The Burden of Suboptimal Insulin Dosing in People with Diabetes in Spain: Barriers and Solutions from the Physician Perspective.

Background: This study aimed to determine physicians' perceptions of the extent of suboptimal insulin dosing and the barriers and solutions to optimal dosing in people with diabetes (PwD) treated with insulin. Methods: A cross-sectional online survey was conducted in four countries with primary care physicians and endocrinologists treating PwD using insulin pens, which included 53 questions on physicians' characteristics and their perceptions of the behaviors of PwD in relation to insulin dosing routines, unmet needs and potential solutions. Analyses were descriptive. Results: Of the 160 physicians (80 primary care physicians, 80 specialists) surveyed in Spain, 58.1% were male and 88.8% had been qualified to practice for more than five years. Most physicians (>65%) indicated that 0-30% of PwD missed or skipped, mistimed, or miscalculated an insulin dose in the last 30 days. Common reasons for these actions were that PwD forgot, were out of their normal routine, were too busy or distracted, or were unsure of how much insulin to take. To optimize insulin dosing, over 75% of physicians considered it very helpful for PwD to have real-time insulin dosing calculation guidance, mobile app reminders, a device automatically recording glucose measurements and/or insulin, having insulin and glucose data in one place, and having the time for more meaningful conversations about insulin dosing routines. Conclusion: According to physicians' perspectives, suboptimal insulin dosing remains common among PwD. This survey highlights the need for integrated and automated insulin dosing support to manage the complexity of insulin treatment, improve communications between PwD and physicians, and ultimately improve outcomes for PwD.

Barriers and solutions for the management of severe hypoglycaemia in people with diabetes in Spain: A Delphi survey.

BACKGROUND AND OBJECTIVE: Severe hypoglycaemia (SH) imposes a significant burden for people with diabetes (PwD), their caregivers (CGs), and the healthcare system. The study aimed to identify barriers and solutions in the management of SH in PwD in Spain, gathering consensus from physicians and nurses. MATERIAL AND METHODS: Expert opinion from physicians and nurses who manage PwD was collected via a 2-round online Delphi method. Consensus was predefined as ≥ 70% of the panellists agreeing or disagreeing with the statement. RESULTS: Physicians (n = 25) and nurses (n = 17) reached ≥ 90% consensus on the following barriers for the management of SH: absence of symptoms, cost to the health system, lack of implementation of glucose monitoring devices, lack of patient training to identify and manage SH, and the fear of SH in children and CGs. Main solutions, identified with ≥ 70% consensus, included training, education, and psychological support using diabetes nurse educators and the use of new glucose monitoring technologies and applications. CONCLUSIONS: This study provides valuable insights on the barriers and solutions in the management of SH in Spain. Structured self-management training, the support of diabetes educators, and the use of insulin delivery devices and glucose monitoring technologies is required for the management of SH.

Disease and Economic Burden of Poor Metabolic and Weight Control in Type 2 Diabetes in Spain: A Systematic Literature Review.

INTRODUCTION: Poor metabolic control and excess body weight are frequently present in people with type 2 diabetes (PwT2D). METHODS: A systematic literature review was conducted to identify observational studies reporting clinical, economic, and health-related quality of life (HRQoL) outcomes associated with poor metabolic (according to HbA1c, blood pressure [BP] and low density lipoprotein cholesterol [LDL-C] levels) and/or weight control (defined by a body mass index [BMI] ≥ 30 kg/m2) in adults with T2D in Spain, including articles published in either Spanish or English between 2013 and 2022 and conference abstracts from the last 2 years. RESULTS: Nine observational studies were included in the analysis. Poor glycemic control (HbA1c ≥ 7%) was associated with cardiovascular disease (CVD), increased requirements for antidiabetic medications, higher and more frequent weight gain, a greater probability of hypoglycemia and dyslipidemia, and worse health-related quality of life (HRQoL). Uncontrolled BP in PwT2D was related with the presence of CVD, worse metabolic control, and higher BMI and abdominal perimeter values. Poor LDL-C control or dyslipidemia was associated with CVD, hypoglycemia, and elevated HbA1c and triglycerides levels. The presence of a BMI ≥ 30 kg/m2 was related to CVD and hypoglycemia, a higher prevalence of metabolic syndrome and worse BP control. Direct medical costs were found to be higher in PwT2D when coexisting with HbA1c levels ≥ 7%, uncontrolled BP or obesity. Increased total costs, including productivity losses, were also detected in those who presented uncontrolled BP and a BMI ≥ 30 kg/m2, and when poor weight control existed together with HbA1c ≥ 8% and poorly controlled BP. CONCLUSION: Gathered evidence supports the high clinical, economic and HRQoL burden of poor metabolic and/or weight control in PwT2D in Spain and reinforces the importance of prioritizing its control to reduce the associated burden, at both the individual and healthcare system levels.

Functional Characterization of a Dual Enhancer/Promoter Regulatory Element Leading Human CD69 Expression.

The CD69 gene encodes a C-type lectin glycoprotein with immune regulatory properties which is expressed on the cell surfaces of all activated hematopoietic cells. CD69 activation kinetics differ by developmental stage, cell linage and activating conditions, and these differences have been attributed to the participation of complex gene regulatory networks. An evolutionarily conserved regulatory element, CNS2, located 4kb upstream of the CD69 gene transcriptional start site, has been proposed as the major candidate governing the gene transcriptional activation program. To investigate the function of human CNS2, we studied the effect of its endogenous elimination via CRISPR-Cas9 on CD69 protein and mRNA expression levels in various immune cell lines. Even when the entire promoter region was maintained, CNS2-/- cells did not express CD69, thus indicating that CNS2 has promoter-like characteristics. However, like enhancers, inverted CNS2 sustained transcription, although at a diminished levels, thereby suggesting that it has dual promoter and enhancer functions. Episomal luciferase assays further suggested that both functions are combined within the CNS2 regulatory element. In addition, CNS2 directs its own bidirectional transcription into two different enhancer-derived RNAs molecules (eRNAs) which are transcribed from two independent transcriptional start sites in opposite directions. This eRNA transcription is dependent on only the enhancer sequence itself, because in the absence of the CD69 promoter, sufficient RNA polymerase II levels are maintained at CNS2 to drive eRNA expression. Here, we describe a regulatory element with overlapping promoter and enhancer functions, which is essential for CD69 gene transcriptional regulation.

Substantial Influence of ERAP2 on the HLA-B*40:02 Peptidome: Implications for HLA-B*27-Negative Ankylosing Spondylitis.

HLA-B*40:02 is one of a few major histocompatibility complex class I (MHC-I) molecules associated with ankylosing spondylitis (AS) independently of HLA-B*27. The endoplasmic reticulum aminopeptidase 2 (ERAP2), an enzyme that process MHC-I ligands and preferentially trims N-terminal basic residues, is also a risk factor for this disease. Like HLA-B*27 and other AS-associated MHC-I molecules, HLA-B*40:02 binds a relatively high percentage of peptides with ERAP2-susceptible residues. In this study, the effects of ERAP2 depletion on the HLA-B*40:02 peptidome were analyzed. ERAP2 protein expression was knocked out by CRISPR in the transfectant cell line C1R-B*40:02, and the differences between the peptidomes from the wild-type and ERAP2-KO cells were determined by label-free quantitative comparisons. The qualitative changes dependent on ERAP2 affected about 5% of the peptidome, but quantitative changes in peptide amounts were much more substantial, reflecting a significant influence of this enzyme on the generation/destruction balance of HLA-B*40:02 ligands. As in HLA-B*27, a major effect was on the frequencies of N-terminal residues. In this position, basic and small residues were increased, and aliphatic/aromatic ones decreased in the ERAP2 knockout. Other peptide positions were also affected. Because most of the non-B*27 MHC-I molecules associated with AS risk bind a relatively high percentage of peptides with N-terminal basic residues, we hypothesize that the non-epistatic association of ERAP2 with AS might be related to the processing of peptides with these residues, thus affecting the peptidomes of AS-associated MHC-I molecules.

CD69 Targeting Enhances Anti-vaccinia Virus Immunity.

CD69 is highly expressed on the leukocyte surface upon viral infection, and its regulatory role in the vaccinia virus (VACV) immune response has been recently demonstrated using CD69-/- mice. Here, we show augmented control of VACV infection using the anti-human CD69 monoclonal antibody (MAb) 2.8 as both preventive and therapeutic treatment for mice expressing human CD69. This control was related to increased natural killer (NK) cell reactivity and increased numbers of cytokine-producing T and NK cells in the periphery. Moreover, similarly increased immunity and protection against VACV were reproduced over both long and short periods in anti-mouse CD69 MAb 2.2-treated immunocompetent wild-type (WT) mice and immunodeficient Rag2-/- CD69+/+ mice. This result was not due to synergy between infection and anti-CD69 treatment since, in the absence of infection, anti-human CD69 targeting induced immune activation, which was characterized by mobilization, proliferation, and enhanced survival of immune cells as well as marked production of several innate proinflammatory cytokines by immune cells. Additionally, we showed that the rapid leukocyte effect induced by anti-CD69 MAb treatment was dependent on mTOR signaling. These properties suggest the potential of CD69-targeted therapy as an antiviral adjuvant to prevent derived infections.IMPORTANCE In this study, we demonstrate the influence of human and mouse anti-CD69 therapies on the immune response to VACV infection. We report that targeting CD69 increases the leukocyte numbers in the secondary lymphoid organs during infection and improves the capacity to clear the viral infection. Targeting CD69 increases the numbers of gamma interferon (IFN-γ)- and tumor necrosis factor alpha (TNF-α)-producing NK and T cells. In mice expressing human CD69, treatment with an anti-CD69 MAb produces increases in cytokine production, survival, and proliferation mediated in part by mTOR signaling. These results, together with the fact that we have mainly worked with a human-CD69 transgenic model, reveal CD69 as a treatment target to enhance vaccine protectiveness.