New Molecules in Type 2 Diabetes: Advancements, Challenges and Future Directions.

Although good glycemic control in patients with type 2 diabetes (T2D) can prevent cardiovascular complications, many diabetic patients still have poor optimal control. A new class of antidiabetic drugs (e.g., glucagon-like peptide-1-GLP-1 receptor agonists, sodium-glucose co-transporters-SGLT2 inhibitors), in addition to the low hypoglycemic effect, exert multiple beneficial effects at a metabolic and cardiovascular level, through mechanisms other than antihyperglycemic agents. This review aims to discuss the effects of these new antidiabetic drugs, highlighting cardiovascular and metabolic benefits, through the description of their action mechanisms as well as available data by preclinical and clinical studies. Moreover, new innovative tools in the T2D field will be described which may help to advance towards a better targeted T2D personalized care in future.

Lipidomic Analysis to Assess the Correlation between Ceramides, Stress Hyperglycemia, and HbA1c in Acute Myocardial Infarction.

Ceramides have been associated with cardiometabolic disease (e.g., acute myocardial infarction (AMI) and type 2 diabetes (T2D)) and adverse outcomes. Acute admission hyperglycemia (AH) is a transient glucose alteration in response to stress. As glycated hemoglobin (HbA1c) reflects the glycemia over a longer period of time, its use may be helpful in distinguishing between the AH and hyperglycemia associated with T2D in the AMI setting. The aim was to assess the correlation of ceramides with both AH (defined as an admission glucose level ≥140 mg/dL in the absence of T2D) and HbA1c-T2D and other demographic, clinical, and inflammatory-related biomarkers in AMI. High-performance liquid chromatography-tandem mass spectrometry was used to identify nine ceramide species, and their three ratios, in 140 AMI patients (FTGM coronary unit, Massa, Italy). The ceramides did not correlate with stress hyperglycemia, but specific species were elevated in T2D-AMI. Moreover, some ceramides were associated with other cardiometabolic risk factors. Ceramides assessment may be helpful in better understanding the pathogenic molecular mechanisms underlying myocardial acute events and cardiometabolic risk, as a basis for the future evaluation of their role as prognostic predictors and therapeutic targets in T2D-AMI patients.

Insulin resistance and cardiometabolic indexes: comparison of concordance in working-age subjects with overweight and obesity.

PURPOSE: The aim of the study was to evaluate indexes of insulin resistance and cardiometabolic risk in a large population of workers with overweight or obesity, in order to identify a possible efficient, cheap and simple strategy to apply in workers' health surveillance. METHODS: The evaluation of IR and cardiometabolic risk indexes (HOMA, QUICKI, Ty/HDLC, TyG, insuTAG, Castelli risk indexes 1 and 2, non-HDLC, TRL-C, AIP, and VAI) was performed in a population of 1195 working-age subjects with overweight or obesity (322 males, mean age 49 ± 11 years). RESULTS: The prevalence of IR and cardiometabolic risk was higher among males for all indexes. Aging, waist circumference, BMI, blood pressure, glucose, CRP, fibrinogen and uric acid were correlated more frequently with IR/cardiometabolic indexes in women, homocysteine in men. The percentage of the workers identified as insulin resistant (IR+) or at higher cardiometabolic risk greatly vary according to the different index used. CONCLUSION: With a small group of biomarkers and anthropometric measures (fasting glucose and insulin, lipid profile, BMI and waist circumference) is possible to calculate a number of IR/cardiometabolic indexes, which, likely reflecting different pathophysiological aspects also related to gender, might help in a personalized evaluation of IR and cardiometabolic risk. Graphical abstract.

Fear of COVID-19 in Patients with Acute Myocardial Infarction.

A marked decline in myocardial infarction (AMI) hospitalizations was observed worldwide during the COVID-19 outbreak. The pandemic may have generated fear and adverse psychological consequences in these patients, delaying hospital access. The main objective of the study was to assess COVID fear through the FCV-19S questionnaire (a self-report measure of seven items) in 69 AMI patients (65 ± 11 years, mean ± SD; 59 males). Females presented higher values of each FCV-19S item than males. Older subjects (>57 years, 25th percentile) showed a higher total score with respect to those in the first quartile. The percentage of patients who responded "agree" and "strongly agree" in item 4 ("I am afraid of losing my life because of the coronavirus") and 3 ("My hands become clammy when I think about the coronavirus") was significantly greater in the elderly than in younger patients. When cardiovascular (CV) patients were compared to a previously published general Italian population, patients with CV disease exhibited higher values for items 3 and 4. Measures should be put in place to assist vulnerable and high CV risk patients, possibly adding psychologists to the cardiology team.

Oxidative Stress Biomarkers in the Relationship between Type 2 Diabetes and Air Pollution.

The incidence and prevalence of type 2 diabetes have increased in the last decades and are expected to further grow in the coming years. Chronic hyperglycemia triggers free radical generation and causes increased oxidative stress, affecting a number of molecular mechanisms and cellular pathways, including the generation of advanced glycation end products, proinflammatory and procoagulant effects, induction of apoptosis, vascular smooth-muscle cell proliferation, endothelial and mitochondrial dysfunction, reduction of nitric oxide release, and activation of protein kinase C. Among type 2 diabetes determinants, many data have documented the adverse effects of environmental factors (e.g., air pollutants) through multiple exposure-induced mechanisms (e.g., systemic inflammation and oxidative stress, hypercoagulability, and endothelial and immune responses). Therefore, here we discuss the role of air pollution in oxidative stress-related damage to glycemic metabolism homeostasis, with a particular focus on its impact on health. In this context, the improvement of new advanced tools (e.g., omic techniques and the study of epigenetic changes) may provide a substantial contribution, helping in the evaluation of the individual in his biological totality, and offer a comprehensive assessment of the molecular, clinical, environmental, and epidemiological aspects.

"Acute Myocardial Infarction in the Time of COVID-19": A Review of Biological, Environmental, and Psychosocial Contributors.

Coronavirus disease 2019 (COVID-19) has quickly become a worldwide health crisis.Although respiratory disease remains the main cause of morbidity and mortality in COVID patients,myocardial damage is a common finding. Many possible biological pathways may explain therelationship between COVID-19 and acute myocardial infarction (AMI). Increased immune andinflammatory responses, and procoagulant profile have characterized COVID patients. All theseresponses may induce endothelial dysfunction, myocardial injury, plaque instability, and AMI.Disease severity and mortality are increased by cardiovascular comorbidities. Moreover, COVID-19has been associated with air pollution, which may also represent an AMI risk factor. Nonetheless,a significant reduction in patient admissions following containment initiatives has been observed,including for AMI. The reasons for this phenomenon are largely unknown, although a real decreasein the incidence of cardiac events seems highly improbable. Instead, patients likely may presentdelayed time from symptoms onset and subsequent referral to emergency departments because offear of possible in-hospital infection, and as such, may present more complications. Here, we aim todiscuss available evidence about all these factors in the complex relationship between COVID-19and AMI, with particular focus on psychological distress and the need to increase awareness ofischemic symptoms.

Hydrogen sulfide and cardiovascular disease: Doubts, clues, and interpretation difficulties from studies in geothermal areas.

Hydrogen sulfide (H2S) represents one of the main pollutants originating from both geologic phenomena such as volcanoes, geysers, fumaroles and hot springs, and geothermal plants that produce heat and electricity. Many increasing data suggest that H2S retains a variety of biological properties, and modulates many pathways related to cardiovascular pathophysiology although its role as beneficial/adverse determinant on cardiovascular disease (CVD) is not clearly established. In this review, the current knowledge on the association between H2S exposure and risk of CVD in geothermal areas has been examined. The few epidemiological studies carried out in geothermal areas suggest, in some cases, a protective role of H2S towards CVD, while in others a positive association between exposure to H2S and increased incidence of CVD. Most of the studies have an ecological design that does not allow to produce evidence to support a causal relationship and also often lack for an adequate adjustment for individual CVD risk factors. The review has also considered the potential role of two other aspects not sufficiently explored in this relationship: the production of endogenous H2S that is a gasotransmitter producing beneficial effects on cardiovascular function at low concentration and the intake of H2S-releasing drugs for the treatment of patients affected by hypertension, inflammatory diseases, and CVD. Thus, a threshold effect of H2S and the shift of action as beneficial/adverse determinant given by the synergy of exogenous exposure and endogenous production cannot be excluded. In this complex scenario, an effort is warranted in the future to include a more comprehensive evaluation of risk for CVD in relation to H2S emissions, especially in geothermal areas.

Low concordance between HbA1c and OGTT to diagnose prediabetes and diabetes in overweight or obesity.

BACKGROUND: Glycated haemoglobin (HbA1c) test, introduced for diagnosing prediabetes and diabetes by the American Diabetes Association for some years, is currently under extensive discussion for contradictory data on the concordance between this test and the oral glucose tolerance test (OGTT). HYPOTHESIS: To assess concordance between HbA1c and OGTT to diagnose prediabetes and diabetes in subjects with overweight or obesity, focusing on possible gender-related differences. METHODS: A total of 949 outpatients with overweight or obesity at risk for diabetes (mean age 50 ± 15 years; 660 F) were enrolled and underwent HbA1c test and OGTT. RESULTS: In both genders, HbA1c test identified more patients with prediabetes than OGTT (42% vs 22% in males, 40% vs 18% in females, respectively): a slight concordance between HbA1c and OGTT (60% of total tests in both genders). In subjects diagnosed by OGTT, post-OGTT insulin levels and HOMA INDEX were significantly higher than those found in HbA1c(+) cases. Instead, those diagnosed with HbA1c were significantly older and showed higher uric acid than those with both tests (-). CONCLUSIONS: HbA1c test and OGTT did not reach full concordance for the diagnosis of diabetes and prediabetes in both genders. The two tests likely reflect different physiopathological aspects of dysglycaemia, suggesting that the 'diagnostic thresholds' could be reconsidered in light of the discordance observed.

Undernutrition and Overnutrition Burden for Diseases in Developing Countries: The Role of Oxidative Stress Biomarkers to Assess Disease Risk and Interventional Strategies.

The increased life expectancy, urbanization, and unhealthy lifestyle characterized by a shift towards a sedentary lifestyle and decreased energy expenditure are considered the main drivers of epidemiological transition. In particular, developing countries are facing a double burden caused by coexisting under- and over-nutrition, which causes a change in the disease profile from infectious diseases to a chronic degenerative pattern. This review discusses the under- and over-nutrition context in Mauritania and India, two countries that are experiencing a nutritional transition, and where we began a collaboration with local medical staff to integrate interventional and diagnostic guidelines. If many studies about diet and its relationship to non-communicable diseases are available for India, very few nutrition and cardiovascular risk studies have been conducted in Mauritania. Presently, with the exponential increase of nutrition-related diseases, targeted approaches are needed to provide balanced diets in parallel with the development of national preventive health systems and screening programs adapted to local needs. In this context, the measurement of oxidative stress biomarkers could be promising as an additive tool to assess cardiovascular (CV) risk in general population, and ameliorating prevention in patients at CV risk or with overt CV disease. Moreover, the possibility of improving the outcome by the direct employment of antioxidant remains plausible. Moreover, studies on the content of antioxidant in different foods may be helpful to develop a balanced diet, and achieve the maximal nutritional and functional properties of cultivars with benefits for human health.

The prognostic impact of objective nutritional indices in elderly patients with ST-elevation myocardial infarction undergoing primary coronary intervention.

BACKGROUND: The prognostic impact of nutritional status in ST-elevation myocardial infarction (STEMI) patients is poorly understood. METHODS: We used the controlling nutritional status (CONUT) score and the prognostic nutritional index (PNI) score on outcomes of 945 patients with acute STEMI undergoing primary percutaneous coronary intervention with stent. RESULTS: During a median follow-up of 2years (1-3.3years, interquartile range), 56 patients (5.9%) died for all-cause of death. In the dead group, the CONUT and PNI scores were more severe than in the alive group. Elderly patients (≥71years) had nutritional indices more serious than patients <71years. In the whole population of the study, both CONUT and PNI correlated with clinical markers of poor prognosis such as brain natriuretic peptide (BNP), creatinine and liver enzymes. Kaplan-Meier curves revealed that the patients with severe CONUT but not patients with severe PNI index had the highest event rate for all-cause death, with a log-rank of p<0.001. The Cox proportional hazard analyses showed that, contrary to PNI score, the CONUT score was associated with increased risk of all-cause death for both unadjusted model and age- and sex-adjusted model, while in a full-adjusted model the best predictors were age and BNP. CONCLUSIONS: In STEMI patients, the nutritional status evaluated by the CONUT score, in addition to other comorbidities, can affect the prognosis in elderly patients. These results suggest a personalized nutritional treatment as well as an accurate assessment of the appropriateness of lipid-lowering treatment after coronary revascularization.

Low magnesium is not a significant predictor of hard events in acute myocardial infarction.

BACKGROUND: Although magnesium (Mg) has recognized cardioprotective properties and hypomagnesemia is common in patients with acute myocardial infarction (AMI), data regarding the role of Mg as prognostic factor for adverse events are scarce, as well as there are conflicting results on the use of Mg as adjuvant therapy in AMI. AIM: To evaluate the role of Mg as predictor for hard events (HE, all cause death, and nonfatal myocardial infarction) in AMI patients. DESIGN AND PATIENTS: We studied 406 AMI patients (306 males, age: 67 ± 12 years, mean ± SD). Patient data were collected from the Institute electronic databank which saves demographic, clinical, instrumental, therapeutical and follow-up data of all patients admitted to our Coronary Unit. RESULTS: During a mean follow-up period of 21 ± 18 months, the combined endpoint accounted for 63 HE, 44 (11%) deaths (35 cardiac deaths), 19 (5%) nonfatal MI. The multiple regression model identified glycemia as the only independent determinant of Mg in AMI pts. (T value = - 2.8, standard coefficient = - 0.15, p < 0.01). The Kaplan-Meier survival estimates failed to show a significantly worst outcome in patients presenting low Mg (< 0.783 mmol/L, 25th percentile). Aging (> 67 years-50th percentile), and ejection fraction (< 40%) remained as prognostic factors for HE in the adjusted Cox multivariate proportional hazard model (HR = 2.8, 95% CI = 1.6-5, p < 0.001; HR = 3.2, 95% CI = 1.9-5.3 p < 0.001, respectively). CONCLUSION: The present findings do not support a significant role of low Mg as predictor for HE in AMI.

Gender differences for uric acid as predictor of hard events in patients referred for coronary angiography.

AIM: To assess gender differences in uric acid (UA) as predictor for hard events (HE, mortality and nonfatal myocardial infarction) in a large cohort of patients referred for coronary angiography. Design & patients: 3020 inpatients (2177 males, age: 68 ± 9 years, mean ± SD) were retrospectively studied, collecting data from the Institute electronic databank which included demographic, clinical, instrumental and follow-up data. RESULTS: Although the Kaplan-Meier survival estimates showed a significantly worst outcome in female patients, high UA did not remained a significant predictor for HE after adjustment. Moreover, UA correlated with antioxidant capacity in both sexes. CONCLUSION: Hyperuricemia was not an independent risk for HE, and being correlated with antioxidant capacity, its elevation appears more likely compensatory than causative for HE.

Challenges of LADA Diagnosis and Treatment: Lessons From 2 Case Reports.

Latent autoimmune diabetes in adults (LADA) is a subtype of autoimmune diabetes, which shares characteristics of both Type 1 and 2 diabetes (T1D and T2D), and for this reason, it is often confused with other types of diabetes, misdiagnosed, and inappropriately treated. Two cases were presented (41-year-old and 50-year-old females), one occasionally diagnosed during routine health checkup, the other one identified as having T2D, and as far as misclassified and not optimally treated. Now, after approximately 9 months of LADA diagnosis, the first patient has an optimal metabolic control while maintaining the values of glycated hemoglobin to around 7% with small doses of analogue insulin (lispro 4-6 UI) before meals and long acting insulin (glargine 4-6 UI) at bedtime. The second patient, after approximately 2 years from the LADA diagnosis, has an optimal metabolic control, with maintenance of glycated hemoglobin to around 6.5%, and stable C-peptide level (around 1.5 ng/mL), only with dietary and exercise habits. To avoid misclassification, any patient who does not fit the typical T2D profile, or with poor glycemic control, and who does not follow the expected clinical course, as become insulin dependent sooner than expected, should be investigated to exclude LADA. To define the best therapeutic approach, each patient must be evaluated and therapy tailored on his/her specific profile, considering as very low insulin doses may be effective to maintain a successful metabolic control and the only dietary approach may be sufficient until the insulin-secretory capacity remains good.

The Mediterranean Lifestyle as a Non-Pharmacological and Natural Antioxidant for Healthy Aging.

Oxidative stress has been suggested to affect age-associated physiological dysfunction. Therefore, it is speculated that antioxidant supplements could have a potential role in preventing age-related diseases and death. Among different dietary habits, the highly antioxidant Mediterranean dietary pattern, which includes high vegetable and fruit intake, consumption of legumes, cereals, and fish, low intake of meat and dairy derivatives, moderate red wine consumption, and use of extra-virgin olive oil, is characterized by other aspects than food, such as conviviality, sensory stimulation, socialization, biodiversity, and seasonality that can reinforce the Mediterranean diet's (MeD) beneficial effects on wellbeing, quality of life, and healthy aging. The present review aims to discuss available data on the relationship between oxidative stress and aging, biomarkers of oxidative stress status, protective effects of the MeD, and the adoption of the Mediterranean lifestyle as a non-pharmacological and natural tool to cope with oxidative stress damage for a longer life span, and-even more important-healthy aging beyond the biological, psychological, and social challenges that old age entails.

Conventional insulin vs insulin infusion therapy in acute coronary syndrome diabetic patients.

AIM: To evaluate the impact on glucose variability (GLUCV) of an nurse-implemented insulin infusion protocol when compared with a conventional insulin treatment during the day-to-day clinical activity. METHODS: We enrolled 44 type 2 diabetic patients (n = 32 males; n = 12 females) with acute coronary syndrome (ACS) and randomy assigned to standard a subcutaneous insulin treatment (n = 23) or a nurse-implemented continuous intravenous insulin infusion protocol (n = 21). We utilized some parameters of GLUCV representing well-known surrogate markers of prognosis, i.e., glucose standard deviation (SD), the mean daily δ glucose (mean of daily difference between maximum and minimum glucose), and the coefficient of variation (CV) of glucose, expressed as percent glucose (SD)/glucose (mean). RESULTS: At the admission, first fasting blood glucose, pharmacological treatments (insulin and/or anti-diabetic drugs) prior to entering the study and basal glycated hemoglobin (HbA1c) were observed in the two groups treated with subcutaneous or intravenous insulin infusion, respectively. When compared with patients submitted to standard therapy, insulin-infused patients showed both increased first 24-h (median 6.9 mmol/L vs 5.7 mmol/L P < 0.045) and overall hospitalization δ glucose (median 10.9 mmol/L vs 9.3 mmol/L, P < 0.028), with a tendency to a significant increase in first 24-h glycaemic CV (23.1% vs 19.6%, P < 0.053). Severe hypoglycaemia was rare (14.3%), and it was observed only in 3 patients receiving insulin infusion therapy. HbA1c values measured during hospitalization and 3 mo after discharge did not differ in the two groups of treatment. CONCLUSION: Our pilot data suggest that no real benefit in terms of GLUCV is observed when routinely managing blood glucose by insulin infusion therapy in type 2 diabetic ACS hospitalized patients in respect to conventional insulin treatment.

Early impairment of beta-cell function and insulin sensitivity characterizes normotolerant Caucasian women with previous gestational diabetes.

BACKGROUND AND AIMS: Women with previous gestational diabetes (pGDM) are at high risk of developing type 2 diabetes mellitus. The aim of this study was to evaluate insulin action and insulin secretion in women with pGDM. METHODS AND RESULTS: One hundred and fifty-three pGDM women and 45 with normal glucose tolerance during pregnancy (controls) were studied 1-3years after delivery. Insulin sensitivity (ISI) and beta-cell secretory capacity (beta-index) were derived from 75-g OGTT. Disposition Index was calculated as the product of beta-index and ISI. One hundred and twenty-two pGDM were normotolerant (NGT) and 31 had impaired glucose regulation (IGR) i.e. impaired glucose tolerance and/or impaired fasting glucose. NGT-pGDM, as compared to controls, had significant impairment in insulin action (ISI: 5.46+/-2.81 vs. 7.38+/-3.68, P<0.01) and insulin secretion (beta-index: 4.68+/-1.01 vs. 5.24+/-0.82 pmol/min/m(2); P<0.01). A further impairment was apparent in IGR-pGDM for beta-index (4.16+/-1.09; P<0.05). The disposition index was reduced in NGT-pGDM as compared to controls (33.9%) and further reduced in IGR-pGDM (28.6%, vs. NGT-pGDM; ANOVA P<0.001). In women of normal weight, ISI and beta-index were significantly (P<0.01) impaired in NGT-pGDM compared to controls and further reduced in IGR-pGDM, although a more pronounced defect in insulin secretion was apparent in these women (beta-index: 4.02+/-0.9; P<0.05). CONCLUSIONS: Normotolerant women with pGDM show both impairment in insulin secretion and action irrespective of body weight. A more pronounced defect in insulin secretion seems to characterize normal weight women while a more prominent defect in insulin action is found in overweight women.