RESUMO
PURPOSE: According to preclinical evidence, GLP-1 receptor may be an actionable target in neurodegenerative disorders, including Alzheimer's disease (AD). Previous clinical trials of GLP-1 receptor agonists were conducted in patients with early AD, yielding mixed results. The aim was to assess in a proof-of-concept study whether slow-release exenatide, a long-acting GLP-1 agonist, can benefit the cognitive performance of people with mild cognitive impairment (MCI). METHODS: Thirty-two (16 females) patients were randomized to either slow-release exenatide (n = 17; 2 mg s.c. once a week) or no treatment (n = 15) for 32 weeks. The primary endpoint was the change in ADAS-Cog11 cognitive test score at 32 weeks vs baseline. Secondary endpoints herein reported included additional cognitive tests and plasma readouts of GLP-1 receptor engagement. Statistical analysis was conducted by intention to treat. RESULTS: No significant between-group effects of exenatide on ADAS-Cog11 score (p = 0.17) were detected. A gender interaction with treatment was observed (p = 0.04), due to worsening of the ADAS-Cog11 score in women randomized to exenatide (p = 0.018), after correction for age, scholar level, dysglycemia, and ADAS-Cog score baseline value. Fasting plasma glucose (p = 0.02) and body weight (p = 0.03) decreased in patients randomized to exenatide. CONCLUSION: In patients with MCI, a 32-week trial with slow-release exenatide had no beneficial effect on cognitive performance. TRIAL REGISTRATION NUMBER: NCT03881371, registered on 21 July, 2016.
RESUMO
Heart failure (HF) affects approximately 1-2 % of the adult population. Diabetes mellitus (DM) is one of the most frequent comorbidities in HF, portending a worse prognosis. DM is associated with an increased risk of artery disease, and consequently of post-ischemic HF, but it may also alter directly the myocardial structure and function. Insights into the pathophysiological mechanisms of diabetic cardiomyopathy have been provided by both experimental and clinical investigations. In recent years, it has emerged that the fibrotic process is a result of the convergence of multiple neurohormonal alterations in diabetic cardiomyopathy at the basis of disease progression and phenotype determination: HF with reduced or preserved ejection fraction. Therapies for HF and DM should demonstrate an improved prognosis and have a neutral effect on glucose homeostasis and the risk of HF development.
Assuntos
Diabetes Mellitus/epidemiologia , Diabetes Mellitus/fisiopatologia , Insuficiência Cardíaca/epidemiologia , Insuficiência Cardíaca/fisiopatologia , Coração/fisiopatologia , Modelos Cardiovasculares , Diabetes Mellitus/terapia , Medicina Baseada em Evidências , Insuficiência Cardíaca/terapia , Humanos , Prevalência , Fatores de RiscoRESUMO
BACKGROUND AND AIMS: Leukocyte telomere length (LTL) is a novel marker of cardiovascular (CV) risk. The aim of the study was to investigate the major determinants of LTL in a healthy young population at very low CV risk. METHODS AND RESULTS: LTL was determined in 82 healthy subjects (49M/33F; age37 ± 9yrs), normotensive and not taking any medication with different family history of cardiovascular disease (CVD) (24yes/58no). Fasting blood samples were drawn in all subjects for the determination of lipid profile, high sensitive C-reactive protein, uric acid, Plasminogen Activator Inhibitor-1 (PAI-1), LTL and Endothelial Progenitor Cell (EPC) number. LTL was assessed with a specific real-time PCR reaction in leukocyte DNA samples. LTL resulted inversely correlated with family history of CVD (t = 2.70; p = 0.009), age (r = -0.238; p = 0.032), waist circumference (r = -0.256; p = 0.02), triglycerides (r = -0.218; p = 0.049), PAI-1 (r = -0.288; p = 0.009) and directly correlated with HDL-cholesterol (r = 0.316; p = 0.004) and EPC number (r = 0.358; p = 0.002). At a multivariate analysis, family history of CVD (p = 0.013), EPC count (p = 0.003), and HDL-cholesterol (p = 0.017) were independently associated with LTL (r = 0.62). CONCLUSION: LTL is independently associated to CV risk factors also in healthy young adults.
Assuntos
Doenças Cardiovasculares/genética , HDL-Colesterol/sangue , Leucócitos/patologia , Células-Tronco/citologia , Telômero/patologia , Adulto , Biomarcadores/sangue , Pressão Sanguínea , Proteína C-Reativa/análise , Proteína C-Reativa/metabolismo , Estudos Transversais , Células Endoteliais/citologia , Feminino , Humanos , Leucócitos/ultraestrutura , Modelos Lineares , Masculino , Pessoa de Meia-Idade , Inibidor 1 de Ativador de Plasminogênio/sangue , Reação em Cadeia da Polimerase em Tempo Real , Fatores de Risco , Células-Tronco/metabolismo , Telômero/ultraestrutura , Triglicerídeos/sangue , Ácido Úrico/sangueRESUMO
BACKGROUND AND AIMS: The number of Endothelial Progenitor Cells (EPCs) is considered a novel marker of cardiovascular (CV) disease. It is not clear which are the main determinants of EPC number in apparently healthy subjects in the absence of overt clinical CV or metabolic abnormalities. We evaluated the main clinical determinants of EPC levels in a population of healthy subjects with normal glucose tolerance. METHODS AND RESULTS: EPC number was determined in 122 healthy subjects (73M/49F;36.6 ± 8yrs). Blood samples were collected to test biochemical variables. OGTT was performed and insulin resistance/compensatory hyperinsulinemia was defined according to fasting plasma insulin (FPI) levels. EPCs were identified as cells co-expressing CD133/CD34/KDR antigens by flow-cytometry. CD133(+)/KDR(+) count inversely correlated with BMI (rho=-0.18;p < 0.05), waist circumference (-0.2;<0.05), diastolic (-0.23;<0.01) and systolic blood pressure (-0.21;<0.05), uric acid (-0.24;<0.005), PAI-1 (-0.197; <0.05) and FPI (-0.2;<0.05) and directly correlated with HDL cholesterol (0.182;<0.05). CD34(+)/CD133(+)/KDR(+) count inversely correlated with uric acid (-0.28;<0.005) and FPI (-0.2;<0.05). EPC number was lower in males (p < 0.05) and gender was the only independent predictor of EPC count (p < 0.05). By dividing the population in four subgroups based on gender and insulin resistance, CD133(+)/KDR(+) levels were lower in insulin resistant compared to insulin sensitive males (p < 0.05) with no differences in females. CONCLUSION: The male gender is an independent predictor of low EPC levels in healthy subjects. This might contribute to explaining the higher CV risk in males compared to pre-menopausal age-matched females. In this study a reduced EPC number seems to be associated with insulin resistance in male subjects.
Assuntos
Células Endoteliais/citologia , Hiperinsulinismo/sangue , Resistência à Insulina , Células-Tronco/citologia , Antígeno AC133 , Adulto , Antígenos CD/metabolismo , Antígenos CD34/metabolismo , Biomarcadores , Doenças Cardiovasculares/epidemiologia , Doenças Cardiovasculares/etiologia , Contagem de Células , Estudos Transversais , Células Endoteliais/metabolismo , Feminino , Glicoproteínas/metabolismo , Humanos , Hiperinsulinismo/fisiopatologia , Itália/epidemiologia , Masculino , Peptídeos/metabolismo , Fatores Sexuais , Células-Tronco/metabolismo , Receptor 2 de Fatores de Crescimento do Endotélio Vascular/metabolismoRESUMO
Diabetes and chronic heart failure are interrelated conditions with major medical and economic impact that have to be treated as a distinct entity. Several pathological mechanisms have been investigated and proposed to explain the structural and functional changes associated with diabetic cardiomyopathy. These mechanisms are likely to act synergically and may potentiate one the other. This review outlines recent advances in the pathophysiological mechanisms implicated in the development and progression of diabetic cardiomyopathy and in current therapeutic strategies.