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Ceriello A.,Insititut dInvestigacions Biomediques August Pi I Sunyer and CIBERDEM | Novials A.,Insititut dInvestigacions Biomediques August Pi I Sunyer and CIBERDEM | Canivell S.,Insititut dInvestigacions Biomediques August Pi I Sunyer and CIBERDEM | La Sala L.,Insititut dInvestigacions Biomediques August Pi I Sunyer and CIBERDEM | And 6 more authors.
Diabetes Care | Year: 2014

OBJECTIVE: To test the hypothesis that the simultaneous administration of GLP-1 and insulin may increase their vasodilatory, antiinflammatory, and antioxidant action in type 2 diabetes. RESEARCH DESIGN AND METHODS: In two groups of persons with type 2 diabetes, two sets of experiments were performed. The first group had two normoglycemic-normoinsulinemic clamps with or without GLP-1 and two normoglycemic-hyperinsulinemic clamps with or without GLP-1. The second group had two hyperglycemic-normoinsulinemic clamps and two hyperglycemic-hyperinsulinemic clamps with or without GLP-1. RESULTS: During the normoglycemic-hyperinsulinemic clamp, flow-mediated dilatation (FMD) increased, while soluble intercellular adhesionmolecule (sICAM-1), plasma 8-iso-prostaglandin F2α (8-iso-PGF2α), nitrotyrosine, and interleukin (IL)-6 decreased compared with normoglycemic-normoinsulinemic clamp. Similar results were obtained with the infusion ofGLP-1 during the normoglycemic-normoinsulinemic clamp. The combination of hyperinsulinemia and GLP-1 in normoglycemia was accompanied by a further FMD increase and sICAM-1, 8-iso-PGF2α, nitrotyrosine, and IL-6 decrease. During the hyperglycemic-normoinsulinemic clamp, FMD significantly decreased, while sICAM-1, 8-iso-PGF2α, nitrotyrosine, and IL-6 significantly increased. When hyperglycemia was accompanied by hyperinsulinemia or by the simultaneous infusion of GLP-1, these phenomena were attenuated. The simultaneous presence of hyperinsulinemia and GLP-1 had an increased beneficial effect. CONCLUSIONS: Our results show that the combination of insulin and GLP-1 is more effective than insulin or GLP-1 alone in improving endothelial dysfunction, infl ammation, and oxidative stress in type 2 diabetes. © 2014 by the American Diabetes Association.

Olivieri F.,Marche Polytechnic University | Antonicelli R.,Coronary Care Unit Ospedale U Sestilli | D'Alessandra Y.,Centro Cardiologico Monzino IRCCS | Santini G.,Marche Polytechnic University | And 9 more authors.
International Journal of Cardiology | Year: 2013

Background: Geriatric patients with acute non-ST elevation myocardial infarction (NSTEMI) can frequently present atypical symptoms and non-diagnostic electrocardiogram. The detection of modest cardiac troponin T (cTnT) elevation is challenging for physicians needing to routinely triage these patients. Unfortunately, non-coronary diseases, such as acute heart failure (CHF), may cause cTnT elevation. Circulating microRNAs (miRs) have emerged as biomarkers of MI. However, their diagnostic potential needs to be determined in elderly NSTEMI patients. Methods: 92 NSTEMI patients (82.6 ± 6.9 years old; complicated by CHF in 74% of cases) and 81 patients with acute CHF without AMI (81.3 ± 6.8 years old) were enrolled at presentation. A third group comprised 99 age-matched healthy control subjects (CTR). Plasma levels of miR-1, -21, -133a, -208a, -423-5p and -499-5p were analyzed. Results: MiR-1, -21 -133a and -423-5p showed a 3- to 10-fold increase and miR-499-5p exhibited > 80-fold increase in acute NSTEMI patient vs. CTR. MiR-499-5p and -21 showed a significantly increased expression in NSTEMI vs. CHF. Interestingly, mir-499-5p was comparable to cTnT in discriminating NSTEMI vs. CTR and CHF patients. Its diagnostic accuracy was higher than conventional and hs-cTnT in differentiating NSTEMI (n = 31) vs. acute CHF (n = 32) patients with modest cTnT elevation at presentation (miR-499-5p AUC = 0.86 vs. cTnT AUC = 0.68 and vs. hs-cTnT AUC = 0.70). Conclusions: Circulating miR-499-5p is a sensitive biomarker of acute NSTEMI in the elderly, exhibiting a diagnostic accuracy superior to that of cTnT in patients with modest elevation at presentation. © 2013 Elsevier Ireland Ltd. All rights reserved.

Festa R.,Marche Polytechnic University | Carta M.,San Bortolo Hospital | Ceriello A.,A+ Network | Testa R.,Metabolic and Nutrition Research Center on Diabetes
Diabetes Technology and Therapeutics | Year: 2012

Background: Gestational diabetes mellitus (GDM) is associated with adverse perinatal outcomes, if not treated. International guidelines recommend screening "all or high-risk women" at the initial prenatal visit, when a fasting plasma glucose (FPG) between 92 and 126 mg/dL is diagnostic for GDM. However, glucose testing may be affected by a great pre-analytical variability (usually overlooked), due to, for example, kind of sample (serum/plasma), temperature of storage, time between blood draw and centrifugation (in-tube glycolysis), and use of a glycolysis inhibitor. So GDM may be easily missed. We aimed to evaluate the potential characteristics of this important issue. Subjects and Methods: FPG was tested by both "routine" and "gold standard" protocols in 60 women at the first trimester of gestation, presenting for GDM screening. "Routine" blood plasma was collected in a tube with sodium fluoride, kept at room temperature, centrifuged, and tested 30-45 min after blood draw. "Gold standard" was a specimen from the same blood sample that was centrifuged within 5 min and tested together with the "routine" specimen. Results: In the "routine" protocol, 10 mg/dL on average was lost for each determination. Thirteen cases of GDM and two of overt diabetes (FPG >126 mg/dL) were missed in this preliminary series. Conclusions: The risk for GDM underdiagnosis in the first half of pregnancy appears to be actual and wide. A closer collaboration between clinicians and pathologists is critical, allowing a stricter adherence to the laboratory guidelines to be ensured. © Copyright 2012, Mary Ann Liebert, Inc.

Testa R.,Metabolic and Nutrition Research Center on Diabetes | Olivieri F.,Marche Polytechnic University | Ceriello A.,Institute dInvestigacions Biomedique August Pi I Sunyer IDIBAPS | La Sala L.,Marche Polytechnic University | La Sala L.,Institute dInvestigacions Biomedique August Pi I Sunyer IDIBAPS
Rivista Italiana della Medicina di Laboratorio | Year: 2011

Since the beginning of the twentieth century the study of processes related to aging has been one of the most fascinating topics in biology. Several theories have been developed to understand the key factors of aging, from free radical theory to gene regulation, from the theory of cellular senescence to inflammaging. The definition of senescence is now universally accepted as a 'multifactorial process that operates at different levels of functional organization'. Studies in healthy centenarians have shown that genetic regulation pathways are involved in successful aging, including genes via the insulin/IGF-1, AP-C gene and the genes that code for cytokines and pro- and antiinflammatory properties. Some of the mechanisms of aging may be related to cumulative damage generated by reactive oxygen species that results in reduced ability of the proteasome to degrade damaged proteins, and to DNA repair defects, genetic abnormalities and environmental factors. The relationship between the age-related changes that produce an aging phenotype seems to have a common origin in a global process that alters cell and organ function. Indeed, this progressive inability to withstand stresses makes the organism vulnerable to disease increasing the risk of death. In this overview we briefly look at the most commonly accepted theories of aging. © Springer 2011.

Marra M.,Metabolic and Nutrition Research Center on Diabetes | Marchegiani F.,Advanced Technology Center for Aging Research | Ceriello A.,Insititut dInvestigacions Biomediques August Pi i Sunyer | Sirolla C.,Statistical Center | And 7 more authors.
Nephrology Dialysis Transplantation | Year: 2013

Background Asymmetric dimethylarginine (ADMA) is an endogenous inhibitor of nitric oxide synthase (NOS). Increased levels of ADMA cause impaired vasodilation, leading to endothelial dysfunction and a higher risk for cardiovascular events. In patients with a chronic kidney disease, increased ADMA levels are reported to play a role in the pathogenesis of accelerated atherosclerosis and are an independent risk marker leading to end-stage renal disease and mortality. Circulating ADMA is metabolized by the action of dimethylarginine dimethylamino hydrolase (DDAH) and DDAH2 isoform is the most prevalent in tissues expressing endothelial NOS. DDAH and NOS are co-expressed in the same kidney regional sites supporting the hypothesis that a strict and specific regulation of intracellular ADMA levels is crucial for NO generation in the kidney. Starting from these findings, the study aims to investigate the role of DDAH2 gene promoter polymorphism at position-1151 A/C in determining the levels of ADMA in type 2 diabetic patients (T2DM) with chronic renal impairment.MethodsThree groups of carefully selected subjects of both sexes were enrolled and compared. The first group (control subjects) comprised 286 non-diabetic subjects (mean age 55.8 ± 11.4 years), the second group (T2DM uncomplicated subjects) was made up of 322 T2DM subjects without complications (mean age 64.9 ± 9.6 years) whereas the third group (T2DM CRF subjects) included 110 T2DM patients with chronic renal impairment. The rs805304 DDAH2-1151 A/C promoter polymorphism was determined by a polymerase chain reaction-restriction fragment length polymorphism approach.ResultsT2DM CRF subjects showed significant increased plasma levels of ADMA with respect to those of T2DM uncomplicated subjects and control subjects (0.51 versus 0.39 versus 0.37 μmol/L, P = 0.002, respectively). Analysis of variance showed an interaction between DDAH2-1151 C carrier and groups on ADMA plasma levels (F = 4.36; P < 0.05). ADMA plasma levels were also dependent on groups (F = 4.96; P < 0.01).ConclusionsOur work demonstrates that rs805304 DDAH2-1151 polymorphism plays a central role in determining ADMA in diabetic renal impairment, where patients with DDAH2-1151 C carriers showed the highest ADMA levels. This unfavourable genetic profile is highlighted by pathological kidney conditions such as diabetic CRF. These findings could open new insights on the pathways involving ADMA/DDAH/NOS in the development and progression of chronic renal impairment and therefore of the other micro-macrovascular diabetic complications. © 2012 The Author.

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