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Sodium-glucose co-transporter 2 inhibitors (SGLT2i) have emerged as important agents for the treatment of type 2 diabetes mellitus (T2DM). SGLT2 inhibitors have been associated with improved cardiovascular outcomes, not only through their immediate hemodynamic effects-such as glycosuria and (at least temporary) increased natriuresis-but also due to their multifaceted impact on metabolism. Recently, studies have also focused on the effects of SGLT2 inhibitors on adipose tissue. Aside from the well-documented effects on human adiposity, SGLT2i have shown, both in vitro and in murine models, the ability to reduce fat mass, upregulate genes related to browning of white adipose tissue, influence adipocyte size and fatty acid oxidation, and improve oxidative stress and overall metabolic health. In humans, even though data are still limited, recent evidence seems to confirm that the SGLT2i effects observed in cardiovascular outcome trials could be partially explained by their impact on adipose tissue. This review aims to clarify the impact of SGLT2i on adipose tissue, highlighting their role in metabolic health and their potential to transform treatment strategies for T2DM beyond glucose metabolism., Competing Interests: Declarations. Conflict of interest: The authors declare no competing interests. Informed consent: Not applicable., (© 2024. The Author(s).)

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.

Background: Glucose impairment notably affects the postoperative course of gastrointestinal surgeries. However, evidence on its impact on clinically relevant pancreatic fistulas(CR-POPFs) after pancreaticoduodenectomy(PD) is lacking. This study evaluates if and how preoperative glucose metabolism affects the development of CR-POPF after PD., Methods: One hundred and ten consecutive PDs were included. Patients underwent preoperative metabolic profiling using the Oral Glucose Tolerance Test(OGTT) and the hyperinsulinemic euglycemic clamp procedure. Accordingly, patients were categorized as normal glucose tolerant (NGT), impaired glucose tolerant (IGT), diabetic (DM), and longstanding-DM. Receiver operating characteristics(ROC) analyses were performed to determine the values of metabolic features in prediction of CR-POPF., Results: The CR-POPF rate was 36.3 ​%(40 patients). NGT patients had a higher CR-POPF rate (51.7 ​%) compared to IGT(45.2 ​%), DM (15.8 ​%), and longstanding-DM (25.8 ​%) (p ​= ​0.03). CR-POPF patients had lower median fasting glucose levels (p ​= ​0.01) and higher c-peptide values at all OGTT time points (p ​< ​0.05). Fasting glucose and c-peptide levels had high diagnostic accuracy for CR-POPF (AUC>0.8) and were independent risk factors for CR-POPF (OR: 24.7[95%CI: 3.7-165.3] for fasting glucose; OR: 19.9[95%CI: 3.2-125.3] for c-peptide)., Conclusion: Normoglycemia and normal beta cell function may be risk factors for CR-POPF after PD. Fasting glucose and c-peptide levels effectively predicted CR-POPF development following PD., Clinicaltrials Gov Identifier: NCT02175459., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 The Authors. Published by Elsevier Inc. All rights reserved.)

Aims: A number of studies have suggested that pancreatic α cells produce intact GLP-1, thereby constituting a gut-independent paracrine incretin system. However, the debate on whether human α cells contain intact GLP-1 and whether this relates to the presence of diabetes is still ongoing. This study aimed to determine the presence of proglucagon-derived peptides, including GLP-1 isoforms, in pancreas biopsies obtained during partial pancreatectomy from metabolically profiled human donors, stratified according to pre-surgery glucose tolerance., Methods: We enrolled 61 individuals with no known history of type 2 diabetes (31F/30M, age 64.6 ± 10.6 yrs., BMI 24.2 ± 3.68 kg/m 2 ) scheduled for partial pancreatectomy for periampullary neoplasm. Differences in glucose tolerance and insulin secretion/sensitivity were assessed using preoperative 2 h OGTT, 4 h-Mixed Meal Test and Hyperinsulinemic Euglycemic Clamp. Subjects were subsequently classified as normal glucose tolerant (NGT, n = 19), impaired glucose tolerant (IGT, n = 20) or newly diagnosed diabetes (DM) (n = 22). We measured total GLP-1, intact GLP-1, glucagon, insulin, and C-peptide in pancreas biopsies and plasma from these subjects and correlated the results with their secretory and metabolic parameters., Results: Extractable levels of total GLP-1 were 23.9 ± 2.66 pmol/g, while intact GLP-1 levels were 1.15 ± 0.18 pmol/g. When we examined proglucagon derived peptides (adjusted for glucagon levels), in subjects classified according to glucose tolerance, we observed similar levels of total GLP-1, however, intact GLP-1 was significantly increased in IGT and DM groups and inversely associated with beta cell glucose sensitivity and insulin secretion in vivo., Conclusions: Our data show that development of glucose intolerance and beta cell dysfunction are significantly associated with increased levels of intra-islet intact GLP-1, a potentially beneficial adaptation of the paracrine regulation of insulin secretion in type 2 diabetes., Competing Interests: Declaration of competing interest Authors have no conflicts to declare., (Copyright © 2024 The Authors. Published by Elsevier Inc. All rights reserved.)

Aims: Chronic pancreatitis (CP) is - along with acute pancreatitis - the most frequent cause of diabetes of the exocrine pancreas (DEP). Although insulin deficiency is widely accepted as the major feature of DEP, it is still unclear whether diabetes associated with CP is characterized by additional or different functional defects of the insulin secretory machinery. To identify possible functional defects specifically induced by CP, we performed a cross-sectional study in individuals with normal glucose tolerance (NGT), impaired glucose tolerance (IGT) and diabetes mellitus (DM) comparing patients with and without CP (CP vs. NCP)., Methods: We administered an oral glucose tolerance test (OGTT) to all participants and, according to their glucose tolerance, classified them as NGT, IGT and DM. Insulin sensitivity and beta-cell functional parameters were derived from OGTT, hyperglycemic clamp and hyperinsulinemic euglycemic clamp., Results: Studying 146 subjects, we found that beta-cell function and insulin secretion were significantly lower in CP compared to NCP patients. However, when we classified the subjects according to OGTT-derived glucose tolerance, we found no differences in beta-cell function or in insulin sensitivity between CP and NCP with the same glucose tolerance status. Of note, we found that arginine-stimulated insulin secretion is reduced only in subjects with CP and DM compared to NCP subjects with DM., Conclusions: Patients with CP had no specific alterations in insulin secretion and beta-cell function. However, in patients diagnosed with diabetes, we found a lower arginine-stimulated insulin secretion, a marker of reduced functional mass., Competing Interests: Declaration of competing interest All authors declare that they have no competing interests., (Copyright © 2024. Published by Elsevier B.V.)

The pathogenesis of type 2 diabetes (T2D) involves dysfunction in multiple organs, including the liver, muscle, adipose tissue, and pancreas, leading to insulin resistance and β cell failure. Recent studies highlight the significant role of extracellular vesicles (EVs) in mediating inter-organ communication in T2D. This review investigates the role of EVs, focusing on their presence and biological significance in human plasma and tissues affected by T2D. We explore specific EV cargo, such as miRNAs and proteins, which affect insulin signaling and glucose metabolism, emphasizing their potential as biomarkers. By highlighting the diagnostic and therapeutic potential of EVs, we aim to provide new insights into their role in early detection, disease monitoring, and innovative treatment strategies for T2D., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024. Published by Elsevier B.V.)

Purpose: Physical exercise is a key component in the treatment of type 2 diabetes and plays an important role in maintaining a healthy glucose metabolism even in healthy subjects. To date, no studies have investigated the effect of a single bout of aerobic physical exercise on glucose metabolism in young, moderately active, healthy adults., Methods: We performed an OGTT 7 days before and 24 h after a single bout of physical exercise, to evaluate 1-hour post-load plasma glucose and surrogate indexes of insulin sensitivity and insulin secretion., Results: Glucose levels were significantly reduced after exercise at baseline and one hour after glucose load; similarly, insulin was significantly lower 1 h after glucose load. We found a significant increase in the Matsuda index, confirmed by OGIS index, QUICKI index, and by significant reduction in HOMA-IR. Conversely, we observed a trend to increase in HOMA-B., Conclusion: This is the first study to evaluate the effect of a single bout of exercise on 1-hour glucose levels following OGTT. We found a significant reduction in 1-hour glucose levels following OGTT together with an increased insulin sensitivity. A single 30-minute bout of aerobic exercise also seemed to improve the insulin secretion pattern. Modifications in beta cell secretory capacity during exercise are likely secondary to an improvement in insulin action in insulin dependent tissues., (© 2024. The Author(s).)

Pancreatic islet isolation is critical for type 2 diabetes research. Although -omics approaches have shed light on islet molecular profiles, inconsistencies persist; on the other hand, functional studies are essential, but they require reliable and standardized isolation methods. Here, we propose a simplified protocol applied to very small-sized samples collected from partially pancreatectomized living donors. Islet isolation was performed by digesting tissue specimens collected during surgery within a collagenase P solution, followed by a Lympholyte density gradient separation; finally, functional assays and staining with dithizone were carried out. Isolated pancreatic islets exhibited functional responses to glucose and arginine stimulation mirroring donors' metabolic profiles, with insulin secretion significantly decreasing in diabetic islets compared to non-diabetic islets; conversely, proinsulin secretion showed an increasing trend from non-diabetic to diabetic islets. This novel islet isolation method from living patients undergoing partial pancreatectomy offers a valuable opportunity for targeted study of islet physiology, with the primary advantage of being time-effective and successfully preserving islet viability and functionality. It enables the generation of islet preparations that closely reflect donors' clinical profiles, simplifying the isolation process and eliminating the need for a Ricordi chamber. Thus, this method holds promises for advancing our understanding of diabetes and for new personalized pharmacological approaches.

Background: Sodium-glucose cotransporter-2 (SGLT2) inhibitors have shown controversial results in modulating plasma lipids in clinical trials. Most studies found slight increases in high-density lipoprotein (HDL) cholesterol but few have provided evidence on HDL functionality with disappointing results. However, there is broad agreement that these drugs provide cardiovascular protection through several mechanisms. Our group demonstrated that dapagliflozin improves myocardial flow reserve (MFR) in patients with type 2 diabetes (T2D) with coronary artery disease (CAD). The underlying mechanisms are still unknown, although in vitro studies have suggested the involvement of nitric oxide (NO)., Aim: To investigate changes in HDL-mediated modulation of NO production with dapagliflozin and whether there is an association with MFR., Methods: Sixteen patients with CAD-T2D were enrolled and randomized 1:1 to dapagliflozin or placebo for 4 weeks. Blood samples were collected before and after treatment for each group. The ability of HDL to stimulate NO production in endothelial cells was tested in vitro by incubating human umbilical vein endothelial cells (HUVEC) with apoB-depleted (apoB-D) serum of these patients. The production of NO was assessed by fluorescent assay, and results were expressed as fold versus untreated cells., Results: Change in HDL-mediated NO production remained similar in dapagliflozin and placebo group, even after adjustment for confounders. There were no significant correlations between HDL-mediated NO production and MFR either at baseline or after treatment. No changes were found in HDL cholesterol in either group, while low-density lipoprotein cholesterol (LDL cholesterol) significantly decreased compared to baseline only in treatment group (p = 0.043)., Conclusions: In patients with T2D-CAD, beneficial effects of dapagliflozin on coronary microcirculation seem to be unrelated to HDL functions. However, HDL capacity to stimulate NO production is not impaired at baseline; thus, the effect of drug treatments would be negligible. To conclude, we can assume that HDL-independent molecular pathways are involved in the improvement of MFR in this population., Trial Registration: EudraCT No. 2016-003614-27; ClinicalTrials.gov Identifier: NCT03313752., (© 2023. The Author(s).)

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.

Background: Over the last decades, various approaches have been explored to restore sufficient β-cell mass in diabetic patients. Stem cells are certainly an attractive source of new β-cells, but an alternative option is to induce the endogenous regeneration of these cells., Scope of Review: Since the exocrine and endocrine pancreatic glands have a common origin and a continuous crosstalk unites the two, we believe that analyzing the mechanisms that induce pancreatic regeneration in different conditions could further advance our knowledge in the field. In this review, we summarize the latest evidence on physiological and pathological conditions associated with the regulation of pancreas regeneration and proliferation, as well as the complex and coordinated signaling cascade mediating cell growth., Major Conclusions: Unraveling the mechanisms involved in intracellular signaling and regulation of pancreatic cell proliferation and regeneration may inspire future investigations to discover potential strategies to cure diabetes., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2023 The Authors. Published by Elsevier GmbH.. All rights reserved.)

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.

Our work is aimed at unraveling the role of the first-phase insulin secretion in the natural history of type 2 diabetes mellitus (T2DM) and its interrelationship with insulin resistance and with β cell function and mass. Starting from pathophysiology, we investigate the impact of impaired secretion on glucose homeostasis and explore postmeal hyperglycemia as the main clinical feature, underlining its relevance in the management of the disease. We also review dietary and pharmacological approaches aimed at improving early secretory defects and restoring residual β cell function. Furthermore, we discuss possible approaches to detect early secretory defects in clinical practice. By providing a journey through human and animal data, we attempt a unification of the recent evidence in an effort to offer a new outlook on β cell secretion., Competing Interests: Declaration of interests The authors declare no conflicts of interest., (Copyright © 2023 Elsevier Ltd. All rights reserved.)