Asymmetric and symmetric dimethylarginine as markers of endothelial dysfunction in cerebrovascular disease: A prospective study.

BACKGROUND AND AIM: Asymmetric dimethylarginine (ADMA) and symmetric dimethylarginine (SDMA) have been proposed as mediators of endothelial dysfunction. In this study, we aimed to investigate the diagnostic and prognostic role of ADMA and SDMA in acute cerebrovascular disease. METHODS AND RESULTS: A prospective case-control study was performed, enrolling 48 patients affected by ischemic stroke with no cardioembolic origin, 20 patients affected by TIA, 40 subjects at high cardiovascular risk and 68 healthy subjects. ADMA levels were significantly lower in high-risk subjects (18.85 [11.78-22.83] µmol/L) than in patients with brain ischemic event, both transient (25.70 [13.15-40.20] µmol/L; p = 0.032) and permanent (24.50 [18.0-41.33] µmol/L; p = 0.001). SDMA levels were different not only between high-risk subjects and ischemic patients, but also between TIA and stroke patients, reaching higher levels in TIA group and lower levels in stroke group (1.15 [0.90-2.0] vs 0.68 [0.30-1.07] µmol/L; p < 0.001). SDMA was also correlated with short-term prognosis, with lower levels in case of adverse clinical course, evaluated by type of discharge (p = 0.009) and need of prolonged rehabilitation (p = 0.042). CONCLUSIONS: The present study highlights the relationship between l-arginine, ADMA, SDMA and acute cerebrovascular events. Therefore, our results suggested a potential role of SDMA as a specific marker of transient ischemic damage and as a short-term positive prognostic marker.

Advanced glycation end products and chronic inflammation in adult survivors of childhood leukemia treated with hematopoietic stem cell transplantation.

BACKGROUND: Among survivors of pediatric acute lymphoblastic leukemia (ALL), those who received hematopoietic stem cell transplantation (HSCT) conditioned with total-body irradiation (TBI) show the highest risk of late complications, including cardiovascular (CV) disease. Advanced glycation end products (AGEs) have been associated with CV disease in diabetes mellitus and other clinical conditions. This study explores AGEs plasma levels, inflammatory status, and lipid profile in survivors of pediatric ALL who received HSCT conditioned with TBI. PROCEDURE: Inclusion criteria were (a) previous diagnosis of ALL at age < 18 years, treated with HSCT conditioned with TBI; (b) age > 18 at the time of the study enrollment; (c) off-therapy for at least five years. Radiotherapy other than TBI, preexisting heart disease, glucose metabolism impairment, body mass index > 25, active graft versus host disease (GvHD), smoking, or treatment with cholesterol lowering medications were exclusion criteria. Eighteen survivors and 30 age-matched healthy controls were enrolled. RESULTS: AGEs plasma levels were markedly higher in ALL survivors than in healthy subjects (2.15 ± 2.21 vs 0.29 ± 0.15 pg/mL, P < 0.01). Survivors also showed higher levels of high-sensitivity C-reactive protein (2.32 ± 1.70 vs 0.88 ± 1.09 mg/dL, P < 0.05), IL-1ß (7.04 ± 1.52 vs 4.64 ± 2.02 pg/mL, P < 0.001), IL17 (37.44 ± 3.51 vs 25.19 ± 6.34 pg/mL, P < 0.001), an increased glutathione/reduced glutathione ratio (0.085 ± 0.07 vs 0.041 ± 0.036, P < 0.05) and slight alterations in their lipid profile. CONCLUSIONS: Our data show AGEs accumulation and chronic inflammation in ALL survivors who received HSCT conditioned with TBI. These alterations may contribute to the increased risk of CV disease reported in these subjects.

Self-management education may improve blood pressure in people with type 2 diabetes. A randomized controlled clinical trial.

BACKGROUND AND AIMS: Diabetes is a suitable model to evaluate intervention programmes aimed at chronic diseases, because of its well-defined and measurable process and outcome indicators. In this study, we aimed at investigating the effects of group based self-management education on clinical and psychological variables in type 2 diabetes. METHODS AND RESULTS: Four-year randomized controlled clinical trial (ISRCTN14558376) comparing Group Care and traditional one-to-one care. Clinical and psychological variables were monitored at baseline, 2 and 4 years. Although differences between groups appear to be non-significant at univariate analysis, body weight, BMI and HbA1c, systolic and diastolic blood pressure improved in the patients followed by Group Care but not among Controls. Prescription of lipid-lowering and anti-hypertensive agents did not change among the patients on Group Care, whereas anti-hypertensives were stepped up among Controls without improving their blood pressure. Multivariable analysis suggests that blood pressure improvement among patients on Group Care was independent of BMI, duration of diabetes and antihypertensive medication, suggesting a direct effect of education, presumably by increasing adherence. The "Powerful Others" dimension of the Locus of Control worsened and fear of complications decreased among Controls. CONCLUSIONS: The results confirm that a multidisciplinary structured group educational approach improves blood pressure, presumably through better adherence to healthy lifestyle and medication, in people with type 2 diabetes. CLINICAL TRIAL REGISTRATION NUMBER: ISRCTN14558376.

The co-activator-associated arginine methyltransferase 1 (CARM1) gene is overexpressed in type 2 diabetes.

PURPOSE: We examined the expression of a panel of epigenetic enzymes catalyzing histone tails post-transcriptional modifications, together with effectors of metabolic and inflammatory alterations, in type 2 diabetes. METHODS: Cross-sectional, case-control study of 21 people with type 2 diabetes and 21 matched controls. Total RNA was extracted from white cells and reverse transcribed. PCR primer assays for 84 key genes encoding enzymes known to modify genomic DNA and histones were performed. Western blot was performed on lysates using primary antibodies for abnormally expressed enzymes. Hormones and cytokines were measured by multiplex kits. A Bayesian network was built to investigate the relationships between epigenetic, cytokine, and endocrine variables. RESULTS: Co-activator-associated aRginine Methyltransferase 1 (CARM1) expression showed a five-fold higher median value, matched by higher protein levels, among patients who also had increased GIP, IL-4, IL-7, IL-13, IL-17, FGF basic, G-CSF, IFN-γ, and TNFα and decreased IP-10. In a Bayesian network approach, CARM1 expression showed a conditional dependence on diabetes, but was independent of all other variables nor appeared to influence any. CONCLUSIONS: Increased CARM1 expression in type 2 diabetes suggests that epigenetic mechanisms are altered in human diabetes. The impact of lifestyle and pharmacological treatment on regulation of this enzyme should be further investigated.

Changes in the Prescription of Glucose-Lowering Medications in Patients With Type 2 Diabetes Mellitus After a Cardiovascular Event: A Call to Action From the DATAFILE Study.

Background Evidence accumulated that some glucose-lowering medications protect against cardiovascular events ( CVEs ) in patients with type 2 diabetes mellitus (T2DM) and established cardiovascular disease. The present study evaluated if and how glucose-lowering medication prescription pattern changes in T2DM after a CVE. Methods and Results DATAFILE (Diabetes Therapy After a Cardiovascular Event) was a retrospective multicenter study conducted at 12 diabetes mellitus specialist outpatient clinics in Italy. We identified T2DM patients with an incident CVE for whom a follow-up visit was available after the event. We selected control T2DM patients without an incident CVE , who were matched with cases for age, sex, known diabetes mellitus duration, baseline hemoglobin A1c, kidney function, and follow-up time. We extracted clinical variables and compared prescribed therapies at baseline and follow-up. We included 563 patients with and 497 matched patients without an incident CVE . As expected, patients with a subsequent CVE had a higher baseline prevalence of ischemic heart disease. After a median of 9.5 months, in patients with versus those without a CVE , there was a significant increase in the prescription of beta-blockers, loop diuretics, dual antiplatelet therapy, and, among glucose-lowering medications, a significant decrease in metformin. Hemoglobin A1c marginally declined only in the control group, whereas low-density lipoprotein cholesterol decreased only in patients with CVE . Conclusions This study highlights that occurrence of a CVE in T2DM patients did not prime the prescription of glucose-lowering medications provided with cardiovascular protective effects, even though glucose control remained poor. These data emphasize the need to optimize the therapeutic regimen of T2DM patients with established cardiovascular disease, according to updated guidelines.

Vision-related quality of life and locus of control in type 1 diabetes: a multicenter observational study.

AIMS: Diabetic retinopathy remains asymptomatic until its late stages but remains a leading cause of vision impairment and blindness. We studied quality of life and the ability to deal with the discomfort deriving from the presence of a chronic disease in patients with type 1 diabetes and different stages of retinopathy. METHODS: Multicenter collaborative observational study involving nine centers screening for retinopathy in different areas of Italy. The National Eye Institute 25-item visual functioning questionnaire and the locus of control tool were administered to 449 people with type 1 diabetes between February 2016 and March 2018. Socio-demographic and clinical data were collected. RESULTS: On multivariable analysis, severe retinopathy is associated with worse scores for general vision, ocular pain, near vision activities, distance vision activities, driving, color vision, peripheral vision and lower values of internal control, independently of visual acuity. Women had a perception of worse general health, distance vision activities and driving, and lower internal control and trust in others. Worse scores for visual-specific social functioning, visual-specific mental health, visual-specific role difficulties, visual-specific dependency and peripheral vision were associated with higher HbA1c levels. Fatalism increased with rising HbA1c levels. CONCLUSIONS: These results confirm that a gap exists between patients' knowledge and expectations on retinopathy and providers' expertise and assumptions. To bridge this gap, patient-centered education and engaging approaches may be more effective than simple information given during consultations.

Incidence of prolonged QTc and severe hypoglycemia in type 1 diabetes: the EURODIAB Prospective Complications Study.

AIMS: To assess the independent role of severe hypoglycemia on 7-year cumulative incidence of prolonged QTc in a large cohort of patients with type 1 diabetes. METHODS: People with type 1 diabetes recruited by the EURODIAB Prospective Complications Study who had normal QTc were examined at baseline and after 7 years with standardized methods (n = 1415; mean age ± SD 32.1 ± 9.6 years; diabetes duration 14.2 ± 8.8 years). Hypoglycemic episodes were assessed by a questionnaire. QTc was calculated according to Bazett's formula. In logistic regression analysis, we examined the role of severe hypoglycemia (none, 1-2, or 3 and more episodes/year) on the cumulative incidence of prolonged QTc, independently of age, sex, HbA1c, blood pressure, BMI, physical activity, distal symmetrical and autonomic neuropathy. RESULTS: In total, 264/1415 (17%) patients had incident prolonged QTc. Compared to those with persistently normal QTc, a greater proportion of incident cases had 3 and more hypoglycemic episodes at baseline (16.3 vs 11.2%, p = 0.03) and after 7 years (15.2 vs 9.6%, p = 0.01). In logistic regression analysis, 3 or more episodes of severe hypoglycemia at baseline did not increase cumulative incidence of prolonged QTc (OR 1.34, 95% CI 0.88-2.03). By contrast, severe hypoglycemia at the follow-up examination was associated with higher incidence of QTc prolongation (OR 1.68, 1.09-2.58), which reverted to not significant after adjustment for diabetic neuropathy. CONCLUSIONS: Severe hypoglycemia was not associated with incidence QTc prolongation in type 1 diabetic patients from the EURODIAB PCS.

Hospital admissions for hypertensive crisis in the emergency departments: a large multicenter Italian study.

Epidemiological data on the impact of hypertensive crises (emergencies and urgencies) on referral to the Emergency Departments (EDs) are lacking, in spite of the evidence that they may be life-threatening conditions. We performed a multicenter study to identify all patients aged 18 years and over who were admitted to 10 Italian EDs during 2009 for hypertensive crises (systolic blood pressure ≥220 mmHg and/or diastolic blood pressure ≥120 mmHg). We classified patients as affected by either hypertensive emergencies or hypertensive urgencies depending on the presence or the absence of progressive target organ damage, respectively. Logistic regression analysis was then performed to assess variables independently associated with hypertensive emergencies with respect to hypertensive urgencies. Of 333,407 patients admitted to the EDs over the one-year period, 1,546 had hypertensive crises (4.6/1,000, 95% CI 4.4-4.9), and 23% of them had unknown hypertension. Hypertensive emergencies (n = 391, 25.3% of hypertensive crises) were acute pulmonary edema (30.9%), stroke (22.0%,), myocardial infarction (17.9%), acute aortic dissection (7.9%), acute renal failure (5.9%) and hypertensive encephalopathy (4.9%). Men had higher frequency than women of unknown hypertension (27.9% vs 18.5%, p<0.001). Even among known hypertensive patients, a larger proportion of men than women reported not taking anti-hypertensive drug (12.6% among men and 9.4% among women (p<0.001). Compared to women of similar age, men had higher likelihood of having hypertensive emergencies than urgencies (OR = 1.34, 95% CI 1.06-1.70), independently of presenting symptoms, creatinine, smoking habit and known hypertension. This study shows that hypertensive crises involved almost 5 out of 1,000 patients-year admitted to EDs. Sex differences in frequencies of unknown hypertension, compliance to treatment and risk of hypertensive emergencies might have implications for public health programs.

Obesity is associated with lower mortality risk in elderly diabetic subjects: the Casale Monferrato study.

The relationship between obesity and mortality in people with type 2 diabetes has not been definitely assessed. We have examined this issue in a well-characterized population-based cohort of Mediterranean diabetic people. Standardized anthropometric data from the population-based Casale Monferrato Study have been prospectively analyzed. The cohort included 1,475 people (62.6% aged ≥65 years) who had been recruited in 1991 and followed-up to December 31, 2006. Cox proportional hazards modeling was employed to estimate the independent associations between all-cause and cardiovascular mortality and BMI. Out of 1,475 people, 972 deaths occurred during a 15-year follow-up. Cox regression analyses showed that with respect to BMI <24.2 kg/m(2), values of 30.0 kg/m(2) and over were associated with lower all-cause and cardiovascular mortality risk (HR = 0.68, 95% CI 0.56-0.85, P for trend = 0.001; HR = 0.59, 0.44-0.80, P for trend = 0.002), independently of classical and new risk factors. As interaction between age and BMI was significant, we performed a stratified analysis by age, providing evidence that our finding was entirely due to a significant protective effect of BMI of 30.0 kg/m(2) and over in the elderly (all-cause mortality HR = 0.75, 95% CI 0.58-0.96; cardiovascular mortality HR = 0.67, 95% CI 0.45-0.95). In contrast, obesity was not significantly associated with mortality risk in diabetic subjects aged <65 years. Results were confirmed even excluding from the analysis individuals who died within 2 years of follow-up, smokers and those with CHD. In Mediterranean diabetic people aged ≥65 years, obesity is significantly associated with lower 15-year mortality risk. In contrast, it was not significantly associated with mortality risk in diabetic subjects aged <65 years. As more than two-thirds of people with type 2 diabetes are elderly, our findings, if confirmed, could have clinical implications.

Serum levels of heat shock protein 27 in patients with acute ischemic stroke.

Expression of intracellular heat shock protein 27 (Hsp27) rises in the brain of animal models of cerebral ischemia and stroke. Hsp27 is also released into the circulation and the aim of the present study was to investigated if serum Hsp27 (sHsp27) levels are altered in patients with acute ischemic stroke. sHsp27 was measured in 15 patients with acute ischemic stroke and in 14 control subjects comparable for age, sex, and cardiovascular risk factors. In patients, measurements were performed at admission and 1, 2, and 30 days thereafter. At admission, mean sHsp27 values were threefold higher in patients than in controls. In patients, sHsp27 values dropped after 24 h, rose again at 48 h, and markedly declined at 30 days, indicating the presence of a temporal trend of sHsp27 values following acute ischemic stroke.

Increased QT interval dispersion predicts 15-year cardiovascular mortality in type 2 diabetic subjects: the population-based Casale Monferrato Study.

OBJECTIVE: To evaluate the predictive role of increased corrected QT (QTc) and QT interval dispersion (QTd) on all-cause and cardiovascular mortality in a large, unselected type 2 diabetic population. RESEARCH DESIGN AND METHODS: The prospective study included 1,357 type 2 diabetic patients from the Casale Monferrato Study. At baseline, QTc intervals >0.44 s and QTd intervals >0.08 s were considered abnormally prolonged. Both all-cause and cardiovascular mortality were assessed 15 years after the baseline examination. RESULTS: During the follow-up period, 862 subjects per 12,450 person-years died. Multivariate analysis showed that the hazard ratio (HR) of cardiovascular mortality was significantly increased in subjects with prolonged QTd (1.26 [95% CI 1.02-1.55]) and was only slightly reduced after multiple adjustments. Conversely, prolonged QTc did not increase the HRs for all-cause or cardiovascular mortality. CONCLUSIONS: Increased QTd predicts cardiovascular mortality after a long-term follow-up period in a large, unselected population of type 2 diabetic subjects.

New oral antidiabetic agents.

The pathophysiology of hyperglycemia in type 2 diabetes (T2DM) involves 3 main defects: insulin deficiency, excess hepatic glucose output, and insulin resistance. Oral anti-diabetic agents act in a variety of ways. These include agents that stimulate insulin secretion, reduce hepatic glucose production, delay digestion and absorption of intestinal carbohydrate or improve insulin action. Because of improved knowledge of pathophysiology, new drugs with mechanisms of action focussed on specific pathophysiological alterations have appeared, in order to utilize all the possibilities of treating this condition. Here, we focus on the new agents used in the latest years and the overcoming ones in future, in particular incretin-based therapies, drugs inhibiting kidney glucose reabsorption (SGLT2 inhibitors), and glucokinase activators. The strategy for new drug development advocated here is to establish a broad range of anti-diabetic medicines with different mechanisms of action and potential opportunities for effective combination therapies.

Prevention and treatment of nonalcoholic fatty liver disease.

A better knowledge of the biochemical mechanisms implicated in the development and progression of nonalcoholic fatty liver disease, linking fatty liver to insulin resistance and the metabolic syndrome, has shifted the goal of treatment from a mere clearing of fat from the liver to a systematic treatment of metabolic risk factors for fatty liver. Any attempt to modify the "unhealthy" habits responsible for fatty liver requires an integrated approach, based on the cognitive theory of behaviour by a multidisciplinary team including physicians, psychologists, dieticians and physical exercise experts, and recent data demonstrate that this is feasible and effective. Whenever this goal is not attained, a treatment based on insulin-sensitizers remains the best option, to simultaneously tackle all metabolic alterations of the metabolic syndrome. However, in individual patients, both raised blood pressure and dyslipidemia need to be controlled, in order to reduce cardiovascular risk. In these areas, any attempt should be made to use of drugs less likely to induce a deterioration of glucose control. It remains to be determined whether these treatments are able to modify the natural history of nonalcoholic fatty liver disease in the long term.

Fasting plasma C-peptide and micro- and macrovascular complications in a large clinic-based cohort of type 1 diabetic patients.

OBJECTIVE: A protective effect of residual beta-cell function on microvascular complications of type 1 diabetes has been suggested. Our aim was to retrospectively evaluate the association of fasting plasma C-peptide values with micro- and macrovascular complications. RESEARCH DESIGN AND METHODS: We recruited a clinic-based cohort of 471 type 1 diabetic patients born after 1945 and cared for in the period 1994-2004. Centralized measurements and standardized procedures of ascertainment of micro- and macrovascular complications were employed. Individual cumulative averages of A1C up to 2007 were calculated. RESULTS: Residual beta-cell secretion was detected even many years after diabetes diagnosis. In multivariate linear regression analysis, fasting plasma C-peptide values were positively associated with age at diagnosis (beta = 0.02; P < 0.0001) and triglycerides (beta = 0.20; P = 0.05) and inversely associated with diabetes duration (beta = -0.03; P < 0.0001) and HDL cholesterol (beta = -0.006; P = 0.03). The final model explained 21% of fasting C-peptide variability. With respect to fasting C-peptide values in the lowest tertile (<0.06 nmol/l), higher values were associated with lower prevalence of microvascular complications (odds ratio [OR] 0.59 [95% CI 0.37-0.94]) independently of age, sex, diabetes duration, individual cumulative A1C average during the study period, hypertension, and cardiovascular diseases. No association was evident with macrovascular complications (0.77 [0.38-1.58]). CONCLUSIONS: Our study shows an independent protective effect of residual beta-cell function on the development of microvascular complications in type 1 diabetes, suggesting the potential beneficial effect of treatment that allows the preservation of even modest beta-cell function over time.

What is the clinical usefulness of the metabolic syndrome? The Casale Monferrato study.

OBJECTIVE: Data on the clinical usefulness of the metabolic syndrome with respect to cardiovascular risk are not conclusive. We have assessed this issue in a large population-based cohort of diabetic and nondiabetic people in Southern Europe. METHODS: An Italian population-based cohort of 3729 individuals (2211 without diabetes and 1518 with diabetes) was examined, with centralized measurements, including the Homeostasis Model Assessment (HOMA) index in nondiabetic people. The usefulness of the metabolic syndrome (ATP III criteria) as an indicator of cardiovascular disease (CVD), independently of classical and novel risk factor [C-reactive protein (CRP) and albumin excretion rate (AER)] was assessed by using unconditional logistic regression. RESULTS: One thousand, seven hundred and fifty-three individuals (47.0%) had neither diabetes nor the metabolic syndrome, 458 (12.3%) had the metabolic syndrome only, 442 (11.8%) had type 2 diabetes only and 1076 (28.9%) had both diabetes and the metabolic syndrome. The highest likelihood of having CVD was conferred by both diabetes and the metabolic syndrome [odds ratio (OR) = 4.37, 95% confidence interval (CI) 3.25-5.87], independently of age, sex, low-density lipoprotein-cholesterol, smoke, AER, and CRP values. After further adjustment for its individual components, the association between CVD and the metabolic syndrome was no more evident. Among people with CRP 3 mg/l or less, ORs were similar in nondiabetic people with the metabolic syndrome and in diabetic people without it, whereas among those with CRP greater than 3 mg/l OR was two-fold higher in the latter. Values in upper quartiles of the HOMA-IR conferred a significant two-fold increased OR of CVD, even after adjustment for individual components of the metabolic syndrome, CRP and AER. CONCLUSIONS: The additional information provided by the metabolic syndrome is limited, in both diabetic and nondiabetic people, whereas the HOMA index is a useful indicator of CVD, independently of individual components of the metabolic syndrome, classical and novel risk factors.

C-reactive protein and 5-year survival in type 2 diabetes: the Casale Monferrato Study.

OBJECTIVE: To determine to what extent plasma C-reactive protein (CRP) values influence 5-year all-cause and cardiovascular mortality in type 2 diabetic individuals, independently of albumin excretion rate (AER) and other cardiovascular risk factors, and its incremental usefulness for predicting individual risk of mortality. RESEARCH DESIGN AND METHODS: Measurements of CRP were performed in 2,381 of 3,249 (73.3%) subjects as part of the population-based Casale Monferrato Study. Its association with 5-year all-cause and cardiovascular mortality was assessed with multivariate Cox proportional hazards modeling. The C statistic and measures of calibration and global fit were also assessed. RESULTS: Results are based on 496 deaths in 11.717 person-years of observations (median follow-up 5.4 years). With respect to subjects with CRP < or =3 mg/l, those with higher values had an adjusted hazard ratio (HR) of 1.51 (95% CI 1.18-1.92) for all-cause mortality and 1.44 (0.99-2.08) for cardiovascular mortality. In normoalbuminuric subjects, respective HRs of CRP were 1.56 (1.13-2.15) and 1.65 (1.00-2.74), AER being neither a modifier nor a confounder of CRP association. In analysis limited to diabetic subjects without cardiovascular disease (CVD), adjusted HRs were 1.67 (1.24-2.24) for all-cause mortality and 1.36 (0.83-2.24) for cardiovascular mortality. The improvement in individual risk assessment was marginal when measured with various statistical measures of model discrimination, calibration, and global fit. CONCLUSIONS: CRP measurement is independently associated with short-term mortality risk in type 2 diabetic individuals, even in normoalbuminuric subjects and in those without a previous diagnosis of CVD. Its clinical usefulness in individual assessment of 5-year risk of mortality, however, is limited.