Search

Aim: We examined whether metabolic dysfunction-associated steatotic liver disease (MASLD) with or without significant fibrosis (assessed by validated non-invasive biomarkers) was associated with an increased risk of prevalent chronic kidney disease (CKD) or diabetic retinopathy in people with type 1 diabetes mellitus (T1DM)., Methods: We performed a retrospective multicenter cross-sectional study involving 1,409 adult outpatients with T1DM, in whom hepatic steatosis index (HSI) and fibrosis (FIB)-4 index were calculated for non-invasively detecting hepatic steatosis (defined by HSI > 36), with or without coexisting significant fibrosis (FIB-4 index ≥ 1.3 or < 1.3). CKD was defined as an estimated glomerular filtration rate (eGFR) < 60 mL/min/1.73 m 2 or urine albumin/creatinine ratio ≥ 3.0 mg/mmol. The presence of diabetic retinopathy was also recorded in all participants., Results: Patients with MASLD and significant fibrosis (n = 93) had a remarkably higher prevalence of CKD and diabetic retinopathy than their counterparts with MASLD without fibrosis (n = 578) and those without steatosis (n = 738). After adjustment for sex, diabetes duration, hemoglobin A1c, hypertension, and use of antihypertensive or lipid-lowering medications, patients with SLD and significant fibrosis had a higher risk of prevalent CKD (adjusted-odds ratio 1.76, 95 % confidence interval 1.05-2.96) than those without steatosis. Patients with MASLD without fibrosis had a higher risk of prevalent retinopathy (adjusted-odds ratio 1.49, 95 % CI 1.13-1.46) than those without steatosis., Conclusion: This is the largest cross-sectional study showing that MASLD with and without coexisting significant fibrosis was associated, independently of potential confounders, with an increased risk of prevalent CKD and retinopathy in adults with T1DM., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2023 The Author(s). Published by Elsevier Masson SAS.. All rights reserved.)

Aim: We examined whether different insulin administration modalities, i.e., multiple daily injections (MDI) or continuous subcutaneous insulin infusion (CSII by insulin pumps), are differently associated with the risk of having metabolic dysfunction-associated fatty liver disease (MAFLD), with or without coexisting significant liver fibrosis (assessed by validated non-invasive biomarkers), in adults with type 1 diabetes mellitus (T1DM)., Methods: We conducted a retrospective, multicenter, cross-sectional study involving 1,417 adult individuals with established T1DM treated with MDI or CSII. We calculated hepatic steatosis index (HSI) and fibrosis (FIB)-4 index for non-invasively detecting MAFLD (defined by HSI >36), with or without coexisting significant fibrosis (defined by FIB-4 index ≥ 1.3 or <1.3, respectively)., Results: Compared to the MDI group (n = 1,161), insulin-pump users (n = 256; 18.1%) were more likely to be younger (mean age: 40 vs. 48 years, P < 0.001), had better glycemic control (mean hemoglobin A1c: 7.7%  vs. 7.9%, P = 0.025) and a markedly lower prevalence of MAFLD with coexisting significant fibrosis (2.7%  vs. 8.1%, P = 0.010), but a comparable prevalence of MAFLD without fibrosis. In multinomial logistic regression analysis, CSII therapy was associated with a ∼70%-lower risk of MAFLD with significant fibrosis (unadjusted odds ratio 0.32, 95% confidence interval 0.14-0.70; P = 0.004), but this association was no longer significant after adjustment for age, hemoglobin A1c and other potential confounders., Conclusion: The lower prevalence of MAFLD with coexisting significant fibrosis we observed in adults with T1DM using CSII therapy, compared to those using MDI therapy, is primarily mediated by inter-group differences in age., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2023 Elsevier Masson SAS. All rights reserved.)

Background: We assessed whether hepatic steatosis with or without significant fibrosis (determined by validated non-invasive biomarkers) is associated with an increased 10-year estimated risk for cardiovascular disease (CVD) in people with type 1 diabetes mellitus (T1DM)., Methods: We conducted a retrospective, multicenter, cross-sectional study involving 1,254 adults with established T1DM without pre-existing CVD. We used the hepatic steatosis index (HSI) and fibrosis (FIB)-4 index for non-invasively detecting hepatic steatosis (defined as HSI > 36), with or without coexisting significant fibrosis (defined as FIB-4 index ≥ 1.3 or < 1.3). We calculated the Steno type 1 risk engine and the atherosclerotic CVD (ASCVD) risk score to estimate the 10-year risk of developing a first fatal or nonfatal CVD event., Results: Using the Steno type 1 risk engine, a significantly greater proportion of patients with hepatic steatosis and significant fibrosis (n = 91) had a high 10-year estimated CVD risk compared to those with hepatic steatosis alone (n = 509) or without steatosis (n = 654) (75.8% vs. 23.2% vs. 24.9%, p < 0.001). After adjustment for sex, BMI, diabetes duration, hemoglobin A1c, chronic kidney disease, and lipid-lowering medication use, patients with hepatic steatosis and significant fibrosis had an increased 10-year estimated risk of developing a first fatal or nonfatal CVD event (adjusted-odds ratio 11.4, 95% confidence interval 3.54-36.9) than those without steatosis. We observed almost identical results using the ASCVD risk calculator., Conclusions: The 10-year estimated CVD risk is remarkably greater in T1DM adults with hepatic steatosis and significant fibrosis than in their counterparts with hepatic steatosis alone or without steatosis., (© 2023. BioMed Central Ltd., part of Springer Nature.)

The life history theory assumes that all organisms are under selective pressure to harvest external resources and allocate them to maximise fitness: only organisms making the best use of energy obtain the greatest fitness benefits. The trade-off of energy spans four functions: maintenance, growth, reproduction, and defence against pathogens. The innovative antihyperglycaemic agents glucagon-like peptide 1 (GLP-1) receptor agonists and sodium-glucose cotransporter 2 (SGLT2) inhibitors decrease bodyweight and have the potential to counter low-grade inflammation. These key activities could rewire two components of the life history theory operative in adulthood-ie, maintenance and defence. In this Personal View, we postulate that the benefits of these medications on the cardiovascular system, beyond their glucose-lowering effects, could be mediated by the reduction of the maintenance cost driven by obesity and efforts spent on blunting low-grade inflammation., Competing Interests: Declaration of interests AA received research grants, lecture, and advisory board fees from Mundipharma, Merck Sharp & Dome, AstraZeneca, Novartis, Boehringer Ingelheim, Sanofi, Mediolanum, Novo Nordisk, Eli Lilly, Servier, and Takeda. MLM received lecture fees, advisory fees, and grant support from Mylan, SLA Pharma, Servier Laboratories, Eli Lilly, MSD, and Novo Nordisk. GPF received lecture fees, consultancy fees, grant support, and advisory board fees from Abbott, AstraZeneca, Boehringer Ingelheim, Daiichi Sankyo, Eli Lilly, Novo Nordisk, Sanofi, and Takeda. SDP consulted for Applied Therapeutics, AstraZeneca, Boehringer Ingelheim, Eli Lilly, MSD, Novartis, Novo Nordisk, and Sanofi, and received funding for these consulting services; received grant support from AstraZeneca and Boehringer Ingelheim; and received speaker fees from AstraZeneca, Boehringer Ingelheim, Eli Lilly, MSD, Novartis, Novo Nordisk, and Sanofi. SVdK declares no competing interests., (Copyright © 2022 Elsevier Ltd. All rights reserved.)

Telemedicine is a clinical approach that was seldom used in the day-to-day practice, if not only in certain settings, before the COVID-19 pandemic. As stated by the WHO, telemedicine is: the delivery of health care services, where distance is a critical factor, by all health care professionals using information and communication technologies (ICT) for the exchange of valid information for diagnosis, treatment and prevention of disease and injuries, …. Telemedicine has actually represented the most useful and employed tool to maintain contacts between patients and physicians during the period of physical distance imposed by the pandemic, especially during the lockdown. Diabetes in particular, a chronic disease that often needs frequent confronting between patient and health professionals has taken advantage of the telehealth approach. Nowadays, technological tools are more and more widely used for the management of diabetes. In this review results obtained by telemendicine application in type 1 and type 2 diabetic individuals during COVID-19 are revised, and future perspectives for telemedicine use to manage diabetes are discussed., (© 2022. The Author(s).)

In 2020, the Sars-Cov-2 pandemic is causing a huge and dramatic impact on healthcare systems worldwide. During this emergency, fragile patients suffering from other comorbidities, especially patients susceptible to or affected by cardiovascular disease, are the ones most exposed to the poorer outcomes. Therefore, it is still mandatory to continue to strictly adhere to the rules of cardiovascular prevention. This document aims to provide all doctors with simple and clear recommendations in order to spread useful messages to the widest number of subjects in order to continue the battle against cardiovascular diseases even in times of pandemic.

Patients with type 2 diabetes mellitus die most frequently from cardiovascular disease. Metabolic control is mandatory both for preventing long-term complications and for reducing the negative effects of the exposure of the other risk factors. In this article, we will describe the most commonly used glucose-lowering agents, the pathophysiological mechanisms underlying their cardiovascular protection, the available evidence-based data for this protection, and the contraindications and potential adverse effects., (Copyright © 2018 Wolters Kluwer Health, Inc. All rights reserved.)

Cardiovascular prevention represents a cornerstone of modern strategies to reduce the burden of cardiovascular disease. It is of key importance to prevent cardiovascular diseases and associated events, not only to reduce morbidity and mortality, but also to increase the years of wellness in the aging population and to make the growing socio-economic burden imposed by cardiovascular events more sustainable.The current approach to prevention is based on an integrated use of effective lifestyle measures and, whenever appropriate, of antihypertensive and antidiabetic drugs, lipid-lowering agents and antiplatelet drugs.Given that population characteristics, in terms of ethnicity, demography and lifestyle habits, and healthcare system organizations differ among countries, international guidelines are not always applicable to specific countries and, often, are difficult to translate into daily clinical practice.In order to afford the specific features of Italy, 10 Scientific Societies and Research Institutions, mostly involved in preventive strategies, contributed to the present Italian consensus document, which includes brief, practical recommendations to support the preventive actions within the physician community and the general practice setting.

Background: Microparticles (MPs) are vesicular structures shed from endothelial or circulating blood cells, after activation or apoptosis, and can be considered markers of vascular damage. We aimed to determine the levels of circulating MPs, their content of miRNA-126-3p and 5p, and their relationship with early endothelial activation/damage, in patients with different degree of glucose tolerance., Methods: CD62E + , CD62P + , CD142 + , CD45 + circulating MPs, their apoptotic (AnnexinV + ) fractions, and miRNA-126 expression were determined in 39 prediabetic (PreDM), 68 type 2 diabetic (T2DM), and 53 control (NGT) subjects, along with main anthropometric and biochemical measurements. MPs were analysed by flow cytometry. miRNA-126 was measured by quantitative real-time PCR. Plasma antioxidant capacity was determined by electronic spin resonance; ICAM-1, and VCAM-1 by ELISA., Results: Activated endothelial cell-derived MPs (CD62E + ) were significantly increased in PreDM and T2DM in comparison to NGT (p < 0.0001). AnnexinV + /CD62E + MPs and Annexin V + MPs were significantly increased in T2DM compared to PreDM and NGT (p < 0.001); other MPs were not significantly different among groups. Plasma antioxidant capacity was significantly decreased in PreDM and T2DM compared to NGT (p = 0.001); VCAM-1 significantly increased in PreDM and T2DM in comparison to NGT (p = 0.001). miR-126-3p expression, but not miR-126-5p, in MPs, decreased significantly and progressively from NGT, to PreDM, and T2DM (p < 0.001). In PreDM and T2DM, CD62E + MPs level was significantly and negatively associated with plasma glucose (p = 0.004)., Conclusion: We show for the first time that circulating CD62E + MPs level and miR-126-3p content in MPs are abnormal in subjects with pre-diabetes; the content of miR-126-3p correlates with markers of endothelial inflammation, such as VCAM-1, plasma antioxidant capacity, and microparticles, well-accepted markers of endothelial dysfunction.

Diabetes is an established risk factor for erectile dysfunction (ED). The pathophysiology of ED in diabetic men is multifactorial, but it mainly involves a vascular disorder related to a reduction of endothelial function. Recently, several studies have correlated ED risk factors with vitamin D deficiency. In this study, we evaluate the relationship between 25-hydroxyvitamin D [25(OH)D] levels, erectile dysfunction, and vascular disease, in type 2 diabetes mellitus men (T2DM). In this observational study, 92 T2DM males (58.83 ± 9.73 years) underwent medical history collection, International Index of Erectile Function (IIEF-5) questionnaire, that allows the identification and grading of DE, physical examination, biochemical/hormonal blood tests, and penile echo-color Doppler ultrasonography. T2DM patients with lower 25(OH)D levels (<25 nmol/l) showed higher penile IMT (p < 0.05), waist circonference (p < 0.05), glucose concentrations (p < 0.05), and lower IIEF-5 score (p < 0.005), testosterone concentrations (p < 0.05), and cavernous peak systolic velocity (PSV) (p < 0.05), compared to patients with 25(OH)D >50 nmol/l. 25(OH)D levels were directly correlated with IIEF-5 (R = 0.39; p = 0.0001), testosterone (R = 0.24; p = 0.02), and PSV (R = 0.24; p = 0.04) and inversely with waist (R = -0.33; p = 0.002), HbA1c (R = -0.22; p = 0.03), triglyceride (R = -0.21; p = 0.06), and penile IMT (R = -0.30; p = 0.009). At multivariate analysis, 25(OH)D deficiency remained an independent predictor of DE. We demonstrate a significant association between 25(OH)D deficiency and erectile dysfunction in T2DM men. This association may be due to the influence of 25(OH)D deficiency on cardiovascular risk factor (glycaemia, HDL cholesterol, and triglycerides), testosterone plasma levels and endothelial dysfunction.

Ischemia-reperfusion (IR) leads to severe organ injury and dysfunction. Sirtuins (SIRTs) are a family of histone deacetylases (HDACs) that require nicotinamide adenine dinucleotide (NAD(+)) for the deacetylation reaction. SIRTs play a major role in counteracting cellular stress and apoptosis. This study aimed to investigate the mechanisms of heart protection against apoptosis by SIRTs and the molecular pathways involved in SIRTs regulation and function in a rat model of IR injury. Hearts of male Wistar-Kyoto rats were subjected to 30-min ischemia followed by reperfusion up to 6h. IR increased cardiomyocyte apoptosis; the cleavage of caspase 3, induced a transient upregulation of SIRT1 and downregulation of SIRT6 expression, but decreased SIRT1 activity and reduced NAD(+) content. IR also increased forkhead box protein O1 (FoxO1) expression and FoxO1 binding to SIRT1 promoter region. Resveratrol restored SIRT1 activity and NAD(+) level by an AMPK-dependent mechanism, reduced cardiomyocyte apoptosis, and attenuated caspase 3 cleavage via heat shock factor-1 deacetylation and heat shock protein (HSP) expression upregulation. Our data show new potential molecular mechanisms of up and downstream regulation of SIRT1 in IR. The interplay among FoxO1, SIRT1, NAD(+), AMPK, HSP, and SIRT6 depicts a complex molecular network that protects the heart from apoptosis during IR and may be susceptible to therapeutic interventions., (Copyright © 2015 Elsevier Inc. All rights reserved.)

Background and Aims: Prediabetes increases cardiovascular risk and is associated with excess mortality. In preclinical models, metformin has been shown to exert anti-ageing effects. In this study, we sought to assess whether metformin modulates putative effector longevity programs in prediabetic subjects., Methods and Results: In a randomized, single-blind, placebo-controlled trial, 38 prediabetic subjects received metformin (1500 mg/day) or placebo for 2 months. At baseline and after treatment, we collected anthropometric and metabolic parameters. Gene and protein levels of SIRT1, mTOR, p53, p66Shc, SIRT1 activity, AMPK activation, telomere length, and SIRT1 promoter chromatin accessibility were determined in peripheral blood mononuclear cells (PBMCs). Plasma N-glycans, non-invasive surrogate markers of ageing, were also analysed. Compared to baseline, metformin significantly improved metabolic parameters and insulin sensitivity, increased SIRT1 gene/protein expression and SIRT1 promoter chromatin accessibility, elevated mTOR gene expression with concomitant reduction in p70S6K phosphorylation in subjects' PBMCs, and modified the plasma N-glycan profile. Compared to placebo, metformin increased SIRT1 protein expression and reduced p70S6K phosphorylation (a proxy of mTOR activity). Plasma N-glycans were also favourably modified by metformin compared to placebo., Conclusion: In individuals with prediabetes, metformin ameliorated effector pathways that have been shown to regulate longevity in animal models. ClinicalTrials. gov identifier: NCT01765946 - January 2013., (Copyright © 2015 Elsevier B.V. All rights reserved.)

The prevalence of type 2 diabetes mellitus (T2DM) among elderly people is increasing. Often associated with disabilities/comorbidities, T2DM lowers the chances of successful aging and is independently associated with frailty and an increased risk of hypoglycaemia, which can be further exacerbated by antihyperglycaemic treatment. From this perspective, the clinical management of T2DM in the elderly is challenging and requires individualization of optimum glycaemic targets depending on comorbidities, cognitive functioning and ability to recognize and self-manage the disease. The lack of solid evidence-based medicine supporting treatment guidelines for older people with diabetes further complicates the matter. Several classes of medicine for the treatment of T2DM are currently available and different drug combinations are often required to achieve individualized glycaemic goals. Many of these drugs, however, carry disadvantages such as the propensity to cause weight gain or hypoglycaemia. Dipeptidyl peptidase-4 (DPP-4) inhibitors, a recent addition to the pharmacological armamentarium, have become widely accepted in clinical practice because of their efficacy, low risk of hypoglycaemia, neutral effect on body weight, and apparently greater safety in patients with kidney failure. Although more information is needed to reach definitive conclusions, growing evidence suggests that DPP-4 inhibitors may become a valuable component in the pharmacological management of elderly people with T2DM. The present review aims to delineate the potential advantages of this pharmacological approach in the treatment of elderly people with T2DM., (© 2014 John Wiley & Sons Ltd.)

Context: Acromegaly increases cardiovascular risk, possibly due to the high prevalence of classical risk factors. However, in vitro studies show a protective role of GH/IGF-1 on the endothelium., Objective: The objective of the study was to investigate circulating endothelial progenitor cells (EPCs), a marker of vascular regeneration, in acromegalic patients and how they are affected by acromegaly treatment., Design: This was a cross-sectional case-control and observational study., Setting: The study was conducted at a tertiary ambulatory referral endocrinology center., Patients: Forty-three acromegalic patients (26 active; 17 inactive) and 43 control subjects matched by age, gender, and degree of glucose tolerance participated in the study., Intervention: Circulating EPCs were quantified by flow cytometry based on the expression of CD34, CD133, and kinase insert domain-containing receptor (KDR). Nine patients with active acromegaly were reevaluated after 24 weeks of treatment with somatostatin analogs (SSAs)., Main Outcome Measure: Differences in EPC levels between patients and controls were measured., Results: Acromegalic patients showed a significant reduction of the total CD34(+)KDR(+) EPC population compared with controls, which was more evident in patients without diabetes or hypertension. More definite CD34(+)CD133(+)KDR(+) EPCs were reduced in patients with active compared with those with inactive acromegaly and compared with controls. The number of CD34(+)CD133(+)KDR(+) EPCs correlated with IGF-1 levels (r = -0.45; P < .001), fasting plasma glucose (r = -0.40; P = .004), and the homeostasis model assessment index of insulin resistance (r = -0.32; P = .026). CD34(+)CD133(+)KDR(+) EPCs increased 2-fold after SSA treatment., Conclusions: Acromegalic patients have a reduced endothelial regenerative capacity, possibly due to activation of the GH/IGF-1, rather than concomitant risk factors. Treatment with SSAs can restore immature EPCs to normal levels.

Chronic inflammation and hyperglycaemia, typical features of metabolic diseases, trigger endothelial damage and release of E-selectin, a marker of endothelial activation. In the present study, we investigated molecular pathways involved in the regulation of endothelial cell activation induced by tumour necrosis factor-α (TNF-α) and high glucose. In cultured human umbilical vein endothelial cells (HUVECs), we studied the role of HuR, an ELAV (embryonic lethal, abnormal vision, Drosophila) family RNA-binding protein, and Sirtuin 1 (SIRT1) on E-selectin release and cell adhesion at different glucose concentrations. HuR expression and binding to SIRT1 were also analysed ex vivo in peripheral blood mononuclear cells (PBMCs) of subjects with and without the metabolic syndrome (MS), by immunoprecipitation (IP) of the ribonucleoprotein (RNP) complex. We found that SIRT1 overexpression prevented TNF-α- and high-glucose-dependent nuclear factor-κB (NF-κB)-p65 acetylation, E-selectin promoter activity, E-selectin release and adhesion of THP-1 cells to HUVECs. The same was mimicked by HuR overexpression, which binds and stabilizes SIRT1 mRNA. Importantly, in PBMCs of individuals with MS compared with those without, SIRT1 expression was lower, and the ability of HuR to bind SIRT1 mRNA was significantly reduced, while plasma E-selectin was increased. We conclude that post-transcriptional stabilization of SIRT1 by HuR represses inflammation- and hyperglycaemia-induced E-selectin release and endothelial cell activation. Therefore, increasing SIRT1 expression represents a strategy to counter the accelerated vascular disease in metabolic disorders.

Aim/hypothesis: Monocytes/macrophages play important roles in adipose and vascular tissues and can be polarised as inflammatory M1 or anti-inflammatory M2. We sought to analyse monocyte polarisation status in type 2 diabetes, which is characterised by chronic inflammation., Methods: We enrolled 60 individuals without diabetes and 53 patients with type 2 diabetes. We quantified standard monocyte subsets defined by cluster of differentiation (CD)14 and CD16. In addition, based on the phenotype of polarised macrophages in vitro, we characterised and quantified more definite M1 (CD68(+)CCR2(+)) and M2 (CX3CR1(+)CD206(+)/CD163(+)) monocytes. We also analysed bone marrow (BM) samples and the effects of granulocyte-colony stimulating factor (G-CSF) stimulation in diabetic and control individuals., Results: We found no alterations in standard monocyte subsets (classical, intermediate and non-classical) when comparing groups. For validation of M1 and M2 phenotypes, we observed that M2 were enriched in non-classical monocytes and had lower TNF-α content, higher LDL scavenging and lower transendothelial migratory capacity than M1. Diabetic patients displayed an imbalanced M1/M2 ratio compared with the control group, attributable to a reduction in M2. The M1/M2 ratio was directly correlated with waist circumference and HbA1c and, among diabetic patients, M2 reduction and M1/M2 increase were associated with microangiopathy. A decrease in M2 was also found in the BM from diabetic patients, with a relative M2 excess compared with the bloodstream. BM stimulation with G-CSF mobilised M2 macrophages in diabetic but not in healthy individuals., Conclusions/interpretation: We show that type 2 diabetes markedly reduces anti-inflammatory M2 monocytes through a dysregulation in bone-marrow function. This defect may have a negative impact on microangiopathy.

The metabolic syndrome (MS) is characterized by chronic inflammation. We aimed to determine the association of white blood cell (WBC) count with prevalence and development of the MS and its components in the general population. A cohort of 1,329 subjects from the local working population aged 41.3 ± 7.5 years and recruited since 2000-2008 was followed up for 4.0 ± 1.2 years. WBC count and MS components were determined at baseline and follow-up. To determine whether WBC predicted incident MS, we used a logistic regression analysis adjusted for demographics, baseline variables that define MS components, smoke, medications, and follow-up duration. Cross-sectionally in the whole population, WBC count increased in parallel with the number of MS components in the same individual, and the presence of each component was associated with higher WBC count. Baseline WBC count was significantly higher in subjects with prevalent MS. Among subjects without MS at baseline, those who developed MS had significantly higher WBC than those who did not develop MS at follow-up. Development of each MS component was associated with increased WBC count. WBC count remained significantly associated with MS development after correction for several potential confounders (OR for 1 SD increase in WBC 1.26; 95 % CI 1.01-1.58). In conclusion, elevated WBC is intimately linked to the prevalence and future development of the MS in a young population of working subjects.

Aim: Dipeptidyl peptidase (DPP)-4 in responsible for incretin degradation and some observations suggest that DPP-4 activity is increased in type 2 diabetes (T2D). We aimed to assess the effect of T2D and glucose control on DPP-4 activity., Methods: In the first set (SET1) of patients, we compared plasma DPP-4 activity between 30 T2D and 20 age- and sex-matched non-diabetic subjects. In the second set (SET2), we measured serum DPP-4 activity in 42 T2D patients before and after a trial of glucose control achieved by add-on basal insulin therapy (NCT00699686). Serum/plasma DPP-4 activity was determined using chromogenic and fluorigenic substrates, as well as several positive and negative controls., Results: In SET1, plasma DPP-4 activity was significantly higher in T2D vs. controls (32.2 ± 1.2 U/l vs. 21.2 ± 1.1 U/l, p < 10(-6)). From a meta-analysis of the literature, we found that T2D is associated with a 33% increase in DPP-4 activity compared to controls. In SET2, serum DPP-4 activity was not lowered by intensified glucose control, despite an average haemoglobin A1c (HbA1c) reduction of 1.5%. In both sets of diabetic patients, the use of metformin was associated with a significantly lower DPP-4 activity, independently of age, sex, body mass index and HbA1c., Conclusion: DPP-4 activity is increased in T2D, but is not lowered by glucose control, suggesting that hyperglycaemia is not a direct determinant of DPP-4 activity. However, metformin may indirectly reduce DPP-4 activity., (© 2011 Blackwell Publishing Ltd.)

Diabetes mellitus (DM) alters circulating progenitor cells relevant for the pathophysiology of coronary artery disease (CAD). While endothelial progenitor cells (EPCs) are reduced, there is no data on procalcific polarization of circulating progenitors, which may contribute to vascular calcification in these patients. In a cohort of 107 subjects with and without DM and CAD, we analyzed the pro-calcific versus endothelial differentiation status of circulating CD34+ progenitor cells. Endothelial commitment was determined by expression of VEGFR-2 (KDR) and pro-calcific polarization by expression of osteocalcin (OC) and bone alkaline phosphatase (BAP). We found that DM patients had significantly higher expression of OC and BAP on circulating CD34+ cells than control subjects, especially in the presence of CAD. In patients with DM and CAD, the ratio of OC/KDR, BAP/KDR, and OC+BAP/KDR was about 3-fold increased than in other groups. EPCs cultured from DM patients with CAD occasionally formed structures highly suggestive of calcified nodules, and the expression of osteogenic markers by EPCs from control subjects was significantly increased in response to the toll-like receptor agonist LPS. In conclusion, circulating progenitor cells of diabetic patients show a phenotypic drift toward a pro-calcific phenotype that may be driven by inflammatory signals.

Aims: The hyperglycemic hyperosmolar syndrome (HHS) is a life-threatening diabetic complication. We aimed to portrait the short and long term outcome after a HHS episode and to describe features associated with increased early mortality., Methods: We collected data from consecutive HHS cases, defined based on rigorous glucose and osmolality criteria. We retrieved anthropometric measures, history of diabetes, other cardiovascular risk factors and chronic co-morbidity. Clinical and biochemical parameters were recorded at admission, after 24h and at discharge. We assessed incidence of complications, as well as short (≤ 30 days) and long term mortality., Results: Patients were about 80-year old. Fifty-one cases were included, characterized by severe hyperglycemia (55.5 mosm/L) and hyperosmolality (385 mosm/L). Thirty-three percent developed at least one complication. Short term mortality was 16%; lower Glasgow Coma Scale, higher plasma glucose and mild acidosis were predictive of short term mortality. The long term mortality (median follow-up 1.27 years) was not significantly different from historical mortality data after hypoglycemic coma., Conclusion: In this study, early mortality of HHS was 16% and some clinical features at presentation were predictive of an adverse short term outcome. Long term survival after a HHS episode did not appear to be severely impaired., (Copyright © 2011 Elsevier Ireland Ltd. All rights reserved.)

We hypothesize that type 2 diabetic patients with different phenotypes may show different response to incretin-based therapies. Therefore, we tested whether the presence of metabolic syndrome (MS) influences glycemic response to these drugs. We prospectively followed 211 patients, treated with the GLP-1 analog exenatide (n = 102) or a DPP-4 inhibitor (n = 109) for at least 4 months. Treatment was decided on clinical grounds. We collected baseline data (age, sex, BMI, waist, systolic and diastolic blood pressure, lipid profile, data on diabetic complications and concomitant treatment) and HbA1c at subsequent visits. Patients were divided into groups according to the presence/absence of MS. Compared to patients on exenatide, patients on DPP-4 inhibitors were older and had lower BMI, waist, diastolic blood pressure, fasting plasma glucose, and HbA1c. At means of baseline values, HbA1c reduction was similar in patients treated with exenatide or DPP-4 inhibitors. Patients on exenatide showed significantly higher HbA1c reduction if they had MS (-1.55 ± 0.22%; n = 88) than if they had not (-0.34 ± 0.18%; P = 0.002). Conversely, patients on DPP-4 inhibitors showed significantly lower HbA1c reduction if they had MS (-0.60 ± 0.12%; n = 73) than if they had not (-1.50 ± 0.24%; P < 0.001). Type of MS definition (ATP-III, IDF or WHO) poorly influenced these trends. The interaction between type of therapy (exenatide vs. DPP-4 inhibitors) and MS remained significant after adjusting for age, baseline HbA1c, BMI, and concomitant medications. In conclusion, the presence of MS appears to modify the response to incretin-based therapies. Given the non-randomized nature of this study, these data need to be replicated.

The metabolic syndrome (MS), a predisposing condition for cardiovascular disease, presents disturbances in hemodynamics; impedance cardiography (ICG) can assess these alterations. In subjects with MS, the morphology of the pulses present in the ICG time series is more irregular/complex than in normal subjects. Therefore, the aim of the present study was to quantitatively assess the complexity of ICG times series in 53 patients, with or without MS, through a nonlinear analysis algorithm, the approximate entropy, a method employed in recent years for the study of several biological signals, which provides a scalar index, ApEn. We correlated ApEn computed from ICG times series data during fasting and postprandial phase with the presence of alterations in the parameters defining MS [Adult Treatment Panel (ATP) III (Grundy SM, Brewer HB Jr, Cleeman JI, Smith SC Jr, Lenfant C; National Heart, Lung, and Blood Institute; American Heart Association. Circulation 109: 433-438, 2004) and the International Diabetes Federation (IDF) definition]. Results show that ApEn was significantly higher in subjects with MS compared with those without (1.81 ± 0.09 vs. 1.65 ± 0.13; means ± SD; P = 0.0013, with ATP III definition; 1.82 ± 0.09 vs. 1.67 ± 0.12; P = 0.00006, with the IDF definition). We also demonstrated that ApEn increase parallels the number of components of MS. ApEn was then correlated to each MS component: mean ApEn values of subjects belonging to the first and fourth quartiles of the distribution of MS parameters were statistically different for all parameters but HDL cholesterol. No difference was observed between ApEn values evaluated in fasting and postprandial states. In conclusion, we identified that MS is characterized by an increased complexity of ICG signals: this may have a prognostic relevance in subjects with this condition.

Aims: In diabetes, endothelial damage promotes macroangiopathy and endothelial regeneration is impaired, owing to reduced endothelial progenitor cells (EPCs). Given that insulin influences endothelial biology, we compared the effects of add-on basal insulin analogues on endothelial damage and regeneration in type 2 diabetes (T2D)., Methods: This was a 6-month randomized crossover trial comparing add-on insulin detemir versus glargine in poorly controlled T2D with macroangiopathy. At baseline, crossover (3 months) and study end (6 months), we measured HbA1c, EPCs, circulating endothelial cells (CECs), VCAM-1, ICAM-1 and E-selectin. Body weight and hypoglycaemic episodes were also recorded., Results: Forty-two patients completed the study, randomly assigned to the glargine-detemir (n = 21) or the detemir-glargine (n = 21) schedule. At crossover, EPC levels did not change compared with baseline, but significantly increased at study end. CECs decreased over time and were significantly reduced at study end. ICAM-1, VCAM-1 and E-selectin were significantly reduced at crossover and further decreased at study end. No differences were seen in these effects between detemir and glargine. HbA1c showed a carryover effect and its reduction was similar with detemir and glargine in the first arm. Incidence of hypoglycaemia and weight gain was lower with detemir than with glargine in both arms., Conclusion: Optimized glycaemic control by add-on basal insulin improved indexes of endothelial damage and regeneration. Compared to glargine, detemir achieved similar endothelial protection with lower weight gain and less hypoglycaemia. These results might have implications for therapy of aging T2D patients with cardiovascular disease., (© 2011 Blackwell Publishing Ltd.)

Background and Aims: Common mechanisms for the development of micro- and macroangiopathic diabetic complications have been suggested. We aimed to cross-sectionally investigate strength and characteristics of the association between carotid atherosclerosis and microangiopathy in type 2 diabetic patients., Methods and Results: Common carotid artery intima-media thickness (cIMT), carotid plaque (CP) type and degree of stenosis were evaluated by ultrasound, along with the determination of anthropometric parameters, HbA1c, lipid profile, assessment of diabetic retinopathy and nephropathy, in 662 consecutive patients with type 2 diabetes mellitus (T2DM). Patients were divided according to high/low cIMT, presence/absence of CP and of retinopathy and nephropathy. Patients with CP were older, more prevalently males, past smokers, had longer diabetes duration, significantly lower HDL cholesterol and more prevalent ischemic heart disease (all p<0.05) as compared to those with cIMT < 1 mm. Microangiopathies were more prevalent in patients with CP than in those without. At multivariate logistic regression, factors independently associated with the presence of CP were age, past smoke, HDL cholesterol, retinopathy and retinopathy plus nephropathy. A significant independent correlation of CP stenosis with stage of retinopathy and nephropathy was found. Finally, echolucent CPs were associated with a lower prevalence of proliferative retinopathy than CP containing calcium deposits., Conclusion: In T2DM, retinopathy, alone or in combination with nephropathy, is independently associated to CP, and severity of microangiopathy correlates with severity of carotid atherosclerosis. These observations, together with the different prevalence of proliferative retinopathy according to CP types, point to possible common pathogenic mechanisms in micro- and macrovascular complications., (Copyright © 2009 Elsevier B.V. All rights reserved.)

Background and Aims: A blood glucose (BG) fall after an oral glucose load has never been described previously at a population level. This study was aimed at looking for a plasma glucose trend after an oral glucose load for possible blood glucose fall if any, and for its impact on coronary mortality at a population level., Methods and Results: In subjects from an unselected general population, BG and insulin were detected before and 1 and 2h after a 75-g oral glucose load for insulin sensitivity and β-cell function determination. Blood pressure, blood examinations and left ventricular mass were measured, and mortality was monitored for 18.8±7.7 years. According to discriminant analysis, the population was stratified into cluster 0 (1-h BG < fasting BG; n=497) and cluster 1 (1-h BG ≥ fasting BG; n=1733). To avoid any interference of age and sex, statistical analysis was limited to two age-gender-matched cohorts of 490 subjects from each cluster (n=940). Subjects in cluster 0 showed significantly higher insulin sensitivity and β-cell function, lower visceral adiposity and lower blood pressure values. Adjusted coronary mortality was 8 times lower in cluster 0 than 1 (p<0.001). The relative risk of belonging to cluster 1 was 5.40 (95% CI 2.22-13.1)., Conclusion: It seems that two clusters exist in the general population with respect to their response to an oral glucose load, independent of age and gender. Subjects who respond with a BG decrease could represent a privileged sub-population, where insulin sensitivity and β-cell function are better, some risk factors are less prevalent, and coronary mortality is lower., (Copyright © 2009 Elsevier B.V. All rights reserved.)

Objective: Sirtuins (SIRTs) are NAD(+)-dependent deacetylases that regulate metabolism and life span. We used peripheral blood mononuclear cells (PBMCs) to determine ex vivo whether insulin resistance/metabolic syndrome influences SIRTs. We also assessed the potential mechanisms linking metabolic alterations to SIRTs in human monocytes (THP-1) in vitro., Research Design and Methods: SIRT1-SIRT7 gene and protein expression was determined in PBMCs of 54 subjects (41 with normal glucose tolerance and 13 with metabolic syndrome). Insulin sensitivity was assessed by the minimal model analysis. Subclinical atherosclerosis was assessed by carotid intima-media thickness (IMT). In THP-1 cells exposed to high glucose or fatty acids in vitro, we explored SIRT1 expression, p53 acetylation, Jun NH(2)-terminal kinase (JNK) activation, NAD(+) levels, and nicotinamide phosphoribosyltransferase (NAMPT) expression. The effects of SIRT1 induction by resveratrol and of SIRT1 gene silencing were also assessed., Results: In vivo, insulin resistance and metabolic syndrome were associated with low PBMC SIRT1 gene and protein expression. SIRT1 gene expression was negatively correlated with carotid IMT. In THP-1 cells, high glucose and palmitate reduced SIRT1 and NAMPT expression and reduced the levels of intracellular NAD(+) through oxidative stress. No effect was observed in cells exposed to linoleate or insulin. High glucose and palmitate increased p53 acetylation and JNK phosphorylation; these effects were abolished in siRNA SIRT1-treated cells. Glucose- and palmitate-mediated effects on NAMPT and SIRT1 were prevented by resveratrol in vitro., Conclusions: Insulin resistance and subclinical atherosclerosis are associated with SIRT1 downregulation in monocytes. Glucotoxicity and lypotoxicity play a relevant role in quenching SIRT1 expression.

Purpose: This study aimed to assess vascular endothelial function in patients with ocular hypertension (OHT) or primary open-angle glaucoma (POAG) by measuring: (a) endothelium-dependent flow-mediated vasodilation (FMD) of the brachial artery, and (b) circulating endothelial progenitor cells, which are believed to support the integrity of the vascular endothelium., Methods: We enrolled 25 patients with OHT, 23 with POAG and 26 control subjects, all of whom were aged < 65 years and had no medical history of cardiovascular disease or cardiovascular risk factors. All subjects underwent a complete ophthalmological examination, biochemistry study, assessment of cardiovascular parameters, brachial artery ultrasound assessment of endothelium-dependent FMD, generic circulating progenitor cell (CPC) and circulating endothelial progenitor cell (EPC) count with the use of flow cytometry., Results: Flow-mediated vasodilation values differed significantly in OHT (4.5 +/- 1.1%; p = 0.021) and POAG (4.0 +/- 0.9%; p = 0.003) patients compared with controls (7.7 +/- 0.8%). The CD34(+) KDR(+) EPC count was markedly lower in OHT (28.0 +/- 5.0; p < 0.001) and POAG (24.3 +/- 3.4; p < 0.001) patients compared with controls (73.1 +/- 8.1). Neither FMD not EPCs differed significantly between OHT and POAG patients. No significant differences in CPC count or cardiovascular parameters were found among OHT or POAG patients and controls. The levels of CD34(+) KDR(+) EPCs were directly correlated (p = 0.043) with FMD, and inversely correlated (p = 0.032) with baseline intraocular pressure in OHT and POAG patients., Conclusions: Both OHT and POAG patients without cardiovascular risk factors have previously unreported severely reduced circulating EPCs and reduced FMD, both of which are indicators of endothelial dysfunction and increased risk of cardiovascular events.

Hyperinsulinemia and metabolic diseases are known to be associated with a reduction in life span. In the presence of insulin resistance, insulin signaling is selectively impaired, contributing to longevity shortening. Insulin indeed activates a complex web of intracellular downstream pathways, which are involved in mechanisms regulating longevity, primarily affecting cellular proliferation and apoptosis. Insulin resistance promotes reactive oxygen species (ROS) formation and favors a pro-inflammatory milieu, both these conditions playing a critical role in the reduction of life span. Insulin resistance/hyperinsulinemia also influences longevity regulating other intracellular signaling downstream in a direct or indirect manner, such as the phosphoinositide 3-kinase pathway that appears selectively impaired by insulin resistance. Decreased NAD-dependent deacetylase sirtuin (Sirt) 1 activity may mediate the shortened life span in conditions of insulin resistance. Furthermore, insulin resistance and diabetes may also associate with the telomere shortening, another important regulator of life span. This review will focus on the main intracellular pathways and mediators regulated by insulin and altered by hyperinsulinemia/insulin resistance; it summarizes the underlying mechanisms and provides evidence of these observations in experimental animal models and in human, giving further insight on the hypothesis that insulin signaling may play an important role in life span.

The expanding diabetic epidemic and the high risk of cardiovascular events in diabetic patients suggest that screening heart disease in this population is an important issue. Nonetheless, the advisability of large-scale screening in asymptomatic individuals with diabetes is debated, because available techniques are expensive and have suboptimal diagnostic accuracy. Moreover, all diabetic patients should be treated aggressively as if they all had a positive screening test, because diabetes could be considered a coronary risk equivalent. In this article, we underline the importance of an early diagnosis of coronary artery disease and heart failure in diabetic patients, suggesting that positive screening tests have significant implications in clinical management.

Vascular endothelium plays a major role in maintaining cardiovascular homeostasis. Nitric oxide is the most powerful vasodilating compound. Diabetes disrupts endothelial integrity through an increased oxidative stress. Recent evidence indicates that there is a strong interaction between diabetes, the secretory proteins of adipocytes, called adipokines, and endothelium. Endothelial dysfunction may precede the development of overt DM, and a prolonged and repeated exposure to postprandial hyperglycemia may play an important role in the development of atherosclerosis, even in those who have normal fasting plasma glucose levels.

Background: Cardiovascular risk factors cluster in the metabolic syndrome (MS), but it is not known whether the risk associated with the syndrome is higher than the sum of its parts. In this study, we explored the relationship between clustering cardiometabolic risk factors and carotid intima-media thickness (c-IMT)., Methods and Results: Cardiovascular parameters and c-IMT were determined in 240 middle-aged healthy participants, divided into groups according to their number of MS components. Higher number of MS components were associated with higher mean c-IMT. Analysis of synergy revealed that c-IMT increase at component clustering fitted an additive model. Redefinition of cutpoints for MS traits, optimized to detect high c-IMT, did not improve the interaction between components. When metabolic factors were rendered independent, a synergistic interaction between factors in increasing the likelihood of having a high c-IMT was detected. Synergic as well was the interaction between metabolic factors with other risk factors that are not consequence of insulin resistance, such as low-density lipoprotein-cholesterol level and smoking habit., Conclusion: A stepwise approach reveals that the lack of synergy in the interactions between MS components is attributable to their mutual interdependence, possibly owing to the common pathophysiological background. Indeed, if MS is a unique clinical entity, it should be no more than the sum of its parts.

The current wisdom indicates that insulin's positive effects, normoglycemia, vasodilation, and anti-inflammation, are mediated by the canonical phosphoinositide 3-kinase (PI3K)/Akt pathway whereas the negative effects are mediated by the mitogen-activated protein kinase (MAPK)/extracellular regulated kinase (ERK) pathway. Much of the intracellular oxidant stress is mediated by the MAPK/ERK pathway which is a downstream signal also for other proatherogenic hormones such as angiotensin II. However, recent evidence links MAPK activation to antioxidant activity and vascular protection. We argue against a dichotomization of insulin signaling also in light of the concept that ERK-MAPK represents a critical node in the intracellular insulin network responsible for several positive effects related not only to vascular function but also to life span.

Objective: We evaluated the acute effects of low-dose oral estradiol and sequential progesterone on the insulin-like growth factor (IGF)/growth hormone (GH) axis, IGF-binding proteins (IGFBPs) 1 and 3, and plasma levels of sex hormone-binding globulin (SHBG) in postmenopausal subjects., Study Design: Thirty healthy normal-weight women (mean age: 54.2 +/- 5.7 years) spontaneously postmenopausal for at least 6 months were enrolled. None had used hormone replacement therapy (HRT). Appropriate investigations excluded renal, glucose, lipid and coagulation abnormalities. Breast X-ray and endometrial ultrasound examinations excluded organic pathologies. They received oral cyclical HRT for 1 year, based on the administration of oral estradiol (1 mg/day) for 28 consecutive days plus progesterone (200 mg/day) from day 15 to day 28; out of the whole group, 15 subjects received progesterone orally (group A), while in 15 progesterone was administered transvaginally (group B). On the day before treatment (T0), on day 14 (T14) and on day 28 (T28) of the first cycle, plasma levels of estradiol, progesterone, SHBG, GH, IGF-I and -II, IGFBP-1 and -3, insulin and C-peptide were assayed in all patients. The same parameters were evaluated at T14 and T28 during the 12th month of treatment., Results: At T14, we observed significant increases in the levels of estradiol (from 20 +/- 16 to 115 +/- 71 pg/ml, p < 0.001), SHBG (from 132 +/- 42 to 182 +/- 55 nmol/l, p < 0.001) and IGFBP-1 (from 92 +/- 57 to 127 +/- 87 ng/ml, p < 0.004), while the level of IGF-I decreased (from 197 +/- 138 to 129 +/- 85 ng/ml, p < 0.003). At T28, progesterone levels were significantly higher in the women receiving it orally than transvaginally (8.4 +/- 6.1 vs. 3.7 +/- 3.2 ng/ml, p < 0.025). However, while oral progesterone did not affect the estrogen-induced variations, transvaginal progesterone abrogated the increase in the levels of IGFBP-1. The levels of IGF-II, IGFBP-3, GH, glucose, C-peptide and insulin did not change at any time. At 1 year, the values maintained the same trends. The estrogen-induced variations of SHBG were correlated directly with those of estradiol (r = 0.48) and inversely with those of IGF-I (r = -0.424)., Conclusions: Low-dose oral estradiol reduces plasma levels of IGF-I and increases IGFBP-1 and SHBG concentrations, while GH is unchanged. These effects, significant and immediate, lead us to hypothesize a direct action of estradiol on hepatocytes.

Aims: Circulating progenitor cells are believed to participate in cardiovascular (CV) homeostasis and their exhaustion has been linked to CV damage. As general agreement on their characterization is lacking, this work was carried out to assess the relationships between different antigenic profiles of progenitor cells and CV risk, with special regard to metabolic syndrome (MetSyn)., Methods and Results: CD34, CD133, and KDR were used to quantify circulating progenitors in 214 subjects at different levels of CV risk. In a cross-analysis of six different cell subtypes (CD34(+), CD133(+), CD34(+)CD133(+), CD34(+)KDR(+), CD133(+)KDR(+), and CD34(+)CD133(+)KDR(+)), CD34(+) progenitors showed the best correlation with CV parameters and risk estimates. Components of the MetSyn were all characterized by reduction of CD34(+) cells and acted synergistically in decreasing CD34(+) cell count. Moreover, CD34(+) cell count demonstrated a high performance in detecting high CV risk., Conclusion: These data demonstrate that CD34 identifies progenitor cells linked to CV risk, showing a close negative correlation between CD34(+) cells and CV risk, as well as a synergic detrimental effect of clustered metabolic components. Progenitor cell count may be used as a surrogate marker of CV risk, whereas extensive antigenic characterization may not be useful for this purpose.

Insulin can generate oxygen free radicals. Statins, 3-hydroxy-3-methylglutaryl-coenzyme A reductase inhibitors, exert a powerful antioxidant effect. The present study aimed to clarify the mechanisms through which insulin generates free radicals and to assess whether pravastatin modulates such effects. In cultured skin fibroblasts from human volunteers exposed to high insulin concentration, either in the presence or in the absence of pravastatin, insulin induced translocation of the p47(phox) subunit of NAD(P)H oxidase from the cytosol to the membrane and generation of radical oxygen species through a PKC delta-dependent mechanism. The insulin-induced translocation of p47(phox) was PKC delta dependent and attenuated by pravastatin, but independent of the activation of Akt and Rac1. Insulin-induced Akt phosphorylation was increased by pravastatin and ERK1/2 phosphorylation attenuated. The present study demonstrates a novel mechanism by which insulin stimulates the generation of free radicals in human fibroblasts, ex vivo. It involves phosphatidylinositol 3-kinase, PKC delta, and p47(phox) translocation and promotes ERK1/2 phosphorylation. Pravastatin inhibited radical oxygen species production by inhibiting PKC delta. These observations offer a robust explanation for the positive effects of pravastatin treatment in patients with insulin resistance syndrome.

Patients with chronic severe lung disease are prone to develop pulmonary vascular remodeling, possibly through pulmonary endothelial dysfunction. Circulating endothelial progenitor cells (EPCs) are involved in maintenance of endothelial homeostasis. The aim of this study was to assess whether obstructive and restrictive lung diseases are associated with modification of EPC number in peripheral blood. The study was cross-sectional and involved patients with obstructive (n = 15) and restrictive (n = 15) lung disease on oxygen therapy and 15 control subjects. Circulating EPCs were defined by the surface expression of CD34, CD133, and kinase-insert domain receptor. Results from spirometric tests, blood gas analyses, and blood cell counts have been related to EPC numbers. Patients with chronic hypoxia and severe lung disease showed lower levels of all progenitors than do control subjects. A consensual further reduction of EPC was found in restrictive patients in comparison with obstructive patients. Among restrictive patients, EPC reduction was related to reduced lung volumes and impaired alveolo-arterial diffusion, whereas progenitor cell levels were directly related to erythrocyte number. Considering obstructive patients, significant correlations were found between progenitor cell levels and bronchial obstruction and between progenitor cell levels and arterial oxygen tension. These findings demonstrate a reduction of EPCs in patients with chronic lung disease and long-lasting hypoxia. This alteration was more evident in restrictive patients and correlated to disease severity. Depletion of circulating EPCs may be involved in altered endothelial homeostasis of pulmonary circulation in these disorders.

Objective: Postprandial glycemia is an independent risk factor for cardiovascular disease that is more powerful than fasting glycemia and determines myocardial perfusion defects in type 2 diabetes. We examined the efficacy of two different insulin regimes (regular insulin and insulin analog) in controlling postprandial hyperglycemia and in preventing myocardial perfusion abnormalities., Research Design and Methods: A total of 20 consecutive type 2 diabetic patients and 20 control subjects were enrolled in this randomized, three-way, cross-over, placebo-controlled study. Myocardial perfusion was assessed by myocardial contrast echocardiography (MCE) in fasting and postprandial (120 min) state., Results: Insulin analog was associated with lower, but not statistically significant, postprandial glycemia than regular insulin (glucose increase: 116 +/- 8 vs. 136 +/- 5%, P = NS). However, the area under the curve following insulin analog was significantly lower than regular insulin (18,354 +/- 702 vs. 20,757 +/- 738 mg per 120 min, P = 0.032). Fasting myocardial flow velocity (beta), myocardial blood volume (MBV), and myocardial blood flow (MBF) did not differ between control and type 2 diabetic subjects. Postprandial beta (0.67 +/- 0.24 vs. 0.92 +/- 0.25, P < 0.01), MBV (8.4 +/- 2 vs. 10.9 +/- 1.2, P < 0.01), and MBF (5.6 +/- 2 vs. 9.9 +/- 2.8, P < 0.01) increased significantly in control subjects. In type 2 diabetes, during placebo in the postprandial state, beta increased (0.65 +/- 0.27 vs. 0.89 +/- 0.24, P < 0.01), while MBV (8.34 +/- 1.2 vs. 4.3 +/- 1.3, P < 0.01) and MBF (5.4 +/- 1.5 vs. 3.4 +/- 0.9, P < 0.01) decreased. Similar changes in MCE variables were observed after regular insulin: beta increased (0.65 +/- 0.22 vs. 0.92 +/- 0.12, P < 0.01) and MBV (8.2 +/- 2 vs. 5.2 +/- 1.16, P < 0.01) and MBF (5.4 +/- 1.9 vs. 4.2 +/- 0.86, P < 0.01) were reduced. After insulin analog, postprandial beta (0.66 +/- 0.18 vs. 0.9 +/- 0.18, P < 0.01), MBV (8.2 +/- 1.6 vs. 9.6 +/- 1.2, P < 0.01), and MBF (5.4 +/- 2 vs. 7.2 +/- 1.9, P < 0.01) increased. Values of postprandial MBV and MBF were higher after insulin analog than regular insulin treatment., Conclusions: Insulin analog partially reversed myocardial perfusion abnormalities observed in postprandial state by improving glucose control.

Obesity is a chronic disease, whose incidence is alarmingly growing, affecting not only adults but also children and adolescents. It is associated with severe metabolic abnormalities and increased cardiovascular morbidity and mortality. Adipose tissue secretes a great number of hormones and cytokines that not only regulate substrate metabolism but may deeply and negatively influence endothelial physiology, a condition which may lead to the formation of the atherosclerotic plaque. In this review, the physiology of the endothelium is summarised and the mechanisms by which obesity, through the secretory products of adipose tissue, influences endothelial function are explained. A short description of methodological approaches to diagnose endothelial dysfunction is presented. The possible pathogenetic links between obesity and cardiovascular disease, mediated by oxidative stress, inflammation and endothelial dysfunction are described as well.

Objectives: We sought to establish whether a reduction in endothelial progenitor cells (EPCs) has a putative role in peripheral vascular disease (PVD) of type 2 diabetic patients., Background: Peripheral vascular disease is a common and severe complication of diabetes mellitus. Impaired collateralization of diabetic vasculopathy has been extensively shown, but causes leading to its pathogenesis are not fully understood. Recently, EPCs have been found to contribute to vascular repair and angiogenesis. Diabetes has been associated with low levels of circulating EPCs, but no data are available in the literature on the relationship between EPCs and PVD in diabetes., Methods: Flow cytometric analysis was used to quantify circulating progenitor cells (CPCs, CD34+) and EPCs (CD34+KDR+) in 51 patients and 17 control subjects., Results: The CPCs and EPCs from diabetic patients were reduced by 33% and 40%, respectively, compared with healthy subjects (p < 0.001). An inverse correlation was found between the number of EPCs and the values of fasting glucose (r = -0.49, p = 0.006). Peripheral vascular disease was associated with a 47% reduction in EPCs (p < 0.0001) and EPC levels directly correlated with the ankle-brachial index (r = 0.70, p = 0.01). The subgroup of diabetic patients with PVD also had reduced CPCs by 32% (p = 0.037), whereas patients with ischemic foot lesions had the lowest levels of both EPCs and CPCs (p = 0.02)., Conclusions: Our data demonstrate decreased EPC levels in diabetic patients and, for the first time, show that PVD is associated with an extensively low number of EPCs. Depletion of circulating EPCs in diabetic patients may be involved in the pathogenesis of peripheral vascular complications.

Background and Aims: The combination of high prevalence of inactivity in the older population, and high risk of ill-health and disability associated with inactivity, suggests that interventions that are successful in increasing levels of activity may have a great impact on population health in later life. With advancing age, the risk of developing serious nutritional deficiencies also increases. This study was designed to assess the effects of dietary amino acid supplementation on effort tolerance in healthy elderly subjects with reduced physical activity., Methods: Forty-four subjects (age > 65 years) with sedentary life-style and lower health-related quality of life were studied. Subjects, in an open-label fashion, received an oral amino acid mixture (AAM, 12 g/day) containing essential and non-essential amino acids for a 3-month period. Ambulatory dysfunction resulting in sedentary life-style was assessed by a 6-min walk test. A walking impairment questionnaire (WIQ) was used to evaluate self-perceived ambulatory dysfunction. Maximal isometric muscular strength of the right hand was measured during isometric exercise by a handgrip dynamometer., Results: The 6-min walk distance increased from 214.5 +/- 32 to 262.8 +/- 34.8 m (p < 0.001) after AAM treatment. The baseline scores on the three subscales of WIQ changed significantly during treatment: WIQ distance increased from 56.2 +/- 12.9 to 66.3 +/- 12.8% (p < 0.001); WIQ speed from 52 +/- 12.6 to 69.2 +/- 14.8% (p < 0.001) and WIQ stairs from 74.4 +/- 22.6 to 94.2 +/- 25% (p < 0.001), as did maximal isometric muscular strength (16.6 +/- 2.4 vs 19.2 +/- 2.2 kg, p < 0.001). Changes in plasma glucose (+11 +/- 11 mg/dL), total cholesterol (0 +/- 39 mg/dL), HDL cholesterol (0 +/- 17 mg/dL), and triglycerides (-11 +/- 58 mg/dL) were not significant between baseline and AAM., Conclusions: An oral amino acid supplement, as used in this pilot study, improves ambulatory capacity and maximal isometric muscle strength in elderly subjects without affecting the main metabolic parameters. Amino acid supplementation may thus represent useful non-pharmacological intervention to maintain physical fitness in these subjects.

Objective: Long-term exposure to alcohol is associated with an improvement in insulin sensitivity. At this time, however, there is no definitive proof that alcohol per se has an effect on the insulin sensitivity index (S(i)) in type 2 diabetes patients. The aim of the present study was to assess the role of acute moderate alcohol intake on insulin sensitivity and insulin secretion in comparable subjects with and without type 2 diabetes., Research Design and Methods: Frequently sampled intravenous glucose tolerance tests (FSIGTs) were performed twice on eight healthy and eight type 2 diabetic volunteers. Forty grams of alcohol (vodka 40% wt/vol) or tap water were sipped from time -60 min to the end of the FSIGT., Results: Lactate area under the curve (AUC) was higher in both groups during the alcohol study than in the control study. Free fatty acid (FFA) AUC was higher in type 2 diabetic subjects than in control subjects; alcohol slightly reduced FFA by 17% in control subjects (34 +/- 4 mmol. min(-1). l(-1); P = 0.1) but significantly decreased FFA by 23% in type 2 diabetic subjects (54 +/- 10; P = 0.007). Beta-cell response was markedly reduced in type 2 diabetic subjects regardless of the type of study. Alcohol significantly increased S(i) in both groups., Conclusions: Acute alcohol consumption improves insulin action without affecting beta-cell secretion. This effect may be partly due to the inhibitory effect of alcohol on lipolysis. Alcohol intake increases insulin sensitivity and may partly explain both the J-shaped relationship between the prevalence of diabetes and the amount of alcohol consumption and the decreased mortality for myocardial infarction.

Unlabelled: To evaluate the role of elevation of non-esterified fatty acids on forearm nitric oxide (NO) dependent and independent relaxation, four studies were performed in the forearms of 14 normals: (1). endothelium-dependent and -independent vasodilations were assessed during acetylcholine (Ach) and sodium nitroprusside (SNP) infusions; (2). flow-mediated vasodilation (FMD) was assessed; (3) .bradykinin (BK) was infused during NO and prostaglandin inhibition (NO clamp); (4). blood flow (FBF) was measured during Ouabain, a Na(+)/K(+) ATPase, and BaCl(2), rectifying potassium channel (K(IR)) blockers, respectively. All studies were performed before and after 120 min. Intralipid+heparin (high-NEFA) infusion. Ach-mediated FBF increase was lower at high-NEFA (332+/-34 vs. 436+/-44% at 45 microg l forearm(-1) min(-1); % of ratio infused: control arm P<0.05), while SNP response was similar. FMD did not differ before and during high-NEFA, which induced a blunted response of FBF during BK with or without NO clamp. Ouabain and BaCl(2)-mediated FBF inhibition was lower (P<0.01) at high-NEFA. During ouabain alone FBF decreased slightly., In Conclusion: High-NEFA exerts a negative role on both NO-dependent and independent vasodilations. The decrease in FBF, mediated by K(IR) inhibition, is blunted by high-NEFA: these substrates interfere with hemodynamic/metabolism coupling, possibly through the inhibition of these channels.