messa a punto di un metodo per la valutazione delle proprieta antiossidanti delle HDL

Le HDL –lipoproteine ad alta densità- presentano numerose funzioni ateroprotettive, tra le quali spiccano le proprietà antiossidanti; in alcune condizioni patologiche la loro funzionalità fisiologica può essere ridotta, indipendentemente dalle concentrazioni di colesterolo HDL, e questa disfunzionalità delle HDL può condurre ad un più rapido e importante sviluppo di aterosclerosi. Al fine di stimare il rischio cardiovascolare globale, molto più importante rispetto alle concentrazioni di colesterolo HDL risulta perciò la misurazione della loro funzionalità, per cui la ricerca sulle HDL attualmente è diretta principalmente alla messa a punto di metodi che permettano una stima delle funzioni biologiche di queste lipoproteine. Con questo lavoro di tesi è stato messo a punto un metodo biochimico fluorimetrico per la quantificazione delle proprietà antiossidanti delle HDL, rivalutando e migliorando passaggio per passaggio il metodo originale, il quale risultava non convincente; l’efficacia del nuovo metodo è stata validata con dati preliminari di 109 pazienti appartenenti allo studio europeo SUMMIT, con risultati incoraggianti in vista di una futura validazione con casistiche più numerose

Impact of empagliflozin on subclinical left ventricular dysfunctions and on the mechanisms involved in myocardial disease progression in type 2 diabetes: rationale and design of the EMPA-HEART trial.

BACKGROUND: Asymptomatic left ventricular (LV) dysfunction is highly prevalent in type 2 diabetes patients. Unlike the other hypoglycemic drugs, SGLT2 inhibitors have shown potential benefits for reducing cardiovascular death and risk factors, aside from lowering plasma glucose levels. With this study we aim at determining whether the treatment with empagliflozin is associated with an improvement in LV functions in diabetic patients with asymptomatic LV dysfunction against Sitagliptin, which is presumably neutral on myocardial function. To determine changes in LV systolic and diastolic functions we will use speckle-tracking echocardiography, a novel sensitive, non-invasive, bedside method allowing the calculation of LV global longitudinal strain (GLS), an index of myocardial deformability, as well as 3D echocardiography, which allows a better evaluation of LV volumes and mass. METHODS: The EMPA-HEART trial will be a phase III, open label, active-controlled, parallel groups, single centre, exploratory study conducted in Pisa, Italy. A cohort of 75 diabetic patients with normal LV systolic (2D-Echo EF > 50%) and renal (eGFR sec MDRD > 60 ml/min/1.73 mq) functions and no evidence of valvular and/or ischemic heart disease will be randomized to either Empagliflozin 10 mg/die or Sitagliptin 100 mg/die. The primary outcome is to detect a change in GLS from baseline to 1 and 6 months after treatment initiation. The secondary outcomes include changes from baseline to 6 months in 3-D Echocardiography EF, left atrial volume and E/E', VO2max as measured at cardiopulmonary test, cardiac autonomic function tests (R-R interval during Valsalva manoeuvre, deep-breathing, lying-to-standing), and the determination of a set of plasma biomarkers aimed at studying volume, inflammation, oxidative stress, matrix remodelling, myocyte strain and injury. DISCUSSION: SGLT2 inhibitors might affect myocardial functions through mechanisms acting both directly and indirectly on the myocardium. The set of instrumental and biohumoral tests of our study might actually detect the presence and entity of empagliflozin beneficial effects on the myocardium and shed light on the mechanisms involved. Further, this study might eventually provide information to design a clinical strategy, based on echocardiography and/or biomarkers, to select the patients who might benefit more from this intervention. Trial registration EUDRACT Code 2016-0022250-10

Early time-restricted carbohydrate consumption vs conventional dieting in type 2 diabetes: a randomised controlled trial

AIMS/HYPOTHESIS Early time-restricted carbohydrate consumption (eTRC) is a novel dietary strategy that involves restricting carbohydrate-rich food intake to the morning and early afternoon to align with circadian variations in glucose tolerance. We examined the efficacy, feasibility and safety of eTRC in individuals with type 2 diabetes under free-living conditions. METHODS In this randomised, parallel-arm, open label, controlled trial, participants with type 2 diabetes and overweight/obesity (age 67.2±7.9 years, 47.8% women, BMI 29.4±3.7 kg/m$^{2}$, HbA$_{1c}$ 49±5 mmol/mol [6.6±0.5%]) were randomised, using computer-generated random numbers, to a 12 week eTRC diet or a Mediterranean-style control diet with matched energy restriction and macronutrient distribution (50% carbohydrate, 30% fat and 20% protein). The primary outcome was the between-group difference in HbA$_{1c}$ at 12 weeks. Body composition, 14 day flash glucose monitoring and food diary analysis were performed every 4 weeks. Mixed meal tolerance tests with mathematical beta cell function modelling were performed at baseline and after 12 weeks. RESULTS Twelve (85.7%) participants in the eTRC arm and 11 (84.6%) participants in the control arm completed the study, achieving similar reductions in body weight and fat mass. The two groups experienced comparable improvements in HbA$_{1c}$ (-3 [-6, -0.3] mmol/mol vs -4 [-6, -2] mmol/mol, corresponding to -0.2 [-0.5, 0]% and -0.3 [-0.5, -0.1]%, respectively, p=0.386), fasting plasma glucose, flash glucose monitoring-derived glucose variability and mixed meal tolerance test-derived glucose tolerance, insulin resistance, insulin clearance and plasma glucagon levels, without changes in model-derived beta cell function parameters, glucagon-like peptide-1, glucose-dependent insulinotropic polypeptide and non-esterified fatty acid levels. The two diets similarly reduced liver function markers and triglyceride levels, being neutral on other cardiometabolic and safety variables. In exploratory analyses, diet-induced changes in body weight and glucometabolic variables were not related to the timing of carbohydrate intake. CONCLUSIONS/INTERPRETATION The proposed eTRC diet provides a feasible and effective alternative option for glucose and body weight management in individuals with type 2 diabetes, with no additional metabolic benefits compared with conventional dieting. TRIAL REGISTRATION ClinicalTrials.gov NCT05713058 FUNDING: This study was supported by the European Society for Clinical Nutrition and Metabolism (ESPEN) and the Italian Society of Diabetology (SID)

Impact of Nutrient Type and Sequence on Glucose Tolerance: Physiological Insights and Therapeutic Implications

Pharmacological and dietary interventions targeting postprandial glycemia have proved effective in reducing the risk for type 2 diabetes and its cardiovascular complications. Besides meal composition and size, the timing of macronutrient consumption during a meal has been recently recognized as a key regulator of postprandial glycemia. Emerging evidence suggests that premeal consumption of non-carbohydrate macronutrients (i.e., protein and fat “preloads”) can markedly reduce postprandial glycemia by delaying gastric emptying, enhancing glucose-stimulated insulin release, and decreasing insulin clearance. The same improvement in glucose tolerance is achievable by optimal timing of carbohydrate ingestion during a meal (i.e., carbohydrate-last meal patterns), which minimizes the risk of body weight gain when compared with nutrient preloads. The magnitude of the glucose-lowering effect of preload-based nutritional strategies is greater in type 2 diabetes than healthy subjects, being comparable and additive to current glucose-lowering drugs, and appears sustained over time. This dietary approach has also shown promising results in pathological conditions characterized by postprandial hyperglycemia in which available pharmacological options are limited or not cost-effective, such as type 1 diabetes, gestational diabetes, and impaired glucose tolerance. Therefore, preload-based nutritional strategies, either alone or in combination with pharmacological treatments, may offer a simple, effective, safe, and inexpensive tool for the prevention and management of postprandial hyperglycemia. Here, we survey these novel physiological insights and their therapeutic implications for patients with diabetes mellitus and altered glucose tolerance

Impact of acute changes of left ventricular contractility on the transvalvular impedance: validation study by pressure-volume loop analysis in healthy pigs

BACKGROUND: The real-time and continuous assessment of left ventricular (LV) myocardial contractility through an implanted device is a clinically relevant goal. Transvalvular impedance (TVI) is an impedentiometric signal detected in the right cardiac chambers that changes during stroke volume fluctuations in patients. However, the relationship between TVI signals and LV contractility has not been proven. We investigated whether TVI signals predict changes of LV inotropic state during clinically relevant loading and inotropic conditions in swine normal heart. METHODS: The assessment of RVTVI signals was performed in anesthetized adult healthy anesthetized pigs (n = 6) instrumented for measurement of aortic and LV pressure, dP/dtmax and LV volumes. Myocardial contractility was assessed with the slope (Ees) of the LV end systolic pressure-volume relationship. Effective arterial elastance (Ea) and stroke work (SW) were determined from the LV pressure-volume loops. Pigs were studied at rest (baseline), after transient mechanical preload reduction and afterload increase, after 10-min of low dose dobutamine infusion (LDDS, 10 ug/kg/min, i.v), and esmolol administration (ESMO, bolus of 500 µg and continuous infusion of 100 µg·kg-1·min-1). RESULTS: We detected a significant relationship between ESTVI and dP/dtmax during LDDS and ESMO administration. In addition, the fluctuations of ESTVI were significantly related to changes of the Ees during afterload increase, LDDS and ESMO infusion. CONCLUSIONS: ESTVI signal detected in right cardiac chamber is significantly affected by acute changes in cardiac mechanical activity and is able to predict acute changes of LV inotropic state in normal heart

Super-resolution with Toraldo pupils: analysis with electromagnetic numerical simulations

The concept of super-resolution refers to various methods for improving the angular resolution of an optical imaging system beyond the classical diffraction limit. In optical microscopy, several techniques have been developed with the aim of narrowing the central lobe of the illumination Point Spread Function (PSF). In Astronomy a few methods have been proposed to achieve reflector telescopes and antennas with resolution significantly better than the diffraction limit but, to our best knowledge, no working system is in operation. A possible practical approach consists of using the so-called "Toraldo Pupils" (TPs) or variable transmittance filters. These pupils were introduced by G. Toraldo di Francia in 1952,1 and consist of a series of discrete, concentric circular coronae providing specific optical transparency and dephasing in order to engineer the required PSF. The first successful laboratory test of TPs in the microwaves was achieved in 2003,2 and in the present work we build upon these initial measurements to perform electromagnetic (EM) numerical simulations of TPs, using a commercial full-wave software tool. These simulations were used to study various EM effects that can mask and/or affect the performance of the pupils and to analyze the near-field as well as the far-field response. Our EM analysis confirms that at 20 GHz the width of the central lobe in the far-field generated by a TP significantly decreases compared to a clear circular aperture with the same diameter

Disruption of fasting and post-load glucose homeostasis are largely independent and sustained by distinct and early major beta-cell function defects: a cross-sectional and longitudinal analysis of the relationship between insulin sensitivity and cardiovascular risk (RISC) study cohort

Background/aims: Uncertainty still exists on the earliest beta-cell defects at the bases of the type 2 diabetes. We assume that this depends on the inaccurate distinction between fasting and post-load glucose homeostasis and aim at providing a description of major beta-cell functions across the full physiologic spectrum of each condition. Methods: In 1320 non-diabetic individuals we performed an OGTT with insulin secretion modeling and a euglycemic insulin clamp, coupled in subgroups to glucose tracers and IVGTT; 1038 subjects underwent another OGTT after 3.5 years. Post-load glucose homeostasis was defined as mean plasma glucose above fasting levels (δOGTT). The analysis was performed by two-way ANCOVA. Results: Fasting plasma glucose (FPG) and δOGTT were weakly related variables (stβ = 0.12) as were their changes over time (r = −0.08). Disruption of FPG control was associated with an isolated and progressive decline (approaching 60%) of the sensitivity of the beta-cell to glucose values within the normal fasting range. Disruption of post-load glucose control was characterized by a progressive decline (approaching 60%) of the slope of the full beta-cell vs glucose dose-response curve and an early minor (30%) decline of potentiation. The acute dynamic beta-cell responses, neither per se nor in relation to the degree of insulin resistance appeared to play a relevant role in disruption of fasting or post-load homeostasis. Follow-up data qualitatively and quantitatively confirmed the results of the cross-sectional analysis. Conclusion: In normal subjects fasting and post-load glucose homeostasis are largely independent, and their disruption is sustained by different and specific beta-cell defects

Laboratory measurements of super-resolving Toraldo pupils for radio astronomical applications

The concept of super-resolution refers to various methods for improving the angular resolution of an optical imaging system beyond the classical diffraction limit. Although several techniques to narrow the central lobe of the illumination Point Spread Function have been developed in optical microscopy, most of these methods cannot be implemented on astronomical telescopes. A possible exception is represented by the variable transmittance filters, also known as "Toraldo Pupils" (TPs) since they were introduced for the first time by G. Toraldo di Francia in 1952 (Toraldo di Francia, Il Nuovo Cimento (Suppl.) 9, 426, 1952). In the microwave range, the first successful laboratory test of TPs was performed in 2003 (Mugnai et al. Phys. Lett. A 311, 77-81, 2003). These first results suggested that TPs could represent a viable approach to achieve super-resolution in Radio Astronomy. We have therefore started a project devoted to a more exhaustive analysis of TPs, in order to assess their potential usefulness to achieve super-resolution on a radio telescope, as well as to determine their drawbacks. In the present work we report on the results of extensive microwave measurements, using TPs with different geometrical shapes, which confirm the correctness of the first experiments in 2003. We have also extended the original investigation to carry out full-wave electromagnetic numerical simulations and also to perform planar scanning of the near-field and transform the results into the far-field