enteroviral infections and development of type 1 diabetes the brothers karamazov within the cvbs

Type 1 diabetes (T1D) is the result of a selective autoimmune destruction of pancreatic islet β-cells, occurring in genetically predisposed subjects, possibly triggered or accelerated by environmental agents (1). Both innate (2) and adaptive (3) immune responses are involved in islet inflammation in T1D. The role of environmental factors has become increasingly relevant, as indicated by the marked recent rise of incidence (4), impossible to explain based on genetic changes alone. One of the environmental risk factors identified by several independent studies in man and in animal models (5) is represented by enteroviral infections, which have been epidemiologically associated to T1D development (6). Enteroviruses may contribute to the pathological events leading to β-cell damage by several different mechanisms, such as virus-induced cytolysis or islet inflammation leading to subclinical β-cell destruction (7). However, it should also be taken into account that in specific settings viral infections may also protect from diabetes development (8). In this issue, two closely related articles written by Oikarinen et al. (9) and Laitinen et al. (10) provide important information on the potential roles of enteroviruses, and more specifically of group B coxsackieviruses (CVB), in modulating susceptibility to T1D development. Neutralizing antibodies against CVBs have been measured in a longitudinal sample series from a large prospective birth cohort in Finland (9) as well as cross-sectionally in children with newly diagnosed T1D and control subjects (10) matched according to sampling time, gender, age, and country,

Targeting microRNAs as a Therapeutic Strategy to Reduce Oxidative Stress in Diabetes

Diabetes mellitus is a group of heterogeneous metabolic disorders characterized by chronic hyperglycaemia as a consequence of pancreatic β cell loss and/or dysfunction, also caused by oxidative stress. The molecular mechanisms involved inβ cell dysfunction and in response to oxidative stress are also regulated by microRNAs (miRNAs). miRNAs are a class of negative gene regulators, which modulate pathologic mechanisms occurring in diabetes and its complications. Although several pharmacological therapies specifically targeting miRNAs have already been developed and brought to the clinic, most previous miRNA-based drug delivery methods were unable to target a specific miRNA in a single cell type or tissue, leading to important off-target effects. In order to overcome these issues, aptamers and nanoparticles have been described as non-cytotoxic vehicles for miRNA-based drug delivery. These approaches could represent an innovative way to specifically target and modulate miRNAs involved in oxidative stress in diabetes and its complications. Therefore, the aims of this review are: (i) to report the role of miRNAs involved in oxidative stress in diabetes as promising therapeutic targets; (ii) to shed light onto the new delivery strategies developed to modulate the expression of miRNAs in diseases

MicroRNA profiling in sera of patients with type 2 diabetes mellitus reveals an upregulation of miR-31 expression in subjects with microvascular complications

Type 2 diabetes (T2D) is a metabolic disease characterized by chronic hyperglycaemia due to a combination of resistance to insulin action and an inadequate compensatory insulin secretory response. Chronic hyperglycemia is associated with long-term micro- and macrovascular complications leading to dysfunction of several organs including kidney, heart, eye and nervous system. Early identification of chronic diabetic complications is necessary in order to prevent dysfunction and failure of these different organs. MicroRNAs (or miRNAs) are small endogenous RNAs, which negatively regulate gene expression. Recently, it has been demonstrated that miRNAs can be secreted by cells, thus being detectable in serum and in other biological fluids. Circulating microRNAs have been proposed as possible biomarkers of several diseases. Here, we performed a miRNAs expression profiling in the sera of T2D patients with or without vascular complications in order to find specific biomarkers to characterize T2D complications. We analyzed the expression of 384 microRNAs in serum pools from 3 groups of T2D patients: 12 T2D patients without any chronic complications, 12 T2D patients with macrovascular complications and 12 with microvascular complications. We found 223 miRNAs expressed in T2D,224 inT2D with microvascular and221 inT2D with macrovascular complications. Among expressed microRNAs, 45 resulted upregulated and 23 downregulated in microvascular patients sera, while 13 upregulated and 41 downregulated in macrovascular T2D patients compared to those without complications. We focused and validated microRNA miR-31 expression in single sera from each group, which resulted significantly upregulated in patients with microvascular complications and may be indeed related to the presence of microangiopathy. In conclusion, our study has identified miR-31 as a promising biomarker for diabetic microvascular complications; further prospective studies in the clinical setting are however required to establish the real utility of measuring serum circulating levels of this microRNA

Real-world use of oral versus subcutaneous semaglutide in a cohort of type 2 diabetic patients: which option to which patient?

Purpose To evaluate the variables influencing the therapeutic choice toward oral versus subcutaneous semaglutide in a cohort of diabetic subjects.Methods We retrospectively collected data of 292 patients followed at the Diabetes Unit of the University Hospital of Siena and the Hospital of Grosseto, who were prescribed oral (n = 115) or subcutaneous (n = 177) semaglutide between October 2021 and October 2022.Results Oral semaglutide was preferentially prescribed in older subjects with longer disease duration in replacement of other antidiabetic drugs, while subcutaneous semaglutide was preferentially prescribed in add-on to metformin in subjects with higher body weight and BMI. After 6 months, both formulations significantly improved glycemic control and body weight, however injectable semaglutide showed a greater efficacy on A1c levels, weight loss, BMI and waist circumference reduction. No differences were found in terms of adverse events.Conclusion In our experience, injectable semaglutide is preferred in patients with excess weight and shorter disease duration, while the oral formulation was used later and especially after therapeutic failure of previous therapies. Follow-up data indicate similar tolerability and efficacy of both formulations, despite subcutaneous semaglutide demonstrated greater efficacy

Beyond Glycemic Control in Diabetes Mellitus: Effects of Incretin-Based Therapies on Bone Metabolism

Diabetes mellitus (DM) and osteoporosis (OP) are common disorders with a significant health burden, and an increase in fracture risk has been described both in type 1 (T1DM) and in type 2 (T2DM) diabetes. The pathogenic mechanisms of impaired skeletal strength in diabetes remain to be clarified in details and they are only in part reflected by a variation in bone mineral density. In T2DM, the occurrence of low bone turnover together with a decreased osteoblast activity and compromised bone quality has been shown. Of note, some antidiabetic drugs (e.g., thiazolidinediones, insulin) may deeply affect bone metabolism. In addition, the recently introduced class of incretin-based drugs (i.e., GLP-1 receptor agonists and DPP-4 inhibitors) is expected to exert potentially beneficial effects on bone health, possibly due to a bone anabolic activity of GLP-1, that can be either direct or indirect through the involvement of thyroid C cells. Here we will review the established as well as the putative effects of incretin hormones and of incretin-based drugs on bone metabolism, both in preclinical models and in man, taking into account that such therapeutic strategy may be effective not only to achieve a good glycemic control, but also to improve bone health in diabetic patients

Impact of the 2014 American Academy of Pediatrics recommendation and of the resulting limited financial coverage by the Italian Medicines Agency for palivizumab prophylaxis on the RSV-associated hospitalizations in preterm infants during the 2016-2017 epidemic season: a systematic review of seven Italian reports

Background: The only pharmacologic prophylaxis against respiratory syncytial virus (RSV) infection in preterm infants is the humanized monoclonal antibody palivizumab. After the 2014 modification of the American Academy of Pediatrics (AAP) recommendations, the Italian Medicines Agency (AIFA) limited the financial coverage for palivizumab prescriptions to otherwise healthy preterm infants with < 29 weeks of gestational age (wGA) aged < 12 months at the beginning of the 2016-2017 RSV season. However, due to the effect on disease severity and hospitalizations following this limitation, shown by several Italian clinical studies, in November 2017 AIFA reinstated the financial coverage for these infants. In this systematic review, we critically summarize the data that show the importance of palivizumab prophylaxis. Methods: Data from six Italian pediatric institutes and the Italian Network of Pediatric Intensive Care Units (TIPNet) were retrieved from the literature and considered. The epidemiologic information for infants 29-36 wGA, aged < 12 months and admitted for viral-induced acute lower respiratory tract infection were retrospectively reviewed. RSV-associated hospitalizations were compared between the season with running limitation, i.e. 2016-2017, versus 2 seasons before (2014-2015 and 2015-2016) and one season after (2017-2018) the AIFA limitation. Results: During the 2016-2017 RSV epidemic season, when the AIFA limited the financial coverage of palivizumab prophylaxis based on the 2014 AAP recommendation, the study reports on a higher incidences of RSV bronchiolitis and greater respiratory function impairment. During this season, we also found an increase in hospitalizations and admissions to the Pediatric Intensive Care Units and longer hospital stays, incurring higher healthcare costs. During the 2016-2017 epidemic season, an overall increase in the number of RSV bronchiolitis cases was also observed in infants born full term, suggesting that the decreased prophylaxis in preterm infants may have caused a wider infection diffusion in groups of infants not considered to be at risk. Conclusions: The Italian results support the use of palivizumab prophylaxis for otherwise healthy preterm (29-36 wGA) infants aged < 6 months at the beginning of the RSV season

Understanding reasons and factors for participation and non-participation to a medication adherence program for patients with diabetic kidney disease in Switzerland: a mixed methods study.

An interprofessional medication adherence intervention led by pharmacists, combining motivational interviews and feedback with electronic monitor (EM) drug assessment, was offered to all consecutive patients with diabetic kidney disease (DKD) (estimated glomerular filtration rate < 60 mL/min/1.73 m <sup>2</sup> ) visiting their nephrologist or endocrinologist. Approximately 73% (202/275) of eligible patients declined to participate, and the factors and reasons for refusal were investigated. Sociodemographic and clinical data of included patients and those who refused were collected retrospectively for those who had previously signed the general consent form. Multivariate logistic regression analysis was performed to identify independent variables associated with non-participation. Patients who refused or accepted the adherence study were invited to participate in semi-structured interviews. Verbatim transcription, thematic analysis, and inductive coding were performed. Patients who refused to participate were older (n = 123, mean age 67.7 years, SD:10.4) than those who accepted (n = 57, mean age 64.0 years, SD:10.0, p = 0.027) and the proportion of women was higher among them than among patients who accepted it (30.9% vs 12.3%, p = 0.007). The time from diabetes diagnosis was longer in patients who refused than in those who accepted (median 14.2 years IQR 6.9-22.7 vs. 8.6 years, IQR 4.5-15.9, p = 0.003). Factors associated with an increased risk of non-participation were female sex (OR 3.8, 95% CI 1.4-10.0, p = 0.007) and the time from diabetes diagnosis (OR 1.05, 95% CI 1.01-1.09, p = 0.019). The included patients who were interviewed (n = 14) found the interprofessional intervention useful to improve their medication management, support medication literacy, and motivation. Patients who refused to participate and who were interviewed (n = 16) explained no perceived need, did not agree to use EM, and perceived the study as a burden and shared that the study would have been beneficial if introduced earlier in their therapeutic journey. Other barriers emerged as difficult relationships with healthcare providers, lack of awareness of the pharmacist's role, and negative perception of clinical research. Investigating the factors and reasons for participation and non-participation in a study helps tailor intervention designs to the needs of polypharmacy patients. Patients who refused the adherence intervention may not be aware of the benefits of medication management and medication literacy. There is an urgent need to advocate for interprofessional outpatient collaborations to support medication adherence in patients with DKD. Trial registration Clinicaltrials.gov NCT04190251_PANDIA IRIS