The classic description of diabetic kidney disease (DKD) involves progressive stages of glomerular hyperfiltration, microalbuminuria, proteinuria, and a decline in the estimated glomerular filtration rate (eGFR), leading to dialysis. In recent years, this concept has been increasingly challenged as evidence suggests that DKD presents more heterogeneously. Large studies have revealed that eGFR decline may also occur independently from the development of albuminuria. This concept led to the identification of a new DKD phenotype: non-albuminuric DKD (eGFR < 60 mL/min/1.73 m², absence of albuminuria), whose pathogenesis is still unknown. However, various hypotheses have been formulated, the most likely of which is the acute kidney injury-to-chronic kidney disease (CKD) transition, with prevalent tubular, rather than glomerular, damage (typically described in albuminuric DKD). Moreover, it is still debated which phenotype is associated with a higher cardiovascular risk, due to contrasting results available in the literature. Finally, much evidence has accumulated on the various classes of drugs with beneficial effects on DKD; however, there is a lack of studies analyzing the different effects of drugs on the various phenotypes of DKD. For this reason, there are still no specific guidelines for therapy in one phenotype rather than the other, generically referring to diabetic patients with CKD.

Non-alcoholic fatty liver disease (NAFLD) is the most common hepatic pathology in industrialized countries, affecting about 25% of the general population. NAFLD is a benign condition, however, it could evolve toward more serious diseases, including non-alcoholic steatohepatitis (NASH), fibrosis, cirrhosis, and finally, hepatocellular carcinoma (HCC). Liver biopsy is still the gold standard for NAFLD diagnosis. Due to the risks associated with liver biopsy and the impossibility to apply it on a large scale, it is now necessary to identify non-invasive biomarkers, which may reliably identify patients at higher risk of progression. Therefore, several lines of research have tried to address this issue by identifying novel biomarkers using omics approaches, including lipidomics, metabolomics and RNA molecules’ profiling. Thus, in this review, we firstly report the conventional biomarkers used in clinical practice for NAFL and NASH diagnosis as well as fibrosis staging, and secondly, we pay attention to novel biomarkers discovered through omics approaches with a particular focus on RNA biomarkers (microRNAs, long-noncoding RNAs), showing promising diagnostic performance for NAFL/NASH diagnosis and fibrosis staging.

Statins are a class of drugs widely prescribed as frontline therapy for lowering plasma LDL-cholesterol in cardiovascular risk prevention. Several clinical reports have recently suggested an increased risk of type 2 diabetes associated with chronic use of these drugs. The pathophysiology of this effect remains to be fully elucidated but impaired β-cell function constitutes a potential mechanism. The aim of this study was to explore the effect of a chronic treatment with lipophilic and hydrophilic statins on β-cell function, using human pancreatic islets and rat insulin-secreting INS-1 cells; we particularly focused on the role of mitochondria and oxidative stress. The present study demonstrates, for the first time, that atorvastatin (lipophilic) but not pravastatin (hydrophilic) affected insulin release and mitochondrial metabolism due to the suppression of antioxidant defense system and induction of ROS production in pancreatic β-cell models. Mevalonate addition and treatment with a specific antioxidant (N-AcetylCysteine) effectively reversed the observed defects. These data demonstrate that mitochondrial oxidative stress is a key element in the pathogenesis of statin-related diabetes and may have clinical relevance to design strategies for prevention or reduction of statin induced β-cell dysfunction and diabetes in patients treated with lipophilic statins.

Context: Prediabetes is associated with atherosclerotic vascular damage. Objective: We investigated the correlation of endogenous secretory receptor for advanced glycation end-products (esRAGE), total soluble RAGE (sRAGE) and markers of inflammation, with early cardiovascular disease in subjects with prediabetes. We particularly focused on individuals with prediabetes identified only by glycated hemoglobin A1c (HbA1c) (5.7–6.4%) who had normal fasting glucose and were normotolerant after oral glucose tolerance test. Design: This was a cross-sectional study. Setting: The study was conducted in the Department of Clinical and Molecular Medicine, University of Catania, Italy. Main Outcome Measure: sRAGE, esRAGE, carboxymethyl-lysine, S100A12, HbA1c, fasting glycemia, oral glucose tolerance test, pulse wave velocity, and intima-media thickness were evaluated in subjects with prediabetes. Patients: Three hundred eighty subjects without previous history of diabetes were stratified into three groups: controls (n = 99), prediabetes (n = 220), and new-onset type 2 diabetes (n = 61). Results: Subjects with prediabetes exhibited the following: lower esRAGE (0.29 ± 0.18 vs 0.45 ± 0.26 ng/mL; P < .05) and higher S100A12 levels than controls. RT-PCR analysis in mononuclear cells revealed that the mRNA expression level of the esRAGE splice variant progressively decreased in patients with prediabetes and type 2 diabetes with respect to controls. No difference was observed in sRAGE and carboxymethyl-lysine plasma levels between the groups. After multiple regression analyses, only age, HbA1c, and hs-CRP were independently associated with esRAGE levels. Age, HbA1c, and esRAGE were the major determinants of intima-media thickness, whereas S100A12 and systolic blood pressure were the major determinants of pulse wave velocity. When we analyzed the subjects with HbA1c prediabetes (normal fasting glucose/normotolerant and HbA1c 5.7–6.4%), esRAGE and inflammatory markers plasma levels still remained significantly different in respect to controls. Conclusions: Subjects with HbA1c prediabetes exhibited significantly reduced esRAGE levels and increased levels of markers of inflammation. These alterations are associated with early markers of cardiovascular disease.

Incretin therapies, which are used to treat diabetic patients, cause a chronic supra-physiological increase in GLP-1 circulating levels. It is still unclear how the resulting high hormone concentrations may affect pancreatic alpha cells. The present study was designed to investigate the effects of chronic exposure to high GLP-1 levels on a cultured pancreatic alpha cell line. α-TC1-6 cell line was cultured in the presence or absence of GLP-1 (100 nmol/l) for up to 72 h. In our model GLP-1 receptor (GLP-1R) was measured. After the cells were exposed to GLP-1 the levels of glucagon secretion were measured. Because GLP-1 acts on intracellular cAMP production, the function of GLP-1R was studied. We also investigated the effects of chronic GLP-1 exposure on the cAMP/MAPK pathway, Pax6 levels, the expression of prohormone convertases (PCs), glucagon gene (Gcg) and protein expression, glucagon and GLP-1 production. In our model, we were able to detect GLP-1R. After GLP-1 exposure we found a reduction in glucagon secretion. During further investigation of the function of GLP-1R, we found an activation of the cAMP/MAPK/Pax6 pathway and an increase of Gcg gene and protein expression. Furthermore we observed a significant increase in PC1/3 protein expression, GLP-1 intracellular content and GLP-1 secretion. Our data indicate that the chronic exposure of pancreatic alpha cells to GLP-1 increases the ability of these cells to produce and release GLP-1. This phenomenon occurs through the stimulation of the transcription factor Pax6 and the increased expression of the protein convertase PC1/3.