Pleiotropic and Potentially Beneficial Effects of Reactive Oxygen Species on the Intracellular Signaling Pathways in Endothelial Cells.

Endothelial cells (ECs) are exposed to molecular dioxygen and its derivative reactive oxygen species (ROS). ROS are now well established as important signaling messengers. Excessive production of ROS, however, results in oxidative stress, a significant contributor to the development of numerous diseases. Here, we analyze the experimental data and theoretical concepts concerning positive pro-survival effects of ROS on signaling pathways in endothelial cells (ECs). Our analysis of the available experimental data suggests possible positive roles of ROS in induction of pro-survival pathways, downstream of the Gi-protein-coupled receptors, which mimics insulin signaling and prevention or improvement of the endothelial dysfunction. It is, however, doubtful, whether ROS can contribute to the stabilization of the endothelial barrier.

Diabetes and Pancreas: Why So Difficult? Potential Mechanisms of Elevated Serum Pancreatic Enzymes.

Diabetes mellitus has been associated with a higher risk of exocrine pancreas disorders despite inconsistencies among studies, presumably due to the presence of several (often unmeasured) confounding factors. As a direct consequence of this uncertainty, the relationship between anti-diabetic therapies and pancreatic adverse reactions is difficult to evaluate and remains far from being clarified. Indeed, the on going debate on the safety of incretin-based therapies does not lie in any definite conclusion. Serum level of amylases and lipase reflects the balance between production from different tissues and clearance, but it may be also influenced by numerous molecular, cellular, and systems mechanisms. The present review tries to provide an overview of potential biochemical pathways that may underlie pancreatic hyperenzymemia in health and diabetes mellitus.

Dietary Intake of Proteins and Calories Is Inversely Associated With The Oxidation State of Plasma Thiols in End-Stage Renal Disease Patients.

OBJECTIVES: Oxidative stress contributes to the pathogenesis of protein-energy wasting in maintenance hemodialysis (MHD) patients, but knowledge of specific effectors and mechanisms remains fragmented. Aim of the study was to define whether and how food intake is involved in the causal relationship between oxidative stress and protein-energy wasting. METHODS: Seventy-one adult MHD patients and 24 healthy subjects (control) were studied cross-sectionally with analyses of diet record and of oxidative stress, as measured by a battery of plasma thiols including the protein sulfhydryl (-SH) group (PSH) levels (a marker of total protein-SH reducing capacity), the protein thiolation index (PTI, the ratio between disulfide, i.e., oxidized and reduced -SH groups in proteins), low molecular mass (LMM) thiols, LMM disulfides, and mixed LMM-protein disulfides. In addition, interleukin-6 (IL-6), albumin, C-reactive protein, and neutrophil gelatinase-associated lipocalin (NGAL) were measured as markers of inflammation. RESULTS: The patients showed low energy (22.0 ± 8.4 kcal/kg/day) and adequate protein (1.0 ± 0.4 g/kg/day) intakes, high levels of cystine (CySS; patients vs. CONTROL: 113.5 [90.9-132.8] vs. 68.2 [56.2-75.7] µM), cysteinylated proteins (CySSP; 216.0 [182.8-254.0] vs. 163.5 [150.0-195.5] µM), and high PTI (0.76 [0.61-0.88] vs. 0.43 [0.40-0.54]; P < .001 in all comparisons). In patients, variation of CySSP was explained by a standard regression model (R = 0.775; P = .00001) that included significant contributions of protein intake (ß = -0.361), NGAL (ß = 0.387), age (ß = 0.295), and albumin (ß = 0.457). In the same model, variation of PTI (R = 0.624; P = .01) was explained by protein intake (ß = -0.384) and age (ß = 0.326) and NGAL (ß = 0.311). However, when PSH was entered as dependent variable (R = 0.730; P = .0001), only serum albumin (ß = 0.495) and age (ß = -0.280), but not dietary intake or NGAL, contributed to the model. CONCLUSIONS: In MHD, markers of thiol oxidation including CySSP and PTI show independent association with dietary intake and NGAL, whereas PSH, a marker of thiol-reducing capacity, did not associate with these same variables. The mechanism(s) responsible for inverse association between oxidative stress and food intake in MHD remain undefined.

Insulin administration: present strategies and future directions for a noninvasive (possibly more physiological) delivery.

Insulin is a life-saving medication for people with type 1 diabetes, but traditional insulin replacement therapy is based on multiple daily subcutaneous injections or continuous subcutaneous pump-regulated infusion. Nonphysiologic delivery of subcutaneous insulin implies a rapid and sustained increase in systemic insulin levels due to the loss of concentration gradient between portal and systemic circulations. In fact, the liver degrades about half of the endogenous insulin secreted by the pancreas into the venous portal system. The reverse insulin distribution has short- and long-term effects on glucose metabolism. Thus, researchers have explored less-invasive administration routes based on innovative pharmaceutical formulations, which preserve hormone stability and ensure the therapeutic effectiveness. This review examines some of the recent proposals from clinical and material chemistry point of view, giving particular attention to patients' (and diabetologists') ideal requirements that organic chemistry could meet.

Comparison of Nutrition Profile and Diet Record Between Veteran and Nonveteran End-Stage Renal Disease Patients Receiving Hemodialysis in Veterans Affairs and Community Clinics in Metropolitan South-Central Texas.

BACKGROUND: U.S. military veterans have high rates of chronic disease and social disadvantage, which are risk factors for protein-energy wasting (PEW). It is not known whether this translates into high prevalence of PEW in veterans with end-stage renal disease. METHODS: We compared the clinical, socioeconomic, and nutrition status and the diet of 33 veteran and 38 nonveteran clinically stable patients receiving maintenance hemodialysis (MHD) in south-central Texas. RESULTS: The whole cohort included 82% Mexican Americans (MAs), 72% type 2 diabetics, and 73% males. The body mass index was 28.9 ± 6.2, while energy intake was 21.5 ± 8.2 kcal/kg/d and protein intake was 1.0 ± 0.4 g/kg/d. Serum albumin (bromocresol purple) was 3.5 ± 0.4 g/dL, transferrin was 171.9 ± 27.8 mg/d, C-reactive protein was 2.9 (1.4-6.5) mg/L, interleukin-6 (IL-6) was 8.3 (4.2-17.9) pg/mL, neutrophil gelatinase-associated lipocalin was 729 (552-1256) ng/mL, and the malnutrition-inflammation score was 8.8 ± 3.0. In group comparison that adjusted for sex and ethnicity, the veterans had better household income, less MAs (60% vs 100%), more males (94% vs 55%), more use of a renin-angiotensin-aldosterone system blockade (66% vs 33%), and lower IL-6 levels (4.4 [3.1-5.8] vs 15.4 [8.3-20.5] pg/mL; P = .01) than nonveterans. In regression analysis, the lower serum IL-6 level in veterans was independently explained by dialysis clinic, sex, and, possibly, household income (intermediate significance). CONCLUSION: In a relatively small cohort of clinically stable MHD patients, the veterans showed equivalent nutrition status and dietary intake and less inflammation than the nonveterans, thus not supporting the possibility that veteran MHD patients may have worse nutrition than the nonveteran counterpart.

Improving CardioCheck PA analytical performance: three-year study.

BACKGROUND: Cardiovascular prevention requires a diagnostic approach for population-based screening programmes aimed at early identification of modifiable risk factors. Dyslipidaemia, which is a major risk factor for cardiovascular disease, remains largely undiagnosed and undertreated. Point-of-care testing (POCT) provides immediate results for clinical decision-making, however, quality assessment is essential to ensure system performance requirements. CardioChek PA (CCPA), a portable whole blood analyser for rapid lipid measurement, has been on the market since 2002 but with limited evidence of performance levels. The aim of the study was to assess analytical performance issues of the device and possibly contribute to their solution. METHODS: Over a 3-year period, we repeatedly evaluated CCPA accuracy, precision, and discrepancies between instruments and between test strip lots by comparison with laboratory method. At our initial evaluation, the CCPA analyser underestimated total cholesterol (bias 6.5%) and gave within-assay CVs above 6% for all lipid fractions. Our results solicited sequential improvements to the CCPA system by the manufacturer up to the performance level certified by the Cholesterol Reference Method Laboratory Network in 2013: total error 1.3% for total cholesterol and 3.1% for high density lipoprotein (HDL) cholesterol. CONCLUSIONS: POCT diagnostic tests need continuous quality management, including both quality control and quality assurance, to monitor the analytical process. A 3-year external quality surveillance provided information useful in improving POCT performance. As a result, the device is now adequate for use in screening programmes aimed at early detection of lipid disorders.

Anethole dithiolethione lowers the homocysteine and raises the glutathione levels in solid tissues and plasma of rats: a novel non-vitamin homocysteine-lowering agent.

High homocysteine (Hcys) levels are suspected to contribute to the pathogenesis of cardiovascular disease and of other chronic conditions. Failure of B vitamins to reduce the incidence of cardiovascular events while lowering the Hcys levels, has prompted the search for alternative treatments. We tested the ability of anethole dithiolethione (ADT) to lower the Hcys levels in rats and we explored possible underlying mechanisms. Parenteral administration of 10mg/kg ADT to normal rats for 3 days lowered the Hcys levels between 51.4% and 31.5% in kidneys, liver, testis and plasma. Concomitantly, glutathione (GSH) increased between 112% and 28% in kidneys, brain, liver and plasma whereas protein thiolation index decreased 30%. In hyperhomocysteinemic rats, the plasma Hcys levels dropped 70% following a single ip injection of 10mg/kg ADT, while they decreased 55% following oral administration of 2mg/kg/day ADT for one week. Significant additive effects occurred when sub-therapeutic doses of ADT and folic acid were used in combination. To test the possible mechanism(s) of these actions, we perfused isolated rat livers and kidneys with albumin-bound Hcys, the prevalent form of plasma Hcys, and physiological thiols and disulfides at different ratios. In both organ preparations, the elimination rate of albumin-bound Hcys was progressively faster as the amount of reduced thiols was increased in the perfusate. These findings indicate that ADT shifts the redox ratio of GSH and other thiols with their oxidized forms toward the reduced forms, thus favoring the dissociation of albumin-bound Hcys and its transfer to renal and hepatic cells for further processing.

Micro-method for the determination of glutathione in human blood.

A new procedure is described for the visible-range spectrophotometric analysis of glutathione (GSH) in microvolumes of blood (as low as 0.5 µL) collected by fingerstick. Samples are diluted 1 to 300 (v/v) in a stabilizing solution, followed by determination of haemoglobin concentration and by acid deproteination. GSH is then measured in the clear supernatant by colorimetry using DTNB, i.e., 5,5'-dithio-bis(2-nitrobenzoic acid), in aqueous solution at pH 7.8. The DTNB reagent is prepared and kept at pH 6.2 until just prior its addition, thus avoiding spontaneous decomposition of the reagent. The assay is rapid, easy to adapt to large-scale studies and it avoids artefactual oxidation of GSH, a common methodological shortcoming. The method is precise with 1.7 to 3.4% intra-day relative standard deviation (RSD) and 2.2 to 4.2% inter-day RSD, and accurate with -1.4% to 2.3% intra-day relative error (RE) and -2.8% to 1.6% inter-day RE. GSH is recovered by 97.5 to 100% at all tested concentrations. The new colorimetric micro-method was validated by a reliable previously reported HPLC method. The procedure is suitable for minimally invasive investigation of oxidative stress in peripheral blood.

Sitagliptin as add-on therapy in insulin deficiency: biomarkers of therapeutic efficacy respond differently in type 1 and type 2 diabetes.

BACKGROUND: Sitagliptin has been proven to be effective and safe as add-on to insulin in adult patients with type 2 diabetes and absolute insulin deficiency. Recently, it has been suggested to extend the use of dipeptidyl-peptidase-4 inhibitors to type 1 diabetes. The aim of this study was to evaluate and compare the effects of a long-term, fixed-dose combination of sitagliptin and metformin as add-on to insulin on body mass index, fasting plasma glucose, fructosamine, HbA(1c), lipids, and daily dose of insulin in both type 1 diabetes and insulin-treated type 2 diabetes. METHODS: We recruited 25 patients with type 1 diabetes (mean age 51 ± 10 years, mean disease duration 26 ± 13 years) and 31 insulin-treated type 2 diabetic patients (mean age 66 ± 8 years, mean disease duration 19 ± 9 years), who received sitagliptin with metformin as a fixed-dose combination (50/1000 mg once or twice daily) or sitagliptin (100 mg once daily, if intolerant to metformin) in addition to ongoing insulin therapy for 46 ± 19 weeks and 56 ± 14 weeks, respectively. RESULTS: After 21 ± 9 weeks, patients with type 1 diabetes had a significantly lower body mass index, fasting plasma glucose, fructosamine, HbA(1c), and daily insulin requirement. After 49 ± 17 weeks, they maintained their weight loss and total daily insulin dose and showed a significant reduction in low-density lipoprotein cholesterol levels, whereas their HbA(1c) had returned to baseline values. In patients with type 2 diabetes, long-term treatment remained weight-neutral but had persistent beneficial effects on short-term, intermediate-term, and long-term biomarkers of metabolic control, as well as on low-density lipoprotein cholesterol levels and insulin requirement. CONCLUSION: Clinical outcomes differed according to type of diabetes in terms of quality and over time. In type 2 diabetes, the combination therapy significantly improved metabolic control and the lipid profile, and decreased insulin requirements, even in the absence of clinically significant weight loss. In type 1 diabetes, the combined therapy only temporarily improved metabolic control, but significantly decreased body weight, low-density lipoprotein cholesterol levels, and insulin requirements.

Tissue oxygen demand in regulation of the behavior of the cells in the vasculature.

The control of arteriolar diameters in microvasculature has been in the focus of studies on mechanisms matching oxygen demand and supply at the tissue level. Functionally, important vascular elements include EC, VSMC, and RBC. Integration of these different cell types into functional units aimed at matching tissue oxygen supply with tissue oxygen demand is only achieved when all these cells can respond to the signals of tissue oxygen demand. Many vasoactive agents that serve as signals of tissue oxygen demand have their receptors on all these types of cells (VSMC, EC, and RBC) implying that there can be a coordinated regulation of their behavior by the tissue oxygen demand. Such functions of RBC as oxygen carrying by Hb, rheology, and release of vasoactive agents are considered. Several common extra- and intracellular signaling pathways that link tissue oxygen demand with control of VSMC contractility, EC permeability, and RBC functioning are discussed.

Study of skin vasomotion in type 1 diabetic patients and of its possible relationship with clinical and laboratory variables.

Vascular oscillation (vasomotion) occurs in the microcirculation and is thought to be a significant contributor to tissue perfusion. Our aim was to assess skin vasomotion (SV) of type 1 diabetic patients (T1D-pts) and its relationship with clinical or laboratory variables of the studied T1D-pts. Forearm endothelial-, sympathetic- and myogenic-dependent SV were assessed basally and after 3 min of forearm ischemia in 40 T1D-pts and 50 healthy controls, by spectral analysis of laser-Doppler (LD) signal at the frequency ranges of 0.009-0.02 Hz, 0.021-0.06 Hz and 0.061-0.2 Hz, respectively. Post-ischemic per cent increase (PI%-increase) in power spectral density (PSD) of skin endothelial- and sympathetic-dependent VS was significantly reduced in T1D-pts compared to controls (p < 0.0005, p < 0.0001, respectively). Linear regression analysis showed a significant positive relationship between PI%-increase of endothelial-dependent SV and heart rate variation during laying-standing test (R = 0.65, p = 0.00001), and a negative relationship between PI%-increase in PSD of skin LD signal 0.009-1.6 Hz spectrum and glycated haemoglobin serum levels (R = 0.44, p = 0.0036) in T1D-pts. These results are consistent with reduced skin endothelial- and sympathetic-dependent stimulated SV and with relationships between some clinical or laboratory variables and SV parameters in the T1D-pts studied.

Peripheral microvascular dysfunction as an independent predictor of atherosclerotic damage in type 1 diabetes patients: a preliminary study.

It has been recently hypothesized that peripheral microvascular dysfunction may contribute to atherosclerotic damage (AD) in diabetic patients. In order to test this hypothesis, we assessed forearm skin post-occlusive reactive hyperaemia (skin-PORH), an index of peripheral microvascular function, using laser-Doppler flowmetry, in 40 type 1 diabetes patients (T1D-pts), aged 49 ± 11 years, with no known cardiovascular complications, and in 50 age and sex-matched healthy control subjects (CS). T1D-pts also underwent carotid arteries ultrasound scanning (Ca-US) and ankle-brachial index (ABI) measurement. An arbitrary index of AD (AD-index), ranging from "0" (normal ABI, normal Ca-US) to "3" (abnormal ABI, one or more plaques at the Ca-US), was determined in T1D-pts. Linear and multiple regression analyses were performed to identify independent predictors of AD in T1D-pts. T1D-pts had a lower skin-PORH compared with CS (p = 0.015). In T1D-pts AD-index resulted to be negatively related with skin-PORH (R = 0.44; p < 0.005) or deep-breathing test (DBT) (R = 0.53; p < 0.0005), and positively related with systolic arterial pressure (R = 0.31; p < 0.05), microalbuminuria (R = 0.46; p < 0.005), patients' age (R = 0.51; p < 0.001) and diabetes duration (R = 0.39; p < 0.05). At the multiple regression analysis skin-PORH (R = 0.36; p < 0.005), patients' age R = 0.24; p < 0.05) and DBT (R = 0.4 - p < 0.005) resulted to be independent predictors of AD-index in T1D-pts. These preliminary findings support the hypothesis that peripheral microvascular dysfunction may contribute to AD in T1D-pts.

Differences in circadian time structure of diastolic blood pressure between diabetes mellitus and essential hypertension.

BACKGROUND: Abnormal circadian blood pressure patterns have been associated with cardiovascular disease in diabetes mellitus. We have described that the acrophase of diastolic blood pressure (DBP) registered in type 1 diabetes (T1D) patients was significantly earlier than normal and DBP ecphasia was more pronounced in patients with lower heart rate variability during deep breathing. The aim of this study was to compare the circadian rhythm characteristics of BP among different groups: normotensive (NT) control subjects, patients affected by T1D and type 2 diabetes (T2D), and patients with essential hypertension (HT). FINDINGS: We retrospectively evaluated ambulatory blood pressure monitoring records in 30 NT, 20 T1D, 20 T2D, 20 HT whose fasting plasma glucose and HbA1c were contemporaneously measured. The four groups were well-matched regarding age, gender, and BMI.Systolic blood pressure (SBP) and DBP midline-estimating statistic of rhythm were higher in T1D, T2D, and HT groups. DBP ecphasia was present only in the diabetic individuals: the acrophase of DBP occurred four hours earlier than normal in T1D group, whereas two hours earlier in T2D group. In a multiple regression analysis, only HbA1c and SBP acrophase were statistically significant correlates of DBP acrophase. CONCLUSIONS: People with diabetes mellitus, both type 1 and type 2, have their circadian acrophase of DBP occurring 2-4 hours earlier than normotensive and hypertensive subjects. Altered circadian timing of DBP, potential trigger of cardiovascular events, seems to be a distinguishing feature of diabetes mellitus and correlates with the previous 2-3 months of glycaemic control.

Circadian rhythm of blood pressure in diabetes mellitus: evidence, mechanisms and implications.

Circadian misalignment has been implicated in the development of diabetes mellitus and cardiovascular disease. Circadian rhythms of blood pressure (BP) and heart rate (HR) have long been known and the mechanisms controlling them have been actively investigated in physiology and disease. In this respect, the introduction of 24-hour ambulatory blood pressure monitoring (ABPM) has enabled a more accurate assessment of circadian BP patterns in order to solve diagnostic uncertainty or to establish dipper status. However, attention has been mainly focused on measures of extent (midline estimating statistic of rhythm, MESOR, and amplitude) rather than timing (acrophase) of changes within a cycle. The review summarises 1) evidence for altered characteristics of BP rhythm (in particular, phase shifts along the time axis) in animal and human diabetes mellitus, 2) the mechanisms that have been supposed to underlie the observed changes in cardiovascular function before diabetes onset and during progression of the disease, and 3) the adverse consequences that may result from an altered circadian BP rhythm.

Altered proportions of naïve, central memory and terminally differentiated central memory subsets among CD4+ and CD8 + T cells expressing CD26 in patients with type 1 diabetes.

Type 1 diabetes is an autoimmune process predominantly T-cell mediated. CD26 plays a role in T-cell costimulation, migration, memory development, thymic maturation and emigration patterns. In peripheral blood from 55 patients with type 1 diabetes and 20 healthy controls, CD4(+) and CD8(+) T cells expressing CD26 were differentiated into naïve (N, CD45RA(+)CCR7(+)), central memory (CM, CD45RA(-)CCR7(+)), effector memory (EM, CD45RA(-)CCR7(-)), and terminally differentiated effector memory (TEMRA, CD45RA(+)CCR7(-)). In type 1 diabetes, CD4(+) and CD8(+) T cells expressing CD26 showed a distinctive differentiation profile: percentages and absolute numbers of CM and N cells were reduced, whereas those of TEMRA cells were markedly increased. The indices of intermediate- and long-term glycaemic control were associated negatively with the number of CM and N cells while positively with the number of TEMRA cells. The considerable accumulation of TEMRA T cells in our patients suggests life-long stimulation by protracted antigen exposure (viruses, other agents or residual self-antigens?) or a homeostatic defect in the regulation/contraction of immune responses.

Exploring leukocyte mitochondrial membrane potential in type 1 diabetes families.

Proper cellular function requires the maintenance of mitochondrial membrane potential (MMP) sustained by the electron transport chain. Mitochondrial dysfunction is believed to play a role in the development of diabetes and diabetic complications possibly because of the active generation of free radicals. Since MMP can be investigated in clinical settings using fluorescent probes and living whole blood cells, mitochondrial membrane alterations have been observed in some chronic disorders. We have used the mitochondrial indicator 5,5',6,6'-tetra chloro-1,1',3,3'-tetraethylbenzimidazolyl-carbocyanine iodide (JC-1) in conjunction with flow cytometry to measure the MMP in peripheral blood granulocytes from type 1 diabetes (T1D) families. The intracellular ROS levels and the respiratory burst activity were also measured. Leukocyte MMP was elevated in 20 T1D patients and their 20 non-diabetic siblings compared with 25 healthy subjects without family history of T1D. Fasting plasma glucose was the only correlate of MMP. If confirmed by further observations, the functional implications of mitochondrial hyperpolarisation (probably different among different cells) will require extensive investigation.

Thiol signalling network with an eye to diabetes.

Redox regulatory system controls normal cellular functions. Controlled changes in redox couples potential serve as components for signal transduction, similarly to the phosphorylation cascade. Cellular redox biology requires both compartimentalisation and communication of redox systems: the thermodynamic disequilibrium of the major redox switches allows rapid and sensitive responses to perturbations in redox environments. The many oxidation states of sulphur are found in numerous sulphur species with distinct functional groups (thiols, disulphides, polysulphides, sulphenic, sulphinic and sulphonic acids, etc.), which participate in a complicated network of sulphur-based redox events. Human diseases such as diabetes mellitus and its cardiovascular complications have been associated with increased production of reactive oxygen species and perturbations of thiol redox homeostasis. The review surveys literature related to some etiopathogenic aspects and therapeutic perspectives. The dual toxic-protective property of sulphydryl-donor molecules in experimental settings proposes the general problem of designing antioxidants for therapeutic use.

Circadian blood pressure variability in type 1 diabetes subjects and their nondiabetic siblings - influence of erythrocyte electron transfer.

BACKGROUND: Normotensive non-diabetic relatives of type 1 diabetes (T1D) patients have an abnormal blood pressure response to exercise testing that is associated with indices of metabolic syndrome and increased oxidative stress. The primary aim of this study was to investigate the circadian variability of blood pressure and the ambulatory arterial stiffness index (AASI) in healthy siblings of T1D patients vs healthy control subjects who had no first-degree relative with T1D. Secondary aims of the study were to explore the influence of both cardiovascular autonomic function and erythrocyte electron transfer activity as oxidative marker on the ambulatory blood pressure profile. METHODS: Twenty-four hour ambulatory blood pressure monitoring (ABPM) was undertaken in 25 controls, 20 T1D patients and 20 siblings. In addition to laboratory examination (including homeostasis model assessment of insulin sensitivity) and clinical testing of autonomic function, we measured the rate of oxidant-induced erythrocyte electron transfer to extracellular ferricyanide (RBC vfcy). RESULTS: Systolic blood pressure (SBP) midline-estimating statistic of rhythm and pulse pressure were higher in T1D patients and correlated positively with diabetes duration and RBC vfcy; autonomic dysfunction was associated with diastolic BP ecphasia and increased AASI. Siblings had higher BMI, lower insulin sensitivity, larger SBP amplitude, and higher AASI than controls. Daytime SBP was positively, independently associated with BMI and RBC vfcy. Among non-diabetic people, there was a significant correlation between AASI and fasting plasma glucose. CONCLUSIONS: Siblings of T1D patients exhibited a cluster of sub-clinical metabolic abnormalities associated with consensual perturbations in BP variability. Moreover, our findings support, in a clinical setting, the proposed role of transplasma membrane electron transport systems in vascular pathobiology.

Preserved endothelial-dependent and endothelial-independent skin vasodilator responses in relatives of type 1 diabetes patients.

Since increased plasma and cell levels of oxidative products have been found in non diabetic relatives of type 1 diabetic patients, we hypothesized the occurrence of an endothelial dysfunction in these subjects. To verify this hypothesis we investigated the skin blood flow responses to iontophoresis of both the endothelial-dependent vasodilator acetylcholine (ACh) and the endothelial-independent vasodilator sodium nitroprusside (SNP) in 31 non diabetic healthy relatives (DR) (14 siblings, 17 parents) of 17 type 1 diabetic patients. Twenty healthy control subjects (CS) without a family history of diabetes, matched for age (+/-5 years) and gender, were also investigated. DR and CS did not significantly differ either in basal skin blood flux (6.75+/-0.72 PU and 5.78+/-0.37 PU, respectively) or in skin vasodilator response to both ACh (728+/-53% and 711+/-44%, respectively) and SNP iontophoresis (758+/-71% and 731+/-64%, respectively). This finding is consistent with a preserved skin microvascular endothelial function in the studied subjects. However, since previous data suggest that both nitric oxide (NO) and prostacyclin released form the cutaneous vascular endothelium have an interchanging compensatory role in controlling the skin vasodilator response to ACh iontophoresis, our finding does not allow a defect in NO dependent skin vasodilatation to be excluded in the studied relatives of diabetic patients.