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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.


Testa R.,Metabolic and Nutrition Research Center on Diabetes | Olivieri F.,Marche Polytechnic University | Sirolla C.,Statistical Center | Spazzafumo L.,Statistical Center | And 9 more authors.
Diabetic Medicine | Year: 2011

Objective: The key goal of diabetes management is to prevent complications. While the patho-physiological mechanisms responsible for diabetes complications have been extensively studied, at present it is impossible to predict which patient with diabetes could develop complications. In recent years, the role of leukocyte telomere length in the pathogenesis of cardiovascular disease and Type2 diabetes has been investigated. However, studies aiming to investigate the role of telomeres in the development and progression of Type2 diabetes, as well as diabetic complications, are still lacking. As a consequence, this study aimed to verify whether leukocyte telomere length is associated with the presence and the number of diabetic complications in a sample of patients with Type2 diabetes. Methods This is a cross-sectional study. Nine hundred and one subjects were enrolled, including 501 patients with Type2 diabetes, of whom 284 had at least one complication and 217 were without complications, and 400 control subjects. Leukocyte telomere length was measured by quantitative real-time PCR. Results Patients with diabetes complications had significantly shorter leukocyte telomere length than both patients without diabetes complications and healthy control subjects. Moreover, among patients with diabetes complications, leukocyte telomere length became significantly and gradually shorter with the increasing number of diabetes complications. The magnitude of the effect of the decrease of the abundance of telomeric template vs. a single-copy gene length (T/S ratio) on complications is described by the estimated odds ratio OR=5.44 (95%CI 3.52-8.42). Conclusions The results of the study support the hypothesis that telomere attrition may be a marker associated with the presence and the number of diabetic complications. © 2011 The Authors. Diabetic Medicine © 2011 Diabetes UK.


Ceriello A.,Hospital Clinic Of Barcelona | Ceriello A.,Spanish Biomedical Research Center in Diabetes and Associated Metabolic Disorders | Novials A.,Hospital Clinic Of Barcelona | Novials A.,Spanish Biomedical Research Center in Diabetes and Associated Metabolic Disorders | And 11 more authors.
Nutrition, Metabolism and Cardiovascular Diseases | Year: 2014

Background and aims: Hypoglycemia produces thrombosis activation, but little attention has been paid to the effects of hyperglycemia following recovery from hypoglycemia on thrombosis activation. Methods and results: In both twenty-two healthy subjects and twenty-one matched persons with type 1 diabetes, recovery from a 2-h induced hypoglycemia was obtained by reaching normo-glycemia or hyperglycemia for another 2h. After this, normal glycemia was maintained for the following 6h. Hyperglycemia after hypoglycemia was also repeated with the concomitant infusion of vitamin C. In both controls and people with diabetes, the recovery with normo-glycemia was accompanied by a significant improvement of Von Willebrand factor (vWF), prothrombin fragment 1+2 (F1+2), thrombin-antithrombin III-complexes (TAT), P-selectin, plasminogen activator inhibitor-1 (PAI-1), nitrotyrosine and 8-iso-prostaglandin F2α (8-iso-PGF2α) (p<0.01 vs hypoglycemia for all the parameters), all directly affected by hypoglycemia itself (p<0.01 vs baseline for all the parameters). On the contrary, the recovery with hyperglycemia after hypoglycemia worsens all these parameters (p<0.01 vs normoglycemia for all the parameters), an effect persisting even after the additional 6h of normo-glycemia. The effect of hyperglycemia following hypoglycemia was partially counterbalanced when vitamin C was infused (p<0.01 vs hyperglycemia alone for all the parameters), suggesting that hyperglycemia following hypoglycemia may activate thrombosis through the oxidative stress production. Conclusion: This study shows that, in type 1 diabetes as well as in controls, the way in which recovery from hypoglycemia takes place could play an important role in favoring the activation of thrombosis and oxidative stress, widely recognized cardiovascular risk factors. © 2013 Elsevier B.V.


PubMed | IRCCS Gruppo Multimedica, Metabolic and Nutrition Research Center on Diabetes and Hospital Clinic Of Barcelona
Type: Journal Article | Journal: Nutrition, metabolism, and cardiovascular diseases : NMCD | Year: 2014

Hypoglycemia produces thrombosis activation, but little attention has been paid to the effects of hyperglycemia following recovery from hypoglycemia on thrombosis activation.In both twenty-two healthy subjects and twenty-one matched persons with type 1 diabetes, recovery from a 2-h induced hypoglycemia was obtained by reaching normo-glycemia or hyperglycemia for another 2 h. After this, normal glycemia was maintained for the following 6 h. Hyperglycemia after hypoglycemia was also repeated with the concomitant infusion of vitamin C. In both controls and people with diabetes, the recovery with normo-glycemia was accompanied by a significant improvement of Von Willebrand factor (vWF), prothrombin fragment 1 + 2 (F1 + 2), thrombin-antithrombin III-complexes (TAT), P-selectin, plasminogen activator inhibitor-1 (PAI-1), nitrotyrosine and 8-iso-prostaglandin F2 (8-iso-PGF2) (p < 0.01 vs hypoglycemia for all the parameters), all directly affected by hypoglycemia itself (p < 0.01 vs baseline for all the parameters). On the contrary, the recovery with hyperglycemia after hypoglycemia worsens all these parameters (p < 0.01 vs normoglycemia for all the parameters), an effect persisting even after the additional 6 h of normo-glycemia. The effect of hyperglycemia following hypoglycemia was partially counterbalanced when vitamin C was infused (p < 0.01 vs hyperglycemia alone for all the parameters), suggesting that hyperglycemia following hypoglycemia may activate thrombosis through the oxidative stress production.This study shows that, in type 1 diabetes as well as in controls, the way in which recovery from hypoglycemia takes place could play an important role in favoring the activation of thrombosis and oxidative stress, widely recognized cardiovascular risk factors.


Achilli A.,University of Perugia | Olivieri A.,University of Pavia | Pala M.,University of Pavia | Kashani B.H.,University of Pavia | And 21 more authors.
PLoS ONE | Year: 2011

Mitochondrial dysfunction has been implicated in rare and common forms of type 2 diabetes (T2DM). Additionally, rare mitochondrial DNA (mtDNA) mutations have been shown to be causal for T2DM pathogenesis. So far, many studies have investigated the possibility that mtDNA variation might affect the risk of T2DM, however, when found, haplogroup association has been rarely replicated, even in related populations, possibly due to an inadequate level of haplogroup resolution. Effects of mtDNA variation on diabetes complications have also been proposed. However, additional studies evaluating the mitochondrial role on both T2DM and related complications are badly needed. To test the hypothesis of a mitochondrial genome effect on diabetes and its complications, we genotyped the mtDNAs of 466 T2DM patients and 438 controls from a regional population of central Italy (Marche). Based on the most updated mtDNA phylogeny, all 904 samples were classified into 57 different mitochondrial sub-haplogroups, thus reaching an unprecedented level of resolution. We then evaluated whether the susceptibility of developing T2DM or its complications differed among the identified haplogroups, considering also the potential effects of phenotypical and clinical variables. MtDNA backgrounds, even when based on a refined haplogroup classification, do not appear to play a role in developing T2DM despite a possible protective effect for the common European haplogroup H1, which harbors the G3010A transition in the MTRNR2 gene. In contrast, our data indicate that different mitochondrial haplogroups are significantly associated with an increased risk of specific diabetes complications: H (the most frequent European haplogroup) with retinopathy, H3 with neuropathy, U3 with nephropathy, and V with renal failure. © 2011 Achilli et al.


Ceriello A.,Insititut dInvestigacions Biomediques August Pi I Sunyer | Esposito K.,The Second University of Naples | Testa R.,Metabolic and Nutrition Research Center on Diabetes | Bonfigli A.R.,Metabolic and Nutrition Research Center on Diabetes | And 2 more authors.
Diabetes Care | Year: 2011

OBJECTIVE - Glucagon-like peptide 1 (GLP-1) stimulates insulin secretion. However, GLP-1 also improves endothelial function in diabetes. RESEARCH DESIGN AND METHODS - Sixteen type 2 diabetic patients and 12 control subjects received a meal, an oral glucose tolerance test (OGTT), and two hyperglycemic clamps, with or without GLP-1. The clamps were repeated in diabetic patients after 2 months of strict glycemic control. RESULTS - During the meal, glycemia, nitrotyrosine, and plasma 8-iso prostaglandin F2α (8-iso-PGF2a) remained unchanged in the control subjects, whereas they increased in diabetic patients. Flow-mediated vasodilation (FMD) decreased in diabetes, whereas GLP-1 increased in both groups. During the OGTT, an increase in glycemia, nitrotyrosine, and 8-iso-PGF2a and a decrease in FMD were observed at 1 h in the control subjects and at 1 and 2 h in the diabetic patients. In the same way, GLP-1 increased in both groups at the same levels of the meal. During the clamps, in both the control subjects and the diabetic patients, a significant increase in nitrotyrosine and 8-iso-PGF2a and a decrease in FMD were observed, effects that were significantly reduced by GLP-1. After improved glycemic control, hyperglycemia during the clamps was less effective in producing oxidative stress and endothelial dysfunction and the GLP-1 administration was most effective in reducing these effects. CONCLUSIONS - Our data suggest that during the meal GLP-1 can simultaneously exert an incretin effect on insulin secretion and a protective effect on endothelial function, reasonably controlling oxidative stress generation. The ability of GLP-1 in protecting endothelial function seems to depend on the level of glycemia, a phenomenon already described for insulin secretion. © 2011 by the American Diabetes Association.


PubMed | Metabolic and Nutrition Research Center on Diabetes
Type: Journal Article | Journal: Rejuvenation research | Year: 2010

Dysglycemia has been coined to define the prediabetic state. It defines high glucose levels below the diabetes cut-offs. The negative effects of dysglycemia, leading to cardiovascular complications, are amplified during aging. Despite this knowledge, treatment of dysglycemia in old subjects is usually overlooked by clinical practice. This article deals with a new theory regarding an intensive therapeutic approach targeting aged people. This hypothesis arises from the recent theory of metabolic memory, which defines early imprinting due to hyperglycemia in cells of the vasculature and of target organs, favoring the development of vascular complications. In addition, metabolic memory determines a durable effect of hypoglycemic treatment that is much longer than the period of therapy. This new evidence could allow us to hypothesize that a treatment of dysglycemia in aged people could remodel their glucose trajectory during aging toward a more optimal one, leading to successful aging.


Testa R.,Metabolic and Nutrition Research Center on Diabetes | Bonfigli A.R.,Metabolic and Nutrition Research Center on Diabetes | Marra M.,Metabolic and Nutrition Research Center on Diabetes | Testa I.,Metabolic and Nutrition Research Center on Diabetes
Rejuvenation Research | Year: 2010

Dysglycemia has been coined to define the prediabetic state. It defines high glucose levels below the diabetes "cut-offs." The negative effects of dysglycemia, leading to cardiovascular complications, are amplified during aging. Despite this knowledge, treatment of dysglycemia in old subjects is usually overlooked by clinical practice. This article deals with a new theory regarding an intensive therapeutic approach targeting aged people. This hypothesis arises from the recent theory of metabolic memory, which defines early imprinting due to hyperglycemia in cells of the vasculature and of target organs, favoring the development of vascular complications. In addition, metabolic memory determines a durable effect of hypoglycemic treatment that is much longer than the period of therapy. This new evidence could allow us to hypothesize that a treatment of dysglycemia in aged people could remodel their glucose "trajectory" during aging toward a more optimal one, leading to successful aging. © 2010, Mary Ann Liebert, Inc.


PubMed | Metabolic and Nutrition Research Center on Diabetes
Type: Journal Article | Journal: Diabetic medicine : a journal of the British Diabetic Association | Year: 2011

The key goal of diabetes management is to prevent complications. While the patho-physiological mechanisms responsible for diabetes complications have been extensively studied, at present it is impossible to predict which patient with diabetes could develop complications. In recent years, the role of leukocyte telomere length in the pathogenesis of cardiovascular disease and Type 2 diabetes has been investigated. However, studies aiming to investigate the role of telomeres in the development and progression of Type 2 diabetes, as well as diabetic complications, are still lacking. As a consequence, this study aimed to verify whether leukocyte telomere length is associated with the presence and the number of diabetic complications in a sample of patients with Type 2 diabetes.This is a cross-sectional study. Nine hundred and one subjects were enrolled, including 501 patients with Type 2 diabetes, of whom 284 had at least one complication and 217 were without complications, and 400 control subjects. Leukocyte telomere length was measured by quantitative real-time PCR.Patients with diabetes complications had significantly shorter leukocyte telomere length than both patients without diabetes complications and healthy control subjects. Moreover, among patients with diabetes complications, leukocyte telomere length became significantly and gradually shorter with the increasing number of diabetes complications. The magnitude of the effect of the decrease of the abundance of telomeric template vs. a single-copy gene length (T/S ratio) on complications is described by the estimated odds ratio OR=5.44 (95%CI 3.52-8.42).The results of the study support the hypothesis that telomere attrition may be a marker associated with the presence and the number of diabetic complications.


Festa R.,Marche Polytechnic University | Carta M.,San Bortolo Hospital | 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.

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