Sodium-glucose co-transporter 2 (SGLT2) inhibitors block glucose reabsorption in the renal proximal tubule, an insulin-independent mechanism that plays a critical role in glycemic regulation in diabetes. In addition to their glucose-lowering effects, SGLT2 inhibitors prevent both renal damage and the onset of chronic kidney disease and cardiovascular events, in particular heart failure with both reduced and preserved ejection fraction. These unexpected benefits prompted changes in treatment guidelines and scientific interest in the underlying mechanisms. Aside from the target effects of SGLT2 inhibition, a wide spectrum of beneficial actions is described for the kidney and the heart, even though the cardiac tissue does not express SGLT2 channels. Correction of cardiorenal risk factors, metabolic adjustments ameliorating myocardial substrate utilization, and optimization of ventricular loading conditions through effects on diuresis, natriuresis, and vascular function appear to be the main underlying mechanisms for the observed cardiorenal protection. Additional clinical advantages associated with using SGLT2 inhibitors are antifibrotic effects due to correction of inflammation and oxidative stress, modulation of mitochondrial function, and autophagy. Much research is required to understand the numerous and complex pathways involved in SGLT2 inhibition. This review summarizes the current known mechanisms of SGLT2-mediated cardiorenal protection.

To date, non-alcoholic fatty liver disease (NAFLD) is the most frequent liver disease, affecting up to 70% of patients with diabetes. Currently, there are no specific drugs available for its treatment. Beyond their anti-hyperglycemic effect and the surprising role of cardio- and nephroprotection, GLP-1 receptor agonists (GLP-1 RAs) have shown a significant impact on body weight and clinical, biochemical and histological markers of fatty liver and fibrosis in patients with NAFLD. Therefore, GLP-1 RAs could be a weapon for the treatment of both diabetes mellitus and NAFLD. The aim of this review is to summarize the evidence currently available on the role of GLP-1 RAs in the treatment of NAFLD and to hypothesize potential future scenarios.

Diabetic neuropathy (DN) is one of the main microvascular complications of both type 1 and type 2 diabetes mellitus. Sometimes, this could already be present at the time of diagnosis for type 2 diabetes mellitus (T2DM), while it appears in subjects with type 1 diabetes mellitus (T1DM) almost 10 years after the onset of the disease. The impairment can involve both somatic fibers of the peripheral nervous system, with sensory-motor manifestations, as well as the autonomic system, with neurovegetative multiorgan manifestations through an impairment of sympathetic/parasympathetic conduction. It seems that, both indirectly and directly, the hyperglycemic state and oxygen delivery reduction through the vasa nervorum can determine inflammatory damage, which in turn is responsible for the alteration of the activity of the nerves. The symptoms and signs are therefore various, although symmetrical painful somatic neuropathy at the level of the lower limbs seems the most frequent manifestation. The pathophysiological aspects underlying the onset and progression of DN are not entirely clear. The purpose of this review is to shed light on the most recent discoveries in the pathophysiological and diagnostic fields concerning this complex and frequent complication of diabetes mellitus.

Background. Evidence has shown a close association between COVID-19 infection and renal complications in both individuals with previously normal renal function and those with chronic kidney disease (CKD). Methods. The aim of this study is to evaluate the in-hospital mortality of SARS-CoV-2 patients according to their clinical history of CKD or estimated glomerular filtration rate (eGFR). This is a prospective multicenter observational cohort study which involved adult patients (≥18 years old) who tested positive with SARS-CoV-2 infection and completed their hospitalization in the period between November 2020 and June 2021. Results. 1246 patients were included in the study, with a mean age of 64 years (SD 14.6) and a median duration of hospitalization of 15 days (IQR 9–22 days). Cox’s multivariable regression model revealed that mortality risk was strongly associated with the stage of renal impairment and the Kaplan–Meier survival analysis showed a progressive and statistically significant difference (p < 0.0001) in mortality according to the stage of CKD. Conclusion. This study further validates the association between CKD stage at admission and mortality in patients hospitalized for COVID-19. The risk stratification based on eGFR allows clinicians to identify the subjects with the highest risk of intra-hospital mortality despite the duration of hospitalization.

Cardiac hypertrophy develops in response to increased workload to reduce ventricular wall stress and maintain function and efficiency. Pathological hypertrophy can be adaptive at the beginning. However, if the stimulus persists, it may progress to ventricular chamber dilatation, contractile dysfunction, and heart failure, resulting in poorer outcome and increased social burden. The main pathophysiological mechanisms of pathological hypertrophy are cell death, fibrosis, mitochondrial dysfunction, dysregulation of Ca 2+ -handling proteins, metabolic changes, fetal gene expression reactivation, impaired protein and mitochondrial quality control, altered sarcomere structure, and inadequate angiogenesis. Diabetic cardiomyopathy is a condition in which cardiac pathological hypertrophy mainly develop due to insulin resistance and subsequent hyperglycaemia, associated with altered fatty acid metabolism, altered calcium homeostasis and inflammation. In this review, we summarize the underlying molecular mechanisms of pathological hypertrophy development and progression, which can be applied in the development of future novel therapeutic strategies in both reversal and prevention.