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1.  Effects of GLP-1 on Forearm Vasodilator Function and Glucose Disposal During Hyperinsulinemia in the Metabolic Syndrome 
Diabetes Care  2013;36(3):683-689.
OBJECTIVE
Patients with the metabolic syndrome (MetS) have impaired insulin-induced enhancement of vasodilator responses. The incretin hormone glucagon-like peptide 1 (GLP-1), beyond its effects on blood glucose, has beneficial actions on vascular function. This study, therefore, aimed to assess whether GLP-1 affects insulin-stimulated vasodilator reactivity in patients with the MetS.
RESEARCH DESIGN AND METHODS
Forearm blood flow responses to acetylcholine (ACh) and sodium nitroprusside (SNP) were assessed in MetS patients before and after the addition of GLP-1 to an intra-arterial infusion of saline (n = 5) or insulin (n = 5). The possible involvement of oxidative stress in the vascular effects of GLP-1 in this setting was investigated by infusion of vitamin C (n = 5). The receptor specificity of GLP-1 effect during hyperinsulinemia was assessed by infusing its metabolite GLP-1(9-36) (n = 5). The metabolic actions of GLP-1 were also tested by analyzing forearm glucose disposal during hyperinsulinemia (n = 5).
RESULTS
In MetS patients, GLP-1 enhanced endothelium-dependent and -independent responses to ACh and SNP, respectively, during hyperinsulinemia (P < 0.001 for both), but not during saline (P > 0.05 for both). No changes in vasodilator reactivity to ACh and SNP were seen after GLP-1 was added to insulin and vitamin C (P > 0.05 for both) and after GLP-1(9-36) was given during hyperinsulinemia (P > 0.05 for both). Also, GLP-1 did not affect forearm glucose extraction and uptake during hyperinsulinemia (P > 0.05 for both).
CONCLUSIONS
In patients with the MetS, GLP-1 improves insulin-mediated enhancement of endothelium-dependent and -independent vascular reactivity. This effect may be influenced by vascular oxidative stress and is possibly exerted through a receptor-mediated mechanism.
doi:10.2337/dc12-0763
PMCID: PMC3579378  PMID: 23069838
3.  Oxidative Stress in Diabetes: Implications for Vascular and Other Complications 
In recent decades, oxidative stress has become a focus of interest in most biomedical disciplines and many types of clinical research. Increasing evidence shows that oxidative stress is associated with the pathogenesis of diabetes, obesity, cancer, ageing, inflammation, neurodegenerative disorders, hypertension, apoptosis, cardiovascular diseases, and heart failure. Based on these studies, an emerging concept is that oxidative stress is the “final common pathway” through which the risk factors for several diseases exert their deleterious effects. Oxidative stress causes a complex dysregulation of cell metabolism and cell–cell homeostasis; in particular, oxidative stress plays a key role in the pathogenesis of insulin resistance and β-cell dysfunction. These are the two most relevant mechanisms in the pathophysiology of type 2 diabetes and its vascular complications, the leading cause of death in diabetic patients.
doi:10.3390/ijms141121525
PMCID: PMC3856020  PMID: 24177571
oxidative stress; reactive oxidative species; diabetes mellitus; insulin resistance; β-cell dysfunction; vascular complications
4.  Adaptive Immunity, Inflammation, and Cardiovascular Complications in Type 1 and Type 2 Diabetes Mellitus 
Journal of Diabetes Research  2013;2013:184258.
Diabetes mellitus (DM) is a pandemics that affects more than 170 million people worldwide, associated with increased mortality and morbidity due to coronary artery disease (CAD). In type 1 (T1) DM, the main pathogenic mechanism seems to be the destruction of pancreatic β-cells mediated by autoreactive T-cells resulting in chronic insulitis, while in type 2 (T2) DM primary insulin resistance, rather than defective insulin production due to β-cell destruction, seems to be the triggering alteration. In our study, we investigated the role of systemic inflammation and T-cell subsets in T1- and T2DM and the possible mechanisms underlying the increased cardiovascular risk associated with these diseases.
doi:10.1155/2013/184258
PMCID: PMC3676957  PMID: 23762872
7.  Effect of Calcitriol on Bone Turnover and Osteocalcin in Recent-Onset Type 1 Diabetes 
PLoS ONE  2013;8(2):e56488.
Background
Vitamin D supplementation in childhood improves the achievement of peak bone mass. We investigated the effect of supplementation with calcitriol on bone turnover in recent-onset type 1 diabetes (T1D). Moreover, the association between osteocalcin and parameters of β-cell function and metabolic control was examined.
Methodology/Principal Findings
We conducted a post-hoc analysis of a double-blind, placebo-controlled study of calcitriol supplementation to preserve β-cell function. 27 recent-onset T1D subjects, mean age 22 years, were randomized to 0.25 µg calcitriol per day or placebo (1∶1) and followed up for one year. Changes in bone formation (osteoclacin) and resorption (beta-CrossLaps) markers, and differences between placebo and calcitriol-treated group were evaluated. At baseline, osteocalcin levels were significantly lower in female than in male patients (P<0.01) while no other metabolic parameters as HbA1c and C-peptide differed between gender. No significant correlations were found in relation to HbA1c, insulin requirement and C-peptide. At 1 year follow-up, no significant differences were observed between calcitriol and placebo groups for osteocalcin and β-CrossLaps. In the placebo group osteocalcin levels were unrelated with parameters of metabolic control, such as C-peptide, insulin requirement or HbA1c. Changes of C-peptide, insulin requirement and HbA1c were not related to osteocalcin levels.
Conclusions
Supplementation with 0.25 µg calcitriol per day to patients with new-onset T1D does not affect circulating markers of bone turnover. OC levels were unrelated to β-cell function and other metabolic parameters suggesting that OC is ineffective to control pancreatic function in presence of aggressive autoimmune destruction.
doi:10.1371/journal.pone.0056488
PMCID: PMC3577896  PMID: 23437144
8.  Effect of α-Lipoic Acid on Platelet Reactivity in Type 1 Diabetic Patients 
Diabetes Care  2012;35(2):196-197.
OBJECTIVE
Type 1 diabetes is associated with increased platelet reactivity. We investigated whether α-lipoic acid (ALA) has any effect on platelet reactivity in these patients.
RESEARCH DESIGN AND METHODS
We randomly assigned 51 type 1 diabetic patients to ALA (600 mg once daily) or placebo for 5 weeks. Platelet reactivity was evaluated by the PFA-100 method and by measuring CD41 and CD62 platelet expression. C-reactive protein (CRP) and 8-iso-prostaglandin F2α serum levels also were measured.
RESULTS
Baseline variables were similar in the two groups. After treatment, closure time was longer (P = 0.006) and CD62P platelet expression was lower, both before (P = 0.002) and after (P = 0.009) ADP stimulation in the ALA group compared with the placebo group. CRP and 8-iso-prostaglandin F2α levels showed no differences between the two groups.
CONCLUSIONS
Our data show that ALA reduces measures of platelet reactivity ex vivo in type 1 diabetic patients, independently of antioxidant or anti-inflammatory effects.
doi:10.2337/dc11-1255
PMCID: PMC3263886  PMID: 22228743
9.  The Oxidative Modification of Von Willebrand Factor Is Associated with Thrombotic Angiopathies in Diabetes Mellitus 
PLoS ONE  2013;8(1):e55396.
The thrombogenic activity of Von Willebrand factor (VWF) is proportional to its molecular size and inversely related to its proteolysis by ADAMTS-13. Oxidation of VWF severely impairs its proteolysis by the metalloprotease. This study was aimed at assessing in patients with type 1 and type 2 diabetes whether protein carbonyls, marker of oxidative stress, are associated with both the level and oxidation status of VWF as well as with micro- and macroangiopathic complications. Eighty-three diabetic patients (41 type 1 and 42 type 2 diabetic subjects) and their respective eighty-three healthy controls were studied after verifying the availability, through institutional databases, of clinical biochemistry records spanning at least 3 years. VWF and protein carbonyls were measured by immunoassays, whereas VWF multimers were studied by SDS-agarose gel electrophoresis. Type 2 diabetic subjects had higher levels of VWF antigen (VWF:ag), VWF activity (VWF:act) and plasma proteins’ carbonyls compared to both their controls and type 1 diabetic subjects. Moreover, high molecular weight VWF multimers and specific VWF-bound carbonyls were significantly increased in subjects with micro- and macro-angiopathic complications. In both type 1 and type 2 diabetic subjects, ADAMTS-13 activity was in the normal range. In a multivariable analysis, only VWF-bound carbonyls were significantly associated with any form of thrombotic angiopathy in the entire group of T1- and T2 diabetic patients. These data provide first evidence that not only high VWF levels but also its oxidation status and the presence of high molecular weight VWF multimers that are not observed in SDS-agarose gel electrophoresis of normal subjects are associated with thrombotic angiopathies in diabetes mellitus. These findings may help identify diabetic patients particularly at risk for these complications and elucidate a new pathophysiological mechanism of thrombotic angiopathies in this clinical setting.
doi:10.1371/journal.pone.0055396
PMCID: PMC3561310  PMID: 23383177
10.  The Charcot Foot in Diabetes 
Diabetes Care  2011;34(9):2123-2129.
The diabetic Charcot foot syndrome is a serious and potentially limb-threatening lower-extremity complication of diabetes. First described in 1883, this enigmatic condition continues to challenge even the most experienced practitioners. Now considered an inflammatory syndrome, the diabetic Charcot foot is characterized by varying degrees of bone and joint disorganization secondary to underlying neuropathy, trauma, and perturbations of bone metabolism. An international task force of experts was convened by the American Diabetes Association and the American Podiatric Medical Association in January 2011 to summarize available evidence on the pathophysiology, natural history, presentations, and treatment recommendations for this entity.
doi:10.2337/dc11-0844
PMCID: PMC3161273  PMID: 21868781
11.  Primary Pancreatic Lymphoma in a Patient with Maturity Onset Diabetes of the Young Type 3 
Primary pancreatic lymphoma (PPL) is an extremely rare disease which occurs in pancreas, accounts for less than 1% of extra-nodal malignant lymphomas and 0,5% of cases of pancreatic masses. We report the case of PPL in a 15 year-old boy suffering from Maturity Onset Diabetes of the Young type 3 (MODY3) diagnosed at the age of 1 year.
doi:10.4084/MJHID.2012.005
PMCID: PMC3279320  PMID: 22348187
12.  No Protective Effect of Calcitriol on β-Cell Function in Recent-Onset Type 1 Diabetes 
Diabetes Care  2010;33(9):1962-1963.
OBJECTIVE
We investigated whether supplementation of the active form of vitamin D (calcitriol) in recent-onset type 1 diabetes can protect β-cell function evaluated by C-peptide and improve glycemic control assessed by A1C and insulin requirement.
RESEARCH DESIGN AND METHODS
Thirty-four subjects (aged 11–35 years, median 18 years) with recent-onset type 1 diabetes and high basal C-peptide >0.25 nmol/l were randomized in a double-blind trial to 0.25 μg/day calcitriol or placebo and followed-up for 2 years.
RESULTS
At 6, 12, and 24 months follow-up, A1C and insulin requirement in the calcitriol group did not differ from the placebo group. C-peptide dropped significantly (P < 0.001) but similarly in both groups, with no significant differences at each time point.
CONCLUSIONS
At the doses used, calcitriol is ineffective in protecting β-cell function in subjects (including children) with recent-onset type 1 diabetes and high C-peptide at diagnosis.
doi:10.2337/dc10-0814
PMCID: PMC2928344  PMID: 20805274
13.  Association Between Osteoprotegerin G1181C and T245G Polymorphisms and Diabetic Charcot Neuroarthropathy 
Diabetes Care  2009;32(9):1694-1697.
OBJECTIVE
Charcot neuroarthropathy is a disabling complication of diabetes. Although its pathogenesis remains unknown, we suppose that genetics may play a relevant role.
RESEARCH DESIGN AND METHODS
We performed a case-control study with 59 subjects with diabetic Charcot neuroarthropathy (Ch group), 41 with diabetic neuropathy without Charcot neuroarthropathy (ND group), and 103 healthy control subjects (H group) to evaluate the impact of two single nucleotide polymorphisms (SNPs) of the osteoprotegerin gene (G1181C and T245G) on the risk of Charcot neuroarthropathy.
RESULTS
Regarding the SNPs of G1181C, we found a significant linkage between the G allele and Charcot neuroarthropathy (Ch vs. ND, odds ratio [OR] 2.32 [95% CI 1.3–4.1], P = 0.006; Ch vs. H, 2.10 [1.3–3.3], P = 0.002; and ND vs. H, 0.90 [0.7–1.9], P = 0.452); similarly, we found a linkage with the G allele of T245G (Ch vs. ND, 6.25 [2.2–19.7], P < 0.001; Ch vs. H, 3.56 [1.9–6.7], P = 0.001; and ND vs. H, 0.54 [0.6–5.7], P = 0.304), supporting a protective role for the allele C and T, respectively. For this reason we investigated the frequency of the protective double homozygosis CC + TT (7% in Ch) that was significantly lower in Ch compared with H (0.18 [0.06–0.5], P = 0.002) and with ND (0.17 [0.05–0.58], P = 0.006), whereas there was no difference between H and ND (1.05 [0.43–2.0], P = 0.468). In a multivariate logistic backward regression model, only weight and the lack of CC and TT genotypes were independently associated with the presence of Charcot neuroarthropathy.
CONCLUSIONS
This is the first study that shows an association between genetic regulation of bone remodeling and Charcot neuroarthropathy.
doi:10.2337/dc09-0243
PMCID: PMC2732132  PMID: 19502537
14.  Group of Signs: A New Method to Evaluate Glycemic Variability 
Background
Glycemic variability is an important parameter used to resolve potential clinical problems in diabetic patients. It is known that glycemic variability generates oxidative stress and potentially contributes to the development of macro- and microvascular complications in diabetes. By controlling glycemic variability, it is possible to reduce these complications and to set the therapy for all patients with diabetes. The aims of this study were to (1) propose a new standardized, objective, and flexible approach to measure glycemic variability by a continuous glucose monitoring system (CGMS)—the group of signs (GOS) method; (2) compare the correlation between mean amplitude of glucose excursion (MAGE), a well-known index of glycemic variability calculated by the physician and the MAGE defined with the GOS method, in order to validate the GOS; and (3) suggest new indexes of glycemic variability.
Methods
We tested the GOS algorithm on data collected by a CGMS every 5 minutes for 24 hours on 50 patients. Consequently, for 8 patients we calculated and compared the physician's MAGE in the standard way and by the GOS method.
Results
Comparison between the two methods has shown high correlations, from a minimum correlation of 86% to a maximum of 98%, with p values <0.01 (Pearson test).
Conclusions
Preliminary data suggest that the proposed algorithm is a valid, efficient, and reliable method able to calculate the standard MAGE on CGMS data systematically and to create other alternative glycemic variability indexes.
PMCID: PMC2769822  PMID: 19885294
continuous glucose monitoring system; diabetic complications; glycemic variability; indices of variability

Results 1-14 (14)