCAM-1 have been found to be increased among type 2 diabetic as compared with nondiabetic subjects. To study the association of plasma sVCAM-1 concentration and risk of cardiovascular and all-cause mortality among nondiabetic and diabetic subjects, we investigated an age-, sex-, and glucose-tolerance-stratified sample (n = 631) of a population-based cohort aged 50-75 years that was followed prospectively. Plasma levels of sVCAM-1 were determined in frozen -70 degrees C baseline samples. After 7.4 years (mean) of follow-up, 107 (17%) subjects had died (42 of cardiovascular causes). In the entire group, increased sVCAM-1 levels were significantly associated with increased risk of cardiovascular mortality (relative risks [RRs] per 100 ng/ml sVCAM-1 increase, 1.10 [1.05-1.15] after adjustment for age, sex, and glucose tolerance status). This RR was somewhat diminished by further adjustment for the presence of hypertension and cardiovascular disease; levels of total, HDL, and LDL cholesterol and homocysteine; the presence of microalbuminuria (a putative marker of endothelial dysfunction); levels of von Willebrand factor (a marker of endothelial dysfunction) and C-reactive protein (a marker of low-grade inflammation); and estimates of glomerular filtration rate. However, the RR remained statistically significant. The RR among type 2 diabetic subjects was 1.13 (1.07-1.20) per 100 ng/ml sVCAM-1 increase after adjustment for age and sex, which was somewhat higher but not significantly different from the RR in nondiabetic subjects (P value for interaction term, 0.12). Further adjustment for other risk factors gave similar results. In conclusion, levels of sVCAM-1 are independently associated with the risk of cardiovascular mortality in type 2 diabetic subjects and therefore might be useful for identifying subjects at increased cardiovascular risk. Increased plasma sVCAM-1 levels may reflect progressive formation of atherosclerotic lesions, or sVCAM-1 itself may have bioactive properties related to cardiovascular risk. Our data, however, argue against the hypotheses of sVCAM-1 levels simply being a marker of endothelial dysfunction, of low-grade inflammation, or of an impaired renal function.

Analysis of coagulation cascade and endothelial cell activation during inhibition of vascular endothelial growth factor/vascular endothelial growth factor receptor pathway in cancer patients.

OBJECTIVE: The angiogenesis inhibitor SU5416 is a potent inhibitor of vascular endothelial growth factor (VEGF) receptor-1 and -2. VEGF may be involved in hemostasis by altering the hemostatic properties of endothelial cells. We analyzed the effects of SU5416 on the coagulation cascade and the vessel wall in patients with advanced cancer. METHODS AND RESULTS: Markers for thrombin generation, activation of the protein C pathway, fibrinolysis, and endothelial cell activation were measured in patients with renal cell carcinoma, soft tissue sarcoma, or melanoma on days 0, 14, and 28 of treatment with SU5416. Three of 17 sampled patients developed a thromboembolic event in the fifth week of treatment. Markers for thrombin generation and fibrinolysis did not show significant changes. We observed a significant increase in endogenous thrombin potential and of parameters reflecting endothelial cell activation (von Willebrand antigen, soluble tissue factor, and soluble E-selectin) in all patients (P< or =0.001). In patients experiencing a thromboembolic event, endogenous thrombin potential, soluble tissue factor, and soluble E-selectin increased to a significantly greater extent (P=0.029, P=0.021, and P=0.007, respectively). CONCLUSIONS: VEGF is not only a permeability, proliferation, and migration factor, but it is also a maintenance and protection factor for endothelial cells.

Serum homocysteine levels are associated with the development of (micro)albuminuria: the Hoorn study.

Microalbuminuria is a strong indicator of the risk of future cardiovascular disease and renal dysfunction. Slightly increased levels of homocysteine, an independent risk factor for atherothrombotic disease, have recently been found to be associated with the presence of (micro)albuminuria. However, it is unknown whether increased homocysteine levels precede the occurrence of (micro)albuminuria. Normoalbuminuric subjects (n=316, 66 with non-insulin-dependent diabetes mellitus [NIDDM]) of an age-stratified, sex-stratified, and glucose tolerance-stratified sample of a population-based cohort study were investigated at baseline and after a mean follow-up duration of 6.1 years. Development of (micro)albuminuria was defined as a mean albumin-to-creatinine ratio >2.0 mg/mmol at the follow-up examination. The cumulative incidence of (micro)albuminuria was 14. 0% (9.7 % to 18.3%) among nondiabetic subjects and 22.7% (12.9% to 32.5%) among NIDDM patients. Age-adjusted, sex-adjusted, and glucose tolerance status-adjusted logistic regression analyses showed development of (micro)albuminuria to be significantly associated with baseline homocysteine levels >19.0 micromol/L compared with homocysteine levels <9.1 micromol/L (odds ratio [OR] 5.1, 95% CI 1.1 to 23.0). For homocysteine levels of 9.1 to 14.0 micromol/L and 14.1 to 19.0 micromol/L, the values were OR 1.2 (95% CI 0.5 to 3.0) and OR 1.8 (95% CI 0.6 to 5.3), respectively. Additional adjustment for baseline insulin resistance, blood pressure, body mass index, presence of cardiovascular disease and retinopathy, current smoking, or estimates of glomerular filtration rate did not materially affect the results. Substituting homocysteine levels as a continuous variable for categories of homocysteine levels showed that a 5-micromol/L increase of the homocysteine level was associated with an increased risk of developing (micro)albuminuria (OR 1.38, 95% CI 0.97 to 1.95). Analyses performed in nondiabetic and diabetic subjects separately gave similar results among nondiabetic subjects. Among diabetic subjects, the association between homocysteine level and (micro)albuminuria could not be estimated, because there was an insufficient number of diabetic subjects with high homocysteine levels. Hyperhomocysteinemia is an independent determinant of the development of (micro)albuminuria among nondiabetic subjects, even after adjustment for estimates of glomerular filtration rate. We could neither confirm nor reject an association between homocysteine levels and the development of (micro)albuminuria among NIDDM subjects. These data suggest that homocysteine may play a pathophysiological role in the development of (micro)albuminuria.

Hyperhomocysteinemia is associated with the presence of retinopathy in type 2 diabetes mellitus: the Hoorn study.

BACKGROUND: Retinopathy is the leading cause of blindness among patients with type 2 diabetes mellitus (DM). Hyperhomocysteinemia is a recently recognized risk factor for cardiovascular disease, independent of established risk factors. OBJECTIVE: To study the association between the homocysteine level and retinopathy among subjects with and without DM. METHODS: We studied an age-, sex-, and glucose tolerance-stratified random sample of a 50- to 75-year-old general white population in the Hoorn Study (N = 625). Retinal vascular changes (retinopathy) were assessed using ophthalmoscopy and/or fundus photography. Hyperhomocysteinemia was defined as a serum total homocysteine level greater than 16 micromol/L. RESULTS: The prevalence of retinopathy was 9.8% (28/285) in subjects with normal glucose tolerance, 11.8% (20/169) in those with impaired glucose tolerance, 9.4% (10/106) in those with newly diagnosed type 2 DM, and 32.3% (21/65) in those with known type 2 DM. The prevalence of retinopathy was 10.3% (39/380) in subjects without hypertension and 16.3% (40/245) in subjects with hypertension; it was 12.0% (64/534) in subjects with a serum total homocysteine level of 16 micromol/L or less and 16.5% (15/91) in those with a serum total homocysteine level of more than 16 micromol/L. After stratification for DM and adjustment for age, sex, glycosylated hemoglobin, and hypertension, the odds ratio (95% confidence interval) for the relation between retinopathy and hyperhomocysteinemia was 0.97 (95% confidence interval, 0.42-2.82) in patients without DM and 3.44 (95% confidence interval, 1.13-10.42) in patients with DM (P =.08 for interaction). CONCLUSION: The findings suggest that hyperhomocysteinemia may be a risk factor for retinopathy in patients with type 2 DM, but probably not in patients without DM. Arch Intern Med. 2000;160:2984-2990

Performance of an NIDDM screening questionnaire based on symptoms and risk factors.

OBJECTIVE: To investigate to what extent a short questionnaire on symptoms and risk factors can be used to identify people at increased risk for undiagnosed NIDDM. RESEARCH DESIGN AND METHODS: A general population sample of 2,364 Caucasian subjects, age 50-74 years, not known to have diabetes, completed a questionnaire on diabetes-related symptoms and risk factors. Subsequently, they underwent an oral glucose tolerance test. A backward stepwise multiple logistic regression was carried out with the absence or presence of newly detected diabetes as the dependent variable and the items from the questionnaire as the independent variables. The selected items were included in a new symptom risk questionnaire, which was evaluated in a different population sample of 786 subjects, age 45-74 years, not known to have diabetes and compared with existing questionnaires. RESULTS: The newly developed symptom-risk questionnaire contains questions concerning the following items, which were independently and significantly (P < 0.05) associated with the presence of previously undiagnosed diabetes: pain during walking with need to slow down, shortness of breath when walking with people of the same age, frequent thirst, age, sex, obesity, parent or sibling with diabetes, use of antihypertensive drugs, and reluctance to use a bicycle for transportation. The 1993 American Diabetes Association questionnaire, the 1995 Herman et aL (17) questionnaire, and the newly developed symptom-risk questionnaire had sensitivities of 59, 72, and 72%; specificities of 57, 55, and 56%; positive predictive values of 5.6, 6.4, and 6.5%; and negative predictive values of 97, 98, and 98%, respectively. CONCLUSIONS: The newly developed symptom-risk questionnaire has good performance characteristics, and the advantage of a variable cutoff makes it a useful screening tool for NIDDM in general practice.

Symptoms and well-being in relation to glycemic control in type II diabetes.

OBJECTIVE: To describe the cross-sectional relation between glycemic control and physical symptoms, emotional well-being, and general well-being in patients with type II diabetes. RESEARCH DESIGN AND METHODS: The study population consisted of 188 patients with type II diabetes between 40 and 75 years of age. Patients were treated with blood glucose-lowering agents or had either a fasting venous plasma glucose level > or = 7.8 mmol/l or an HbA1c level > 6.1%. Multiple regression analyses were performed. Dependent variables were scores on the Type II Diabetes Symptom Checklist, the Profile of Mood States, the Affect Balance Scale, and questions regarding general well-being. The primary determinant under study was HbA1c. In addition, age, sex, neuroticism (indicating a general tendency to complain), insulin use, and comorbidity were included as determinants in all analyses. Other potential determinants taken into consideration were hypoglycemic complaints, marital status, diabetes duration, cardiovascular history, blood pressure, BMI, waist-to-hip ratio, perceived burden of treatment, and smoking. None of these potential determinants had to be included to correct confounding of the relation between HbA1c and well-being scores. RESULTS: Higher HbA1c levels were significantly associated with higher symptom scores (total score, hyperglycemic score, and neuropathic score), with worse mood (total score, displeasure score, depression, tension, fatigue), and with worse general well-being. The relative risks varied between 1.02 and 1.36 for each percentage difference in HbA1c. The relation between HbA1c and some mood states was modified by neuroticism: in the less neurotic patient (i.e., one who is less inclined to complain), the relation was more evident. CONCLUSIONS: These data suggest that better glycemic control in type II diabetes is associated with fewer physical symptoms, better mood, and better well-being, in a nonhypoglycemic HbA1c range.

Randomized study of two different target levels of glycemic control within the acceptable range in type 2 diabetes. Effects on well-being at 1 year.

OBJECTIVE: A randomized trial with 1-year follow-up was conducted in 23 general practices to study the relationship between target values for glycemic control and well-being in type 2 diabetes. RESEARCH DESIGN AND METHODS: A total of 176 patients with type 2 diabetes, aged 40-75 years, were included. General practitioners were encouraged to make decisions according to a standardized step-up regimen until the target level of glycemic control was reached. The random allocation to a strict or a less strict target level of glycemic control (fasting capillary glucose < 6.5 or < 8.5 mmol/l), change in HbA1c and fasting glucose, and initiating insulin or treatment with oral hypoglycemic agents were studied as putative determinants of scores on a type 2 diabetes symptom checklist, a profile of mood states, an affect balance scale, and general well-being. Adjustments were made for baseline scores on the outcome at issue. RESULTS: Positive affect (an odds ratio [OR] [95% CI] of 0.39 [0.19-0.83]) and perceived treatment burden (OR 0.48 [0.23-0.98]) were unfavorably altered in the group randomly allocated to stricter target levels (fasting capillary glucose < 6.5 mmol/l). Patients who had a decrease in HbA1c of 1% or more tended to have comparatively favorable mood (OR displeasure score 0.35 [0.13-0.94]) and general well-being scores at 1 year (ORs of having unfavorable scores ranged from 0.4 to 0.5, NS). CONCLUSIONS: Perceived treatment burden and positive effect are unfavorably affected by random allocation to a strict target level for glycemic control. Improved glycemic control is associated with favorable mood and possibly general well-being in type 2 diabetes.