Effects of Incretin-Based Treatment on the Diastolic (Dys)Function in Patients with Uncontrolled Type 2 Diabetes Mellitus: A Prospective Study with 1-Year Follow-Up.

Left ventricular diastolic dysfunction (DD) is a subclinical cardiac abnormality in patients with type 2 diabetes mellitus (T2DM) that can progress to heart failure (HF) and increase cardiovascular risk. This prospective study evaluated the DD in T2DM patients without atherosclerotic cardiovascular disease after one year of incretin-based drugs added to standard treatment. Of the 138 enrolled patients (49.30% male, mean age 57.86 ± 8.82, mean T2DM history 5 years), 71 were started on dipeptidyl peptidase-4 inhibitor sitagliptin/saxagliptin, 21 on glucagon-like peptide-1 receptor agonist exenatide, and 46 formed the control group (metformin and sulphonylurea/acarbose). At baseline, 71 patients had grade 1 DD, another 12 had grade 2 and 3 DD, and 15 had indeterminate DD. After one year, DD was evidenced in 50 cases. Diastolic function improved in 9 cases, and 27 patients went from grade 1 to indeterminate DD. The active group benefited more, especially patients treated with exenatide; their metabolic and inflammation profiles also improved the most. An in-depth analysis of echocardiographic parameters and paraclinical results in the context of literature data justifies the conclusion that early assessment of diastolic function in T2DM patients is necessary and the benefits of affordable incretin-based treatment may extend to subclinical cardiovascular manifestations such as DD.

Glucagon-like Peptide-1 Receptor Agonists in Patients with Type 2 Diabetes Mellitus and Nonalcoholic Fatty Liver Disease-Current Background, Hopes, and Perspectives.

Nonalcoholic fatty liver disease (NAFLD) represents the most common chronic liver disease worldwide, reaching one of the highest prevalences in patients with type 2 diabetes mellitus (T2DM). For now, no specific pharmacologic therapies are approved to prevent or treat NAFLD. Glucagon-like peptide-1 receptor agonists (GLP-1RAs) are currently evaluated as potential candidates for NAFLD treatment in patients with T2DM. Some representatives of this class of antihyperglycemic agents emerged as potentially beneficial in patients with NAFLD after several research studies suggested they reduce hepatic steatosis, ameliorate lesions of nonalcoholic steatohepatitis (NASH), or delay the progression of fibrosis in this population. The aim of this review is to summarize the body of evidence supporting the effectiveness of GLP-1RA therapy in the management of T2DM complicated with NAFLD, describing the studies that evaluated the effects of these glucose-lowering agents in fatty liver disease and fibrosis, their possible mechanistic justification, current evidence-based recommendations, and the next steps to be developed in the field of pharmacological innovation.

Ischemic Heart Disease in the Context of Different Comorbidities.

Ischemic heart disease (IHD) is a leading cause of morbidity and mortality worldwide [...].

Ultrasound-Based Hepatic Elastography in Non-Alcoholic Fatty Liver Disease: Focus on Patients with Type 2 Diabetes.

Non-alcoholic fatty liver disease (NAFLD) is the most prevalent liver disease and is the hepatic expression of metabolic syndrome. The development of non-invasive methods for the diagnosis of hepatic steatosis and advanced fibrosis in high-risk patients, especially those with type 2 diabetes mellitus, is highly needed to replace the invasive method of liver biopsy. Elastographic methods can bring significant added value to screening and diagnostic procedures for NAFLD in patients with diabetes, thus contributing to improved NAFLD management. Pharmacological development and forthcoming therapeutic measures that address NAFLD should also be based on new, non-invasive, and reliable tools that assess NAFLD in at-risk patients and be able to properly guide treatment in individuals with both diabetes and NAFLD. This is the first review aiming to outline and discuss recent studies on ultrasound-based hepatic elastography, focusing on NAFLD assessment in patients with diabetes.

Association of Inflammatory and Metabolic Biomarkers with Mitral Annular Calcification in Type 2 Diabetes Patients.

(1) Background: Type 2 diabetes mellitus (T2DM) contributes to cardiovascular disease and related mortality through the insidious effects of insulin resistance and chronic inflammation. Mitral annular calcification (MAC) is one such degenerative process promoted by T2DM. (2) Methods: This is a post hoc analysis of insulin resistance, inflammation, and hepatic steatosis markers in T2DM patients without atherosclerotic manifestations, but with incidental echocardiographic detection of mild MAC. (3) Results: 138 consenting patients were 49.3% men, 57.86 years old, with a history of T2DM of 6.16 years and HbA1c 8.06%, of whom sixty had mild MAC (43.47%). The statistically significant differences between patients with/without MAC were higher HOMA C-peptide and C-peptide index for insulin resistance, higher TNF-α for inflammation, and lower estimated glomerular filtration rate. High-sensitive C-reactive protein (hsCRP) was significantly associated with insulin resistance and the strength of the relationship was higher in the MAC group. Predictive of MAC were TNF-α, HOMA C-peptide, and especially hepatic steatosis and hypertension. (4) Conclusions: MAC was more prevalent than reported in the literature. Insulin resistance and inflammation were predictive of MAC, but significant markers differ across studies. Widely available routine tests and echocardiographic assessments are useful in the early identification of mitral annular calcifications in diabetes patients.

New Insights into Non-Alcoholic Fatty Liver Disease and Coronary Artery Disease: The Liver-Heart Axis.

Non-alcoholic fatty liver disease (NAFLD) represents the hepatic expression of the metabolic syndrome and is the most prevalent liver disease. NAFLD is associated with liver-related and extrahepatic morbi-mortality. Among extrahepatic complications, cardiovascular disease (CVD) is the primary cause of mortality in patients with NAFLD. The most frequent clinical expression of CVD is the coronary artery disease (CAD). Epidemiological data support a link between CAD and NAFLD, underlain by pathogenic factors, such as the exacerbation of insulin resistance, genetic phenotype, oxidative stress, atherogenic dyslipidemia, pro-inflammatory mediators, and gut microbiota. A thorough assessment of cardiovascular risk and identification of all forms of CVD, especially CAD, are needed in all patients with NAFLD regardless of their metabolic status. Therefore, this narrative review aims to examine the available data on CAD seen in patients with NAFLD, to outline the main directions undertaken by the CVD risk assessment and the multiple putative underlying mechanisms implicated in the relationship between CAD and NAFLD, and to raise awareness about this underestimated association between two major, frequent and severe diseases.

Ischemic Heart Disease in Patients with Inflammatory Bowel Disease: Risk Factors, Mechanisms and Prevention.

According to new research, a possible association between inflammatory bowel disease (IBD) and an increased risk of ischemic heart disease (IHD) has been demonstrated, but this concern is still debatable. The purpose of this review is to investigate the link between IHD and IBD, as well as identify further research pathways that could help develop clinical recommendations for the management of IHD risk in IBD patients. There is growing evidence suggesting that disruption of the intestinal mucosal barrier in IBD is associated with the translocation of microbial lipopolysaccharides (LPS) and other endotoxins into the bloodstream, which might induce a pro-inflammatory cytokines response that can lead to endothelial dysfunction, atherosclerosis and acute cardiovascular events. Therefore, it is considered that the long-term inflammation process in IBD patients, similar to other chronic inflammatory diseases, may lead to IHD risk. The main cardiovascular risk factors, including high blood pressure, dyslipidemia, diabetes, smoking, and obesity, should be checked in all patients with IBD, and followed by strategies to reduce and manage early aggression. IBD activity is an important risk factor for acute cardiovascular events, and optimizing therapy for IBD patients should be followed as recommended in current guidelines, especially during active flares. Large long-term prospective studies, new biomarkers and scores are warranted to an optimal management of IHD risk in IBD patients.

Antioxidant Activity Evaluation and Assessment of the Binding Affinity to HSA of a New Catechol Hydrazinyl-Thiazole Derivative.

Polyphenols have attained pronounced attention due to their ability to provide numerous health benefits and prevent several chronic diseases. In this study, we designed, synthesized and analyzed a water-soluble molecule presenting a good antioxidant activity, namely catechol hydrazinyl-thiazole (CHT). This molecule contains 3',4'-dihydroxyphenyl and 2-hydrazinyl-4-methyl-thiazole moieties linked through a hydrazone group with very good antioxidant activity in the in vitro evaluations performed. A preliminary validation of the CHT developing hypothesis was performed evaluating in silico the bond dissociation enthalpy (BDE) of the phenol O-H bonds, compared to our previous findings in the compounds previously reported by our group. In this paper, we report the binding mechanism of CHT to human serum albumin (HSA) using biophysical methods in combination with computational studies. ITC experiments reveal that the dominant forces in the binding mechanism are involved in the hydrogen bond or van der Waals interactions and that the binding was an enthalpy-driven process. NMR relaxation measurements were applied to study the CHT-protein interaction by changing the drug concentration in the solution. A molecular docking study added an additional insight to the experimental ITC and NMR analysis regarding the binding conformation of CHT to HSA.

Real-world evidence on the use of a fixed-ratio combination of insulin glargine and lixisenatide (iGlarLixi) in people with suboptimally controlled type 2 diabetes in Romania: a prospective cohort study (STAR.Ro).

OBJECTIVES: To assess the effectiveness and safety of insulin glargine and lixisenatide (iGlarLixi) fixed-ratio combination on a cohort of Romanian adults with type 2 diabetes (T2D). DESIGN: Open-label, 24-week, prospective cohort study. SETTING: 65 secondary care diabetes centres in Romania. PARTICIPANTS: The study included 901 adults with T2D suboptimally controlled with previous oral antidiabetic drugs (OADs)±basal insulin (BI) who initiated treatment with iGlarLixi upon the decision of the investigator. Major exclusion criteria were iGlarLixi contraindications and refusal to participate. 876 subjects received at least one dose of iGlarLixi (intention-to-treat/safety population). PRIMARY AND SECONDARY OUTCOME MEASURES: The primary endpoint was change in glycated haemoglobin (HbA1c) from baseline to week 24 in the modified intention-to-treat population (study participants with HbA1c available at baseline and week 24). Secondary efficacy outcomes were percentage of participants reaching HbA1c targets and change in fasting plasma glucose (FPG). RESULTS: Mean baseline HbA1c was 9.2% (SD 1.4) and FPG was 10.8 mmol/L (2.9). Mean HbA1c change was -1.3% (95% CI: -1.4% to -1.2%, p<0.0001) at week 24. HbA1c levels ≤6.5%, <7% and<7.5% at week 24 were achieved by 72 (8.9%), 183 (22.6%) and 342 (42.3%) participants, respectively. Mean FPG change was -3.1 mmol/L (95% CI: -3.3 to -2.8, p<0.001) at week 24. Mean body weight change was -1.6 kg (95% CI: -1.9 to -1.3, p<0.001) at 24 weeks. Mean iGlarLixi dose increased from 19.5 U (SD 7.7) and 30.1 U (10.0) to 30.2 U (8.9) (ratio 2/1 pen) and 45.0 U (11.6) (ratio 3/1 pen). Adverse events (AEs) were reported by 43 (4.9%) participants (18 (2.1%) gastrointestinal) with 4 (0.5%) reporting serious AEs. 13 (1.5%) participants reported at least one event of symptomatic hypoglycaemia, with one episode of severe hypoglycaemia reported. CONCLUSIONS: In a real-world setting, 24-week treatment with iGlarLixi provided a significant reduction of HbA1c with body weight loss and low hypoglycaemia risk in T2D suboptimally controlled with OADs±BI treatment.

Electrochemotherapy and Other Clinical Applications of Electroporation for the Targeted Therapy of Metastatic Melanoma.

Electrochemotherapy (ECT) is an effective bioelectrochemical procedure that uses controlled electrical pulses to facilitate the increase of intracellular concentration of certain substances (electropermeabilization/ reversible electroporation). ECT using antitumor drugs such as bleomycin and cisplatin is a minimally invasive targeted therapy that can be used as an alternative for oncologic patients not eligible for surgery or other standard therapies. Even though ECT is mainly applied as palliative care for metastases, it may also be used for primary tumors that are unresectable due to size and location. Skin neoplasms are the main clinical indication of ECT, the procedure reporting good curative results and high efficiency across all tumor types, including melanoma. In daily practice, there are many cases in which the patient's quality of life can be significantly improved by a safe procedure such as ECT. Its popularity must be increased because it has a safe profile and minor local adverse reactions. The method can be used by dermatologists, oncologists, and surgeons. The aim of this paper is to review recent literature concerning electrochemotherapy and other clinical applications of electroporation for the targeted therapy of metastatic melanoma.

Self-Reported Satisfaction to Treatment, Quality of Life and General Health of Type 2 Diabetes Patients with Inadequate Glycemic Control from North-Eastern Romania.

Type 2 diabetes mellitus (T2DM) undermines health and quality of life (QoL). This cross-sectional study surveyed 138 consenting T2DM patients from North-Eastern Romania with regard to their satisfaction with treatment, diabetes-related impact on QoL, and general health. The Romanian versions of Diabetes Treatment Satisfaction Questionnaire (DTSQ), Audit of Diabetes Dependent Quality of Life (ADDQoL-19), and 36-Item Short Form Health Survey (SF-36) questionnaires were used. Self-reports were analyzed in conjunction with clinical and metabolic profiling. The patients were 57.86 ± 8.82 years old, 49.3% men, treated with oral glucose-lowering drugs, presenting with inadequate glycemic control but without cardiovascular manifestations. The mean DTSQ and ADDQoL scores were 25.46 ± 0.61 and -2.22 ± 1.2, respectively. Freedom to eat, holidays, journeys, leisure, physical health, sex life, freedom to drink, and feelings about the future scored below average. The mean SF-36 physical and mental health scores were 47.78 ± 1.03 and 50.44 ± 1.38, respectively. The mean SF-6D score was 0.59 ± 0.04 (generated retrospectively using SF-36 data). Negative associations were significant between ADDQoL, age (r = -0.16), and body mass index (r = -0.23), p < 0.01. Overall scores did not correlate with diabetes duration (except DTSQ, r = -1.18, p = 0.02) or HbA1c. The results confirm other researchers' findings in Europe and nearby countries. Our patients seemed satisfied with treatment despite glycemic imbalance and viewed diabetes as a burden on QoL and especially freedom to eat.

Expert Opinion on the Therapeutic Use of the Fixed-Ratio Combination of Insulin Glargine 100 U/mL and Lixisenatide: a Central/Eastern European Perspective.

The fixed-ratio combination (FRC) of a basal insulin and a GLP-1 receptor agonist (GLP-1 RA) has proven to be an effective therapeutic approach. However, physicians face numerous practical questions that cannot be answered by recently published trial results, current guidelines and summaries of product characteristics. In April 2019, a scientific meeting was held with the participation of nine experts from four Central and Eastern European countries to provide expert consensus on the optimal daily use of the insulin glargine and lixisenatide FRC (iGlarLixi). Topics included the positioning and initiation of iGlarLixi and the management of treatment. This paper summarizes the outcomes of the meeting.

Study of the binding affinity between imatinib and α-1 glycoprotein using nuclear spin relaxation and isothermal titration calorimetry.

Imatinib is a selective tyrosine kinase inhibitor, successfully used for the treatment of chronic myelogenous leukaemia and gastrointestinal stromal tumors. Binding of drugs to proteins influence their pharmacokinetic and pharmacodynamics action. In the blood, the drug is distributed in the body in the free form or bound to plasma protein. Albumin and α-1 glycoprotein (AGP) are plasma proteins with the highest affinity for drug substances. Drugs which are weak acids mainly bind to plasma albumin, while drugs that are bases have affinity for α-1 glycoprotein. The main goal of this study is to quantitatively evaluate the interaction between imatinib mesylate (IMT) and α-1 glycoprotein to characterize the nature and forces underlying the formation of a molecular complex. Relaxation experiments provide quantitative information about the relationship between the binding affinity and structure of IMT. Thus, association constant was determined as Ka = 873.36 M-1. The ITC data revealed that the binding was an entropy driven process and the association constant Ka = 3.22 × 103 M-1, with a 1:1 stoichiometry. The results obtained by NMR and ITC were complemented with a molecular docking study.

Association of Antihyperglycemic Therapy with Risk of Atrial Fibrillation and Stroke in Diabetic Patients.

Type 2 diabetes mellitus (DM) is associated with an increased risk of cardiovascular disease (CVD). Atrial fibrillation (AF) and stroke are both forms of CVD that have major consequences in terms of disabilities and death among patients with diabetes; however, they are less present in the preoccupations of scientific researchers as a primary endpoint of clinical trials. Several publications have found DM to be associated with a higher risk for both AF and stroke; some of the main drugs used for glycemic control have been found to carry either increased, or decreased risks for AF or for stroke in DM patients. Given the risk for thromboembolic cerebrovascular events seen in AF patients, the question arises as to whether stroke and AF occurring with modified incidences in diabetic individuals under therapy with various classes of antihyperglycemic medications are interrelated and should be considered as a whole. At present, the medical literature lacks studies specifically designed to investigate a cause-effect relationship between the incidences of AF and stroke driven by different antidiabetic agents. In default of such proof, we reviewed the existing evidence correlating the major classes of glucose-controlling drugs with their associated risks for AF and stroke; however, supplementary proof is needed to explore a hypothetically causal relationship between these two, both of which display peculiar features in the setting of specific drug therapies for glycemic control.

Left Ventricular Diastolic Dysfunction in Type 2 Diabetes-Progress and Perspectives.

In-depth understanding of early cardiovascular manifestations in diabetes is high on international research and prevention agendas given that cardiovascular events are the leading cause of death for diabetic patients. Our aim was to review recent developments in the echocardiographic assessment of left ventricular diastolic dysfunction (LVDD) as a telltale pre-clinical disturbance preceding diabetic cardiomyopathy. We analyzed papers in which patients had been comprehensively assessed echocardiographically according to the latest LVDD guidelines (2016), and those affording comparisons with previous, widely used recommendations (2009). We found that the updated algorithm for LVDD is more effective in predicting adverse cardiovascular events in patients with established LVDD, and less specific in grading other patients (labelled "indeterminate"). This may prove instrumental for recruiting "indeterminate" LVDD cases among patients with type 2 diabetes mellitus (T2DM) in future screening programs. As an interesting consideration, the elevated values of the index E/e' can point to early diastolic impairment, foretelling diabetic cardiomyopathy. Identifying subclinical signs early makes clinical sense, but the complex nature of T2DM calls for further research. Specifically, longitudinal studies on rigorously selected cohorts of diabetic patients are needed to better understand and predict the subtle, slow onset of cardiac manifestations with T2DM as a complicating backdrop.

Concentrations of Lead, Mercury, Arsenic, Cadmium, Manganese, and Aluminum in Blood of Romanian Children Suspected of Having Autism Spectrum Disorder.

Environmental exposure to lead (Pb), mercury (Hg), arsenic (As), cadmium (Cd), manganese (Mn), and aluminum (Al) has been associated with neurodevelopmental disorders including autism spectrum disorder (ASD). We conducted a pilot study during May 2015-May 2107 to estimate blood concentrations of six metals (Pb, Hg, As, Cd, Mn, and Al) and identify their associated factors for children with ASD or suspected of having ASD in Romania. Sixty children, age 2-8 years, were administered versions of ADOS or ADI-R translated from English to Romanian. After assessment, 2-3 mL of blood was obtained and analyzed for the concentrations of the six metals. The mean age of children was 51.9 months and about 90% were male. More than half (65%) of the children were born in Bucharest. Over 90% of concentrations of As and Cd were below limits of detection. Geometric mean concentrations of Pb, Mn, Al, and Hg were 1.14 µg/dL, 10.84 µg/L, 14.44 µg/L, and 0.35 µg/L, respectively. Multivariable linear regression analysis revealed that children who were female, had less educated parents, exhibited pica, and ate cold breakfast (e.g., cereal), watermelon, and lamb had significantly higher concentrations of Pb compared to their respective referent categories (all p < 0.05 except for eating lamb, which was marginally significant, p = 0.053). Although this is the first study that provides data on concentrations of the six metals for Romanian children with ASD, the findings from this study could be useful for designing future epidemiologic studies for investigating the role of these six metals in ASD in Romanian children.

The Mediterranean Diet: From an Environment-Driven Food Culture to an Emerging Medical Prescription.

The Mediterranean diet originates in the food cultures of ancient civilizations which developed around the Mediterranean Basin and is based on the regular consumption of olive oil (as the main source of added fat), plant foods (cereals, fruits, vegetables, legumes, tree nuts, and seeds), the moderate consumption of fish, seafood, and dairy, and low-to-moderate alcohol (mostly red wine) intake, balanced by a comparatively limited use of red meat and other meat products. A few decades ago, the Mediterranean diet drew the attention of medical professionals by proving extended health benefits. The first reports ascertained cardiovascular protection, as multiple large-scale clinical studies, starting with Ancel Keys' Seven Countries Study, showed a marked reduction of atherosclerotic clinical events in populations with a Mediterranean dietary pattern. Ensuing trials confirmed favorable influences on the risk for metabolic syndrome, obesity, type 2 diabetes mellitus, cancer, and neurodegenerative diseases. While its health benefits are universally recognized today by medical professionals, the present state of the Mediterranean diet is challenged by major difficulties in implementing this protective dietary pattern in other geographical and cultural areas and keeping it alive in traditional Mediterranean territories, also tainted by the unhealthy eating habits brought by worldwide acculturation.

Bidirectional Relationship between Gastric Emptying and Plasma Glucose Control in Normoglycemic Individuals and Diabetic Patients.

Gastric emptying and glycemic control pathways are closely interrelated processes. Gastric chyme is transferred into the duodenum with velocities depending on its solid or liquid state, as well as on its caloric and nutritional composition. Once nutrients enter the intestine, the secretion of incretins (hormonal products of intestinal cells) is stimulated. Among incretins, glucagon-like peptide-1 (GLP-1) has multiple glycemic-regulatory effects that include delayed gastric emptying, thus triggering a feedback loop lowering postprandial serum glucose levels. Glycemic values also influence gastric emptying; hyperglycemia slows it down, and hypoglycemia accelerates it, both limiting glycemic fluctuations. Disordered gastric emptying in diabetes mellitus is understood today as a complex pathophysiological condition, with both irreversible and reversible components and high intra- and interindividual variability of time span and clinical features. While limited delays may be useful for reducing postprandial hyperglycemias, severely hindered gastric emptying may be associated with higher glycemic variability and worsened long-term glycemic control. Therapeutic approaches for both gastric emptying and glycemic control include dietary modifications of meal structure or content and drugs acting as GLP-1 receptor agonists. In the foreseeable future, we will probably witness a wider range of dietary interventions and more incretin-based medications used for restoring both gastric emptying and glycemic levels to nearly physiological levels.

Calorimetric and spectroscopic studies of the interaction between zidovudine and human serum albumin.

A quantitative analysis of the interaction between zidovudine (AZT) and human serum albumin (HSA) was achieved using Isothermal titration calorimetry (ITC) in combination with fluorescence and 1H NMR spectroscopy. ITC directly measure the heat during a biomolecular binding event and gave us thermodynamic parameters and the characteristic association constant. By fluorescence quenching, the binding parameters of AZT-HSA interaction was determined and location to binding site I of HSA was confirmed. Via T1 NMR selective relaxation time measurements the drug-protein binding extent was evaluated as dissociation constants Kd and the involvement of azido moiety of zidovudine in molecular complex formation was put in evidence. All three methods indicated a very weak binding interaction. The association constant determined by ITC (3.58×102M-1) is supported by fluorescence quenching data (2.74×102M-1). The thermodynamic signature indicates that at least hydrophobic and electrostatic type interactions played a main role in the binding process.