Nonalcoholic fatty liver disease is associated with a decreased myocardial mechano-energetic efficiency.

BACKGROUND: Nonalcoholic fatty liver disease (NAFLD) is linked to a raised risk of cardiovascular diseases (CVD), although the underlying mechanisms are not completely known. A reduced myocardial mechano-energetic efficiency (MEE) has been found to be an independent predictor of CVD. OBJECTIVE: To evaluate the association between NAFLD and a compromised MEE. METHODS: Myocardial MEE was assessed by a validated echocardiography-derived measure in 699 nondiabetic individuals subdivided into two groups according to ultrasonography defined presence of NAFLD. RESULTS: Subjects with NAFLD displayed higher levels of systolic (SBP) and diastolic blood pressure (DBP), triglycerides, fasting and postload glucose, high-sensitivity C-reactive protein (hsCRP), insulin resistance (IR) estimated by HOMA-IR and liver IR index, and lower values of high-density lipoprotein (HDL) in comparison with those without NAFLD. Presence of NAFLD was associated with increased levels of myocardial oxygen demand and reduced values of MEE. MEE was negatively correlated with male sex, age, BMI, waist circumference, SBP, DBP, total cholesterol, triglycerides, fasting and postload glucose, HOMA-IR and liver IR index, hsCRP and positively with HDL levels. In a multivariable regression analysis, presence of NAFLD was associated with MEE regardless of several cardio-metabolic risk factors such as age, gender, waist circumference, SBP, DBP, total and HDL cholesterol, triglycerides, glucose tolerance and hsCRP (ß = -0.09, P = 0.04), but not independently of IR estimates. CONCLUSION: Ultrasound-defined presence of NAFLD is associated with a decreased MEE, a predictor of adverse cardiovascular events. The relationship between NAFLD and a compromised MEE is dependent of IR.

The use of real time continuous glucose monitoring or flash glucose monitoring in the management of diabetes: A consensus view of Italian diabetes experts using the Delphi method.

Until recently, in Italy, the use of continuous glucose monitoring (CGM) systems has been limited, but is now rapidly increasing, including the so-called real-time CGM (rtCGM) and the intermittently viewed CGM (iCGM), also called Flash Glucose Monitoring (FGM). These technologies overcome many of the limitations of self-monitoring of blood glucose (SMBG) by fingerprick and allow to go beyond HbA1c to check glucose control in diabetes. However, standardized protocols for applying and interpreting rtCGM and FGM data are lacking. In this paper, we delineate a consensus amongst Italian diabetes physicians on the attributes of rtCGM and FGM technologies, and introduce a consistent approach for their use by Italian healthcare professionals. Most experts consider rtCGM and FGM as two separate categories of interstitial subcutaneous fluid (ISF) sensing technologies, and see them as superior to SMBG. Furthermore, there is strong consensus that rtCGM and FGM reduce hypoglycemia risk, increase the amount of time in the target glucose range and augment treatment satisfaction. However, there is still no agreement on the indication of the FGM for subjects who suffer asymptomatic hypoglycemia. Consensus on the role of education in initiating and optimizing use of rtCGM/FGM and about the interpretation of glucose trends was near unanimous, whereas no consensus was reached on the statement that there are no disadvantages/risks of rtCGM/FGM. Some issues remain in rtCGM/FGM management: a) risk of excessive correction of high or low glucose; b) risk of alert fatigue leading to alert silencing or rtCGM termination; c) allergic reaction to the adhesive keeping rtCGM or FGM sensors in place. The panel almost unanimously agreed that sensor accuracy depends on multiple variables, that alarm setting should be individualized, and that global glycemic profile represent an useful tool in interpreting glucose data. More clinical studies and a wider use of these devices will increase the efficacy and effectiveness of continuous glucose monitoring in Italy.

Pharmacogenetics of oral antidiabetes drugs: evidence for diverse signals at the IRS1 locus.

To investigate the role of IRS1 locus on failure to oral antidiabetes drugs (OADs) we genotyped single-nucleotide polymorphisms (SNPs), rs2943641, rs7578326 (tagging all SNPs genome-wide associated with type 2 diabetes (T2D) and related traits at this locus) and rs1801278 (that is, the loss-of-function IRS1 G972R amino acid substitution) in 2662 patients with T2D. Although no association with OAD failure was observed for rs2943641 and rs7578326 SNPs (odds ratio (OR): 1.04, 95% confidence interval (CI): 0.93-1.16 and OR: 0.97, 95% CI: 0.87-1.09 respectively), a significant association was observed for rs1801278 (OR: 1.34, 95% CI: 1.08-1.66). When meta-analyzed with previous published data, an allelic OR of 1.41 (1.15-1.72; P=0.001) was obtained, so that homozygous R972R individuals have >80% higher risk of failing to OADs as compared with their G972G counterparts. In all, though further studies are needed for confirming this finding, our present data point to IRS1 rs1801278 as a potential biomarker for pursuing the goal of stratified medicine in the field of antihyperglycemic treatment in T2D.

Management of diabetes in older adults.

Type 2 diabetes prevalence is high in older adults and is expected to rise in the next decades. Diabetes in the population of frail older adults is accompanied by functional disability, several comorbidities, and premature mortality. A comprehensive geriatric assessment, including functional, cognitive, mental and social status, is advisable for identifying the glycemic targets and glucose-lowering therapies, focused on patient preferences, needs, and risks. The therapeutic options for older adults with diabetes are like those for the adult population. However, the pharmacological treatments must be carefully prescribed and monitored, taking into consideration the patient cognitive capacities, the potentially life-threatening drug-drug interactions, the cardiovascular risk, and with the main goal of avoiding hypoglycemia. Also, a careful nutritional evaluation with appropriate tools, as well as a balanced and periodically monitored physical activity, contribute to an effective tailored care plan, as needed by older adults with diabetes. This review evaluates the currently available hypoglycemic drugs and the current indications to the Italian diabetology community, specifically with regard to the treatment of adults aged 75 years or older with diabetes, including the unmet needs by the guidelines.

Rationale and design of the DARWIN-T2D (DApagliflozin Real World evIdeNce in Type 2 Diabetes): A multicenter retrospective nationwide Italian study and crowdsourcing opportunity.

BACKGROUND: Randomized controlled trials (RCTs) in the field of diabetes have limitations inherent to the fact that design, setting, and patient characteristics may be poorly transferrable to clinical practice. Thus, evidence from studies using routinely accumulated clinical data are increasingly valued. AIMS: We herein describe rationale and design of the DARWIN-T2D (DApagliflozin Real World evIdeNce in Type 2 Diabetes), a multicenter retrospective nationwide study conducted at 50 specialist outpatient clinics in Italy and promoted by the Italian Diabetes Society. DATA SYNTHESIS: The primary objective of the study is to describe the baseline clinical characteristics (particularly HbA1c) of patients initiated on dapagliflozin from marketing authorization approval to the end of 2016. Secondary and exploratory objectives will evaluate the changes in glycaemic and extraglycaemic efficacy parameters after initiation of dapagliflozin or after initiation of comparator glucose lowering medications (DPP-4 inhibitors, gliclazide extended release, and long-acting GLP-1 receptor agonists). An automated software will extract relevant data from the same electronic chart system at all centres, thereby minimizing data treatment and human intervention. CONCLUSION: The study is expected to collect an enormous dataset of information on dapagliflozin- and comparator-using patients. After study completion, the Italian Diabetes Society will launch an open crowdsourcing call on the DARWIN-T2D database, challenging diabetes researchers to apply their ideas and approaches to address new unmet needs and knowledge gaps in diabetes. We believe this will move DARWIN-T2D to the next generation of real world studies.

Hemorheological alterations in adults with prediabetes identified by hemoglobin A1c levels.

BACKGROUND AND AIMS: A link between increased blood viscosity and type 2 diabetes has been previously reported. Herein, we investigated the association of blood viscosity with prediabetes, identified by glycated hemoglobin A1c (HbA1c) according to the new American Diabetes Association criteria, and subclinical atherosclerosis. METHODS AND RESULTS: The study cohort includes 1136 non-diabetic adults submitted to anthropometrical evaluation, an oral glucose tolerance test and ultrasound measurement of carotid intima-media thickness (IMT). Whole blood viscosity was estimated using a validated formula based on hematocrit and total plasma proteins. After adjusting for age, and gender, individuals with HbA1c-defined prediabetes (HbA1c 5.7-6.4% [39-47 mmol/mol]) exhibited significantly higher values of hematocrit, and predicted blood viscosity as compared with controls. Increased levels of IMT were observed in subjects with HbA1c-defined prediabetes in comparison to controls. Predicted blood viscosity was positively correlated with age, waist circumference, blood pressure, cholesterol, triglycerides, fibrinogen, white blood cell, HbA1c, fasting and 2-h post-load glucose levels, fasting insulin, IMT and inversely correlated with HDL and Matsuda index of insulin sensitivity. Of the three glycemic parameters, i.e. HbA1c, fasting and 2-h post-load glucose, only HbA1c showed a significant correlation with predicted blood viscosity (ß = 0.054, P = 0.04) in a multivariate regression analysis model including multiple atherosclerosis risk factors. CONCLUSION: The study shows that individuals with HbA1c-defined prediabetes have increased predicted blood viscosity and IMT. The HbA1c criterion may be helpful to capture individuals with an increased risk of diabetes and cardiovascular disease who may benefit from an intensive lifestyle intervention.

Glucagon-like peptide-1 receptor agonists and atrial fibrillation: a systematic review and meta-analysis of randomised controlled trials.

BACKGROUND: The pharmacological stimulation of GLP-1 receptors is associated with an increase in heart rate. A pooled analysis of patient-level data from phase III trials with albiglutide revealed a significant increase in the risk of atrial fibrillation. Aim of the present meta-analysis is to summarize all available evidence on the effects of individual GLP-1 receptor agonists (RA), and of the whole class, on the incidence of atrial fibrillation. METHODS: A Medline search for GLP-1 RA (exenatide, liraglutide, lixisenatide, albiglutide, dulaglutide, or semaglutide) was performed, collecting all randomized clinical trials with a duration ≥12 weeks, enrolling patients with type 2 diabetes and comparing a GLP-1 RA with placebo or any other non-GLP-1 RA drug. RESULTS: Of the 113 trials fulfilling the inclusion criteria, 19 did not report information on atrial fibrillation, whereas 63 reported zero events in all treatment groups. In the remaining trials (enrolling 17,966 and 15,305 patients in GLP-1 RA and comparator arms, respectively, 55.3% women, with a mean age of 57.0 ± 3.8 years), treatment with GLP-1 RA was not associated with a significant increase in the incidence of atrial fibrillation [Mantel-Haenszel OR (95% CI) 0.87 (0.71-1.05), p = 0.15]. CONCLUSIONS: In conclusion, available data suggest that GLP-1 RA is not associated with atrial fibrillation, with the only possible exception of albiglutide. Newly onset atrial fibrillation deserves to be investigated as an event of special interest in future trials with GLP-1 RA.

Serum phosphorus levels are associated with endothelial dysfunction in hypertensive patients.

BACKGROUND AND AIMS: Recent data demonstrated that serum phosphorus, within the normal range, is an independent predictor of atherosclerotic cardiovascular disease, independently of renal function. Traditional cardiovascular risk factors are important mediators of endothelial dysfunction, the early step of atherosclerosis. We designed this study to evaluate a possible correlation between serum phosphorus and endothelium-dependent vasodilation, evaluated by the strain-gauge plethysmography, in naïve hypertensives. METHODS AND RESULTS: We investigated by strain-gauge plethysmography, the relationship between forearm blood flow (FBF) response to acetylcholine (ACh) and serum phosphorus in 500 patients with uncomplicated, never-treated, essential hypertension, divided by phosphorus tertiles. There were no significant differences among tertiles with the exclusion of forearm blood flow (FBF). Phosphorus (ß = -0.454; P = 0.0001), estimated-glomerular filtration rate (e-GFR, by CKD-EPI formula) (ß = 0.261; P = 0.0001), gender (ß = 0.215; P = 0.0001), BMI (ß = -0.086; P = 0.018), HDL-cholesterol (ß = 0.077; P = 0.036) were significantly related to endothelium-dependent vasodilation. In an additional analysis including serum high sensitivity C-reactive protein (hs-CRP) (measured in 400 patients) in the same model, the link between serum phosphorus and ACh-stimulated FBF did not change (ß = -0.422; P = 0.0001). Clinically relevant, 0.1 mg of phosphorus increase is associated with a reduction of 22% of ACh-stimulated FBF. On multiple logistic regression analysis, the risk of endothelial dysfunction was about twice higher in patients in the second (OR = 1.754, 95% CI = 1.055-2.915; P = 0.030) and three-fold higher in the third tertile (OR = 2.939, 95% CI = 1.598-5.408; P = 0.0001) in comparison with those in the first tertile of phosphorus. CONCLUSION: An impaired ACh-stimulated FBF is associated with serum phosphorus levels, within the normal range, in hypertensives.

Plasma complement C3 levels are associated with insulin secretion independently of adiposity measures in non-diabetic individuals.

BACKGROUND AND AIMS: To evaluate if complement C3 is associated with insulin secretion, as suggested by recent in vitro studies, independently of confounders including adiposity measures. METHODS AND RESULTS: 1010 nondiabetic subjects were stratified into quartiles according to complement C3 values. Insulin secretion was assessed using indexes derived from oral glucose tolerance test (OGTT) in the whole study group and from intravenous glucose tolerance test (IVGTT) in a subgroup (n = 110). Significant differences between quartiles of C3 were observed in body mass index (BMI), waist, fat mass, blood pressure, total cholesterol, high density lipoprotein (HDL), triglycerides, fasting and 2-h post-load glucose, fasting insulin, C reactive protein (hsCRP), fibrinogen, aspartate aminotransferase (AST), alanine aminotransferase (ALT), complement C4, and insulin sensitivity with C3 quartiles exhibiting graded increases in cardio-metabolic risk factors. Differences in insulin secretion indexes between C3 quartiles remained significant after adjustment for age, gender, BMI, insulin sensitivity, blood pressure, total cholesterol, HDL, triglycerides, hsCRP, fibrinogen, and complement C4 levels (P < 0.0001). A multivariable regression analysis revealed that complement C3 is a contributor of insulin secretion, explaining 2.4% and 1.9% of variation of the Stumvoll index for first-phase and second-phase insulin secretion, respectively, and 2.1% of variation of the InsAUC30/GluAUC30 index, independently of gender, age, BMI, waist, fat mass, blood pressure, total cholesterol, HDL, triglycerides, hsCRP, fibrinogen, AST, ALT. CONCLUSIONS: Complement C3 concentrations are associated with insulin secretion independently of important determinants of glucose homeostasis such as gender, age, adiposity, subclinical inflammation, and insulin sensitivity.

Insulin sensitivity, and ß-cell function in relation to hemoglobin A1C.

BACKGROUND AND AIMS: The A1C diagnostic criterion for identifying individuals at increased risk for diabetes, introduced by the American Diabetes Association in 2010, was not defined on the basis of the principal pathophysiological abnormalities responsible for the development and progression of type 2 diabetes; we therefore wished to gain a deeper insight into the metabolic abnormalities characterizing the group of at risk individuals with an A1C value of 5.7-6.4%. METHODS AND RESULTS: As many as 338 non-diabetic offspring of type 2 diabetic patients were consecutively recruited. Insulin secretion was assessed using both indexes derived from oral glucose tolerance test (OGTT), and intravenous glucose tolerance test (IVGTT). Insulin sensitivity was measured by hyperinsulinemic euglycemic clamp. As compared with subjects with A1C <5.7%, individuals with A1C of 5.7-6.4% exhibited lower insulin sensitivity after adjusting for age, gender and body mass index (BMI). Insulin secretion estimated from the OGTT, did not differ between the two groups. By contrast, as compared with subjects with A1C <5.7%, the acute insulin response (AIR) during an IVGTT and both IVGTT-derived and OGTT-derived disposition indexes were reduced in individuals with A1C of 5.7-6.4% after adjusting for age, gender and BMI. As A1C increased to ≥ 5.7%, a sharp decrease in insulin sensitivity and ß-cell function, measured as disposition index, was observed. CONCLUSIONS: Caucasian individuals with A1C ≥ 5.7% exhibit both core pathophysiological defects of type 2 diabetes i.e. insulin resistance and ß-cell dysfunction.

Low circulating insulin-like growth factor-1 levels are associated with high serum uric acid in nondiabetic adult subjects.

BACKGROUND AND AIMS: Low insulin-like growth factor-1 (IGF-1) levels and high uric acid concentrations are associated with cardio-metabolic disorders. Acute IGF-1 infusion decreases uric acid concentration in healthy individuals. In this study, we aimed to examine the relationship between IGF-1 and uric acid levels. METHODS AND RESULTS: 1430 adult non diabetic subjects were stratified into quartiles according to their circulating IGF-1 values. Significant differences in uric acid concentration, measured by the URICASE/POD method were observed between low (quartile 1), intermediate (quartile 2 and 3), and high (quartile 4) IGF-1 levels groups after adjusting for age, gender, and body mass index (P = 0.02). These differences remained significant after adjustment for blood pressure, total cholesterol, high density lipoprotein, triglycerides, fasting and 2 h post-load glucose levels, HOMA-IR index (P = 0.005), liver enzymes (P = 0.03), glucose tolerance status (P = 0.02), growth hormone levels (GH) (P = 0.05), anti-hypertensive treatments (P = 0.04) or diuretics use (P = 0.04)). To clarify the molecular links between IGF-1 and uric acid, we performed an in vitro study, incubating human hepatoma cells with uric acid for 24 or 48 h in the presence of GH and observed a 21% and 26% decrease, respectively, in GH-stimulated IGF-1 mRNA expression (P = 0.02 and P = 0.012, respectively). This effect appears to be mediated by uric acid ability to down regulate GH intracellular signaling; in fact we observed a significant decrease of GH activated JAK2 and Stat5 phosphorylation. CONCLUSIONS: These data demonstrate an inverse relationship between IGF-1 and uric acid levels in adults and suggest that uric acid might affect hepatic IGF-1 synthesis.

Dietary patterns and 1-h post-load glucose in essential hypertension.

BACKGROUND AND AIMS: Normoglucosetolerants (NGT) are considered at low risk, even if a 1-h post-load glucose (PLG) value ≥ 155 mg dl(-1) identifies NGTs at high risk of type-2 diabetes (T2D) and sub-clinical organ damage. Specific dietary factors may affect insulin sensitivity and the risk of T2D. However, it is unknown whether dietary components affect 1-h PLG in hypertensive NGT. Therefore, we investigate the effect of dietary patterns on 1-h PLG. METHODS AND RESULTS: We selected 188 subjects (94 NGTs < 155 mg dl(-1) and 94 NGTs ≥ 155 mg dl(-1) PLG), well matched for age, gender and body mass index (BMI). Insulin sensitivity was evaluated using the Matsuda index. Dietary intake was quantified by a semiquantitative food frequency questionnaire (FEQ) validated in the European Investigation into Cancer and Nutrition (EPIC) study. The NGT ≥ 155 group had significantly reduced insulin sensitivity (40.3 ± 19.8 vs. 73.3 ± 28.8; P < 0.0001). With the exclusion of total calories, lipids, alcohol and fiber consumption we observed a significant difference, between groups, in starch (214.1 ± 52.4 vs. 268.8 ± 71.8 g; P < 0.0001), saturated (27.4 ± 8.7 vs. 24.1 ± 8.5 g; P = 0.009), monounsaturated (45.5 ± 8.9 vs. 48.8 ± 10.7 g; P = 0.023) and polyunsaturated fatty acids (FAs) (14.5 ± 4.0 vs. 16.8 ± 4.7 g; P < 0.0001), fructose (14.5 ± 5.3 vs. 11.2 ± 4.8 g; P < 0.0001), and oligosaccharides (103.2 ± 26.6 vs. 89.9 ± 29.2 g; P = 0.001) consumption. In the whole population, starch was the major predictor of 1-h PLG, explaining 23.2% of variation (P < 0.0001). In the NGT < 155 group, fructose was the strongest predictor, accounting for 15.4% of the variation; BMI, gender and polyunsaturated FAs added another 6.6%, 3.6% and 3.2%, respectively. In the NGT ≥ 155 group, saturated and polyunsaturated FAs were retained as the major predictors of 1-h PLG, explaining 18.2% and 11.4% of the variation. CONCLUSIONS: The present data demonstrate that dietary patterns affect 1-h PLG, remarking the importance of both quantitative and qualitative composition of a diet.

Association of hepatic insulin resistance indexes to nonalcoholic fatty liver disease and related biomarkers.

BACKGROUND AND AIMS: Nonalcoholic fatty liver disease (NAFLD) is linked with insulin resistance, however, if it is differentially associated with surrogate hepatic insulin resistance indexes is still undefined. We examined the relationship between these indexes, NAFLD and its related biomarkers (alanine aminotransferase [ALT], aspartate aminotransferase [AST], gamma-glutamyltransferase [GGT], alkaline phosphatase [ALK], high-sensitive C reactive protein [hsCRP], insulin-like growth factor-1 [IGF-1]). METHODS AND RESULTS: 473 Caucasians subjects underwent liver ultrasonography and oral glucose tolerance tests; homeostasis model assessment (HOMA), glucose(0-30) (area under the curve [AUC]) × insulin(0-30) (AUC) and liver insulin resistance (liver IR) indexes were computed. Liver IR index correlated more strongly than HOMA with GGT, ALK, hsCRP, ALT and AST and more strongly than glucose(0-30) (AUC) × insulin(0-30) (AUC) index with ALT, AST, GGT, ALK, hsCRP, and IGF-1. The ability of these indexes to identify NAFLD was evaluated by the area under the ROC curve; the ROC AUC for liver IR index was higher (0.733) than the ones for HOMA (0.685) and glucose(0-30) (AUC) × insulin(0-30) (AUC) (0.663) indexes. In a logistic regression model subjects in the highest quartile of the three indexes had a higher risk of having NAFLD than those in the lowest quartile (9.85-, 5.12- or 3.99-fold higher for liver IR index, HOMA, glucose(0-30) (AUC) × insulin(0-30) (AUC) index respectively). CONCLUSIONS: we documented significant cross-sectional associations of NAFLD and liver biomarkers with three validated indexes of hepatic insulin resistance, with liver IR index showing the stronger correlation.

The SH2B1 obesity locus and abnormal glucose homeostasis: lack of evidence for association from a meta-analysis in individuals of European ancestry.

BACKGROUND/AIMS: The development of type 2 diabetes (T2D) is influenced both by environmental and by genetic determinants. Obesity is an important risk factor for T2D, mostly mediated by obesity-related insulin resistance. Obesity and insulin resistance are also modulated by the genetic milieu; thus, genes affecting risk of obesity and insulin resistance might also modulate risk of T2D. Recently, 32 loci have been associated with body mass index (BMI) by genome-wide studies, including one locus on chromosome 16p11 containing the SH2B1 gene. Animal studies have suggested that SH2B1 is a physiological enhancer of the insulin receptor and humans with rare deletions or mutations at SH2B1 are obese with a disproportionately high insulin resistance. Thus, the role of SH2B1 in both obesity and insulin resistance makes it a strong candidate for T2D. However, published data on the role of SH2B1 variability on the risk for T2D are conflicting, ranging from no effect at all to a robust association. METHODS: The SH2B1 tag SNP rs4788102 (SNP, single nucleotide polymorphism) was genotyped in 6978 individuals from six studies for abnormal glucose homeostasis (AGH), including impaired fasting glucose, impaired glucose tolerance or T2D, from the GENetics of Type 2 Diabetes in Italy and the United States (GENIUS T2D) consortium. Data from these studies were then meta-analyzed, in a Bayesian fashion, with those from DIAGRAM+ (n = 47,117) and four other published studies (n = 39,448). RESULTS: Variability at the SH2B1 obesity locus was not associated with AGH either in the GENIUS consortium (overall odds ratio (OR) = 0.96; 0.89-1.04) or in the meta-analysis (OR = 1.01; 0.98-1.05). CONCLUSION: Our data exclude a role for the SH2B1 obesity locus in the modulation of AGH.

Low dose aspirin and clinical outcomes in patients with SARS-CoV-2 pneumonia: a propensity score-matched cohort analysis from the National SIMI­COVID­19 Registry.

BACKGROUND: SARS- CoV-2 virus has had dramatic consequences worldwide being able to cause acute respiratory distress syndrome (ARDS), massive thrombosis and pulmonary embolism and, finally, patients' death. In COVID-19 infection, platelets have a procoagulant phenotype that can cause thrombosis in the pulmonary and systemic vascular network. Aspirin is a well-known anti-platelet drug widely used for the prevention of cardiovascular events and systematic reviews suggest a possible benefit of low-dose aspirin (LDA) use in the prevention and treatment of ARDS in patients with COVID-19 infection. However, several studies are available in the literature which do not support any benefits and no association with the patients' outcome. Therefore, currently available data are inconclusive. MATERIALS AND PATIENTS: Data from the nationwide cohort multicenter study of the Italian Society of Internal Medicine (SIMI) were analyzed. We conducted a propensity score-matched cohort analysis to investigate the impact of chronic assumption of LDA on mortality of adult COVID-19 patients admitted in Internal Medicine Units (IMU). Data from 3044 COVID-19 patients who referred to 41 Italian hospitals between February 3rd to May 8th 2020 were analyzed. A propensity score-matched analysis was conducted using the following variables: age, sex, hypertension, hyperlipidemia diabetes, atrial fibrillation, cerebrovascular disease, COPD, CKD and stratified upon LDA usage, excluding anticoagulant treatment. After matching, 380 patients were included in the final analysis (190 in LDA group and 190 in no-LDA group). RESULTS: 66.2% were male, median age was 77 [70-83]. 34.8% of the population died during the hospitalization. Cardiovascular diseases were not significantly different between the groups. After comparison of LDA and no-LDA subgroups, we didn't record a significant difference in mortality rate (35.7% vs 33.7%) duration of hospital stay and ICU admission. In a logistic regression model, age (OR 1.05; 95% CI 1.01-1.09), FiO2 (OR 1.024; 95% CI 1.03-1.04) and days between symptoms onset and hospitalization (OR 0.93; 95% CI 0.87-0.99) were the only variables independently associated with death.

Comparison of A1C, fasting and 2-h post-load plasma glucose criteria to diagnose diabetes in Italian Caucasians.

BACKGROUND AND AIMS: The American Diabetes Association (ADA) has revised criteria for diagnosis of type 2 diabetes recommending an A1C cut point of ≥6.5% in addition to criteria based on glucose levels. We compared A1C, fasting plasma glucose (FPG) or 2-h post-challenge glucose (2-hPG) criteria for the diagnosis of diabetes in a cohort of Italian Caucasians. METHODS AND RESULTS: A total of 1019 individuals without known diabetes completed an oral glucose tolerance test (OGTT) and had A1C measured. Moderate agreement existed for A1C and FPG criteria for diagnosis of type 2 diabetes (κ coefficient = 0.522), with 85.5% of individuals classified as not having diabetes by both A1C and FPG criteria, and 5.8% classified as having diabetes by both A1C and FPG criteria. Discordant classifications occurred for 5.5% of individuals who had an A1C ≥ 6.5% and FPG <126 mg dl(-1), and for 3.2% who had an A1C <6.5% and FPG ≥126 mg dl(-1). Modest agreement existed for A1C and 2-hPG criteria for diagnosis of type 2 diabetes (κ coefficient = 0.427), with 81.8% of individuals classified as not having diabetes by both A1C and 2-hPG criteria, and 6.0% classified as having diabetes by both A1C and 2-hPG criteria. The area under the receiver operating characteristic curve of A1C for identifying subjects with diabetes according to FPG or 2-hPG criteria was 0.856 and 0.794, respectively. Modest agreement existed for A1C and FPG and/or 2-hPG criteria for diagnosis of type 2 diabetes (κ coefficient = 0.446). CONCLUSIONS: A1C ≥ 6.5% demonstrates a moderate agreement with fasting glucose and 2-hPG for diagnosing diabetes among adult Italian Caucasians subjects.

The evaluation of the intracavitary effusions by a bedside ultrasound examination.

OBJECTIVE: This study aims to evaluate the bedside use of the pocket-sized ultrasound (US) device for the detection of the intracavitary effusions. METHODS: We randomly enrolled 40 patients admitted to S. Andrea Hospital of Rome. Every patient received a clinical and biochemical evaluation and a bedside US examination to detect and estimate the intracavitary (pleural, pericardial and intra-abdominal) effusions; the US measurements have been compared to the computed tomography (CT) scans (as gold standard). RESULTS: The patients presented a high prevalence of effusions: right pleural 16/40 = 40% (esteemed volume 236.3±500.7 ml, mean±standard deviation m±SD), left pleural 8/40 = 20% (127.0±377.4 ml), pericardial 12/40 = 30% (47.5±72.8 ml) and intra-abdominal effusions 5/40 = 12.5% of cases (110.9±600.6 ml). Linear regression analysis showed a significant correlation between US and CT measurements: pleural r = 0.973 p <  1×10-38, pericardial r = 0.927 p <  1×10-39, intra-abdominal space r = 0.921 p <  1×10-59. The accuracy of the bedside US at the pleural, pericardial and abdominal level was respectively 98%, 93% and 96% (Cohen's kappa coefficient 0.966, 0.841 and 0.833). CONCLUSIONS: The present study showed a high prevalence of the intracavitary effusions and a high accuracy of the bedside US. The bedside US by a pocket-sized device is promising tool for its advantages of reproducibility and non-invasiveness of the device.

Increased levels of the Akt-specific phosphatase PH domain leucine-rich repeat protein phosphatase (PHLPP)-1 in obese participants are associated with insulin resistance.

AIMS/HYPOTHESIS: We determined the contribution to insulin resistance of the PH domain leucine-rich repeat protein phosphatase (PHLPP), which dephosphorylates Akt at Ser473, inhibiting its activity. We measured the abundance of PHLPP in fat and skeletal muscle from obese participants. To study the effect of PHLPP on insulin signalling, PHLPP (also known as PHLPP1) was overexpressed in HepG2 and L6 cells. METHODS: Subcutaneous fat samples were obtained from 82 morbidly obese and ten non-obese participants. Skeletal muscle samples were obtained from 12 obese and eight non-obese participants. Quantification of PHLPP-1 in human tissues was performed by immunoblotting. The functional consequences of recombinant PHLPP1 overexpression in hepatoma HepG2 cells and L6 myoblasts were investigated. RESULTS: Of the 82 obese participants, 31 had normal fasting glucose, 33 impaired fasting glucose and 18 type 2 diabetes. PHLPP-1 abundance was twofold higher in the three obese groups than in non-obese participants (p = 0.004). No differences were observed between obese participants with normal fasting glucose, impaired fasting glucose or type 2 diabetes. PHLPP-1 abundance was correlated with basal Akt Ser473 phosphorylation (r = -0.48; p = 0.001), BMI (r = 0.44; p < 0.0001), insulin (r = 0.35; p < 0.0001) and HOMA (r = 0.38; p < 0.0001). PHLPP-1 abundance was twofold higher in the skeletal muscle of 12 obese participants than in that of eight non-obese participants (p < 0.0001). Insulin treatment of HepG2 cells resulted in a dose- and time-dependent upregulation of PHLPP-1. Overexpression of PHLPP1 in HepG2 cells and L6 myoblasts resulted in impaired insulin signalling involving Akt/glycogen synthase kinase 3, glycogen synthesis and glucose transport. CONCLUSIONS/INTERPRETATION: Increased abundance of PHLPP-1, production of which is regulated by insulin, may represent a new molecular defect in insulin-resistant states such as obesity.

Glucose tolerance, insulin sensitivity and insulin release in European non-diabetic carriers of a polymorphism upstream of CDKN2A and CDKN2B.

AIMS/HYPOTHESIS: The aim of this study was to investigate the association of the rs10811661 polymorphism near the CDKN2B/CDKN2A genes with glucose tolerance, insulin sensitivity and insulin release in three samples of white people with European ancestry. METHODS: Sample 1 comprised 845 non-diabetic offspring of type 2 diabetes patients recruited in five European centres participating in the EUGENE2 study. Samples 2 and 3 comprised, respectively, 864 and 524 Italian non-diabetic participants. All individuals underwent an OGTT. Screening for the rs10811661 polymorphism was performed using a TaqMan allelic discrimination assay. RESULTS: The rs10811661 polymorphism did not show a significant association with age, BMI and insulin sensitivity. Participants carrying the TT genotype showed a significant reduction in insulin release, measured by an OGTT-derived index, compared with carriers of the C allele, in the three samples. When these results were pooled with those of three published studies, and meta-analysed with a random-effects model, the T allele was significantly associated with reduced insulin secretion (-35.09 [95% CI 14.68-55.52], p = 0.0008 for CC+CT vs TT; and -29.45 [95% CI 9.51-49.38], p = 0.0038, for the additive model). In addition, in our three samples, participants carrying the TT genotype exhibited an increased risk for impaired glucose tolerance (IGT) compared with carriers of the C allele (OR 1.55 [95% CI 1.20-1.95] for the meta-analysis of the three samples). CONCLUSIONS/INTERPRETATION: Our data, together with the meta-analysis of previously published studies, show that the rs10811661 polymorphism is associated with impaired insulin release and IGT, suggesting that this variant may contribute to type 2 diabetes by affecting beta cell function.