Type 2 diabetes mellitus (T2DM) is one of the most widespread diseases worldwide. Lifestyle interventions, including diet and physical activity (PA), are fundamental non-pharmacological components of T2DM therapy. Exercise interventions are strongly recommended for people with or at risk of developing or already with overt diabetes, but adherence to PA guidelines in this population is still challenging. Furthermore, the heterogeneity of T2DM patients, driven by differing residual β-cell functionality, as well as the possibility of practicing different types and intensities of PA, has led to the need to develop tailored exercise and training plans. Investigations on blood glucose variation in response to exercise could help to clarify why individuals do not respond in the same way to PA, and to guide the prescription of personalized treatments. The aim of this review is to offer an updated overview of the current evidence on the effects of different regimens and modalities of PA regarding glucose sensing and β-cell secretory dynamics in individuals with prediabetes or T2DM, with a special focus on β-cell function.

Omega-3 fatty acids reduce triglycerides and have several positive effects on different organs and systems. They are also found in the plasma membrane in variable amounts in relation to genetics and diet. However, it is still unclear whether omega-3 supplementation can reduce the occurrence of major cardiovascular events (MACEs). Two trials, REDUCE-IT (Reduction of Cardiovascular Events with Icosapent Ethyl-Intervention Trial), with highly purified EPA, and STRENGTH (Effect of High-Dose Omega-3 Fatty Acids vs. Corn Oil on Major Adverse Cardiovascular Events in Patients at High Cardiovascular Risk), with a combination of EPA and DHA, have produced different outcomes, triggering a scientific debate on possible explanations for the discrepancies. Furthermore, doubts have arisen as to the anti-inflammatory and anti-aggregating activity of these compounds. Recent studies have, however, highlighted interesting effects of EPA and DHA on erythrocyte membrane fluidity (EMF). EMF is governed by a complex and dynamic biochemical framework, with fatty acids playing a central role. Furthermore, it can be easily measured in erythrocytes from a blood sample using fluorescent probes. Recent research has also shown that EMF could act as a possible cardiovascular risk factor biomarker. This review aims to synthetize the latest evidence on erythrocyte membrane fluidity, exploring its potential role as a biomarker of residual cardiovascular risk and discussing its clinical relevance. Further, we aim to dissect the possible biological mechanisms that link omega-3 modifiable membrane fluidity to cardiovascular health.

Aims/hypothesis: MiRNAs regulate gene expression, influencing beta cell function and pathways. Isoforms of miRNA (isomiRs), sequence variants of miRNAs with post-transcriptional modifications, exhibit cell-type-specific expression and functions. Despite their biological significance, a comprehensive isomiR profile in human pancreatic islets and beta cells remains unexplored. This study aims to profile isomiR expression in four beta cell sources: (1) laser capture microdissected human islets (LCM-HI); (2) collagenase-isolated human islets (CI-HI); (3) sorted beta cells; and (4) the EndoC-βH1 beta cell line, and to investigate their potential role in beta cell function. Methods: Small RNA-seq and/or small RNA dataset analysis was conducted on human pancreatic islets and beta cells. Data were processed using the sRNAbench bioinformatics pipeline to classify isomiRs based on sequence variations. A beta cell-specific isomiR signature was identified via cross-validation across datasets. Correlations between LCM-HI isomiR expression and in vivo clinical parameters were analysed using regression models. Functional validation of isomiR-411-5p-Ext5p(+1) was performed via overexpression in EndoC-βH1 cells and CI-HI, followed by glucose-stimulated insulin secretion (GSIS) assays and/or transcriptomic analysis. Results: IsomiRs constituted 59.2 ± 1.9% (LCM-HI), 59.6 ± 2.4% (CI-HI), 42.3 ± 7.2% (sorted beta cells) and 43.8 ± 1.2% (EndoC-βH1) of total miRNA reads (data represented as mean ± SD), with 3′ end trimming (Trim3p) being the predominant modification. A beta cell-specific isomiR signature of 30 sequences was identified, with isomiR-411-5p-Ext5p(+1) showing a significant inverse correlation with basal insulin secretion (p=0.0009, partial R ²=0.68) and total insulin secretion (p=0.005, partial R ²=0.54). Overexpression of isomiR-411-5p-Ext5p(+1), but not of its canonical counterpart, importantly reduced GSIS by 51% ( ± 15.2%; mean ± SD) (p=0.01) in EndoC-βH1 cells. Transcriptomic analysis performed in EndoC-βH1 cells and CI-HI identified 47 genes significantly downregulated by isomiR-411-5p-Ext5p(+1) (false discovery rate [FDR]<0.05) but not by the canonical miRNA, with enriched pathways related to Golgi vesicle biogenesis (FDR=0.017) and trans-Golgi vesicle budding (FDR=0.018). TargetScan analysis confirmed seed sequence-dependent target specificity for 81 genes uniquely regulated by the isomiR (p=1.1 × 10⁻⁹). Conclusions/interpretation: This study provides the first comprehensive isomiR profiling in human islets and beta cells, revealing their substantial contribution to miRNA regulation. IsomiR-411-5p-Ext5p(+1) emerges as a distinct key modulator of insulin secretion and granule dynamics in beta cells. These findings highlight isomiRs as potential biomarkers and therapeutic targets for diabetes, warranting further exploration of their roles in beta cell biology. Graphical

The role of intrapancreatic fat (WAT) in the development of T2D remains debated. In T2D, β-cell dedifferentiation is one of the mechanisms responsible for β-cell failure but its role in prediabetes is unknown. We aimed to investigate the relation between WAT and β-cell dedifferentiation prior to diabetes onset. We evaluated pancreatic samples from patients without history of diabetes, who had previously undergone an oral glucose tolerance test and hyperglycemic clamp. Subjects were divided into 3 glucose tolerance groups: normal (NGT), altered (IGT) or newly diagnosed diabetes (nDM). Dedifferentiation and WAT% were morphologically assessed. WAT was higher in nDM patients compared to NGT and IGT (WAT nDM 43.79 ± 20.83 %, IGT 10.67 ± 8.5 %, NGT 4.43 ± 4.37 %). We observed a progressive increase in dedifferentiation score, in parallel with worsening glucose tolerance (from NGT to IGT to nDM; 4.8 ± 3.8; 32.37 ± 7.4; 40.38 ± 19 respectively). A strong linear regression established that WAT could statistically significantly predict dedifferentiated β-cells (R = 0.86, p = 0.005), and that the predicted increase in dedifferentiated β-cells was 1.25 points for every extra one-point change in WAT. Interestingly, the WAT and dedifferentiation score variable pair were significantly related to 1-hour post-load glycemia. The accumulation of WAT might be responsible for dedifferentiation, making it a potential new target to curb diabetes onset.

Next-generation sequencing (NGS) is nowadays commonly used for clinical purposes, and represents an efficient approach for the molecular diagnosis of familial hypercholesterolemia (FH). Although the dominant form of the disease is mostly due to the low-density lipoprotein receptor (LDLR) small-scale pathogenic variants, the copy number variations (CNVs) represent the underlying molecular defects in approximately 10% of FH cases. Here, we reported a novel large deletion in the LDLR gene involving exons 4–18, identified by the bioinformatic analysis of NGS data in an Italian family. A long PCR strategy was employed for the breakpoint region analysis where an insertion of six nucleotides (TTCACT) was found. Two Alu sequences, identified within intron 3 and exon 18, could underlie the identified rearrangement by a nonallelic homologous recombination (NAHR) mechanism. NGS proved to be an effective tool suitable for the identification of CNVs, together with small-scale alterations in the FH-related genes. For this purpose, the use and implementation of this cost-effective, efficient molecular approach meets the clinical need for personalized diagnosis in FH cases.