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Background: Gender differences in metabolic response to lifestyle interventions remain poorly explored. This study aimed to evaluate the impact of a six-month Mediterranean diet (MD) intervention combined with regular physical activity on metabolic parameters in overweight adults., Methods: A prospective cohort study was conducted in an obesity clinic in Rome, Italy, involving overweight adults (BMI ≥ 25 kg/m 2 ) motivated to improve their lifestyle. Participants ( n = 205; 107 men and 98 women) self-selected into physical activity groups (aerobic, anaerobic, combined or no activity). Gender-specific metabolic changes were assessed, including lipid profiles, liver markers and fasting glucose., Results: Significant gender differences in metabolic results were observed. Men showed greater reductions in total cholesterol (TC) and LDL, as well as significant reductions in alanine aminotransferase (ALT). Women showed a significant increase in HDL cholesterol. Fasting blood glucose decreased significantly in both sexes, with no differences between the sexes. Activity-specific analysis revealed that anaerobic activity significantly improved lipid metabolism in men, while aerobic activity produced the greatest benefits in women, including increased HDL and improved liver marker profiles., Conclusions: Therapeutic strategies combining MD and physical activity must take into account gender-specific physiological differences and the type of sport activity to optimise metabolic benefits. Personalised approaches may improve the management of cardiovascular risk factors in overweight individuals., Study Registration: This study is registered on ClinicalTrials.gov (NCT06661330).

Background: Gender differences in dietary patterns and physical activity are known to influence metabolic health, but research exploring these differences using principal component analysis (PCA) is limited. This study aims to identify distinct patterns of eating behaviour, body composition and physical activity between men and women, in order to develop tailored interventions., Methods: A cross-sectional study was conducted on 2,509 adults attending a metabolic health centre. Data on eating habits, physical activity and body composition were collected by means of questionnaires and bioimpedance analysis. PCA was used to identify patterns of eating behaviour and physical activity. Statistical analyses were performed to explore gender-specific differences., Results: Based on the PCA, five distinct groups of participants were identified: Balanced Eaters, Focused on Home Cooking, Routine Eaters, Restaurant Lovers and Varied Eaters. Significant gender differences in food preferences were observed, with men consuming more meat and women more vegetables. Men also reported greater participation in strength and endurance sports, while women showed a more structured eating routine., Conclusions: This study, using principal component analysis (PCA), revealed gender-specific patterns in diet, physical activity and body composition. PCA identified five distinct behavioural groups, revealing that men tended to consume more meat and engage in strength training, while women adhered to structured, vegetable-rich diets. The application of PCA provided more insight than traditional analysis, highlighting the complexity of gender-specific behaviour. These results emphasize the need for tailored interventions, focusing on increasing vegetable intake in men and encouraging strength training in women. Future research should exploit PCA to explore behavioural patterns longitudinally for more refined and personalised health strategies., Clinical Trials Registered: This study is registered on ClinicalTrials.gov (NCT06654674)., Competing Interests: Declarations. Ethics approval and consent to participate: The participants provided their written informed consent to participate in this study. The studies were conducted in accordance with local legislation and institutional requirements. The studies involving humans were approved by the IRCCS San Raffaele Ethics Committee (registration number RP 23/13). Consent for publication: Not applicable. Competing interests: The authors declare that they have no competing interests., (© 2024. The Author(s).)

Background/objectives: Obesity is a global health problem with significant chronic disease risks. This study examined gender differences in eating behaviour, body composition, eating frequency and time of hunger in an Italian cohort with obesity (BMI ≥ 30) to inform gender-specific management strategies., Methods: A retrospective analysis of 720 adults (51.5% female, mean age 44.4 ± 13.8 years) assessed body composition and eating behaviour using principal component analysis (PCA) to classify eating profiles (structured, irregular, social and disordered/impulsive eaters)., Results: Males showed higher weight, abdominal circumference and fat mass, while females showed higher fat mass percentages ( p < 0.001). Gender differences were observed in the frequency of meals (e.g., 54.7% of males and 64.7% of females consumed 4-5 meals per day, p = 0.0018) and the time of hunger (males: before dinner; females: morning hunger, p = 0.005). The PCA profiles revealed that the 'structured eaters' had a healthier body composition, whereas the 'disordered/impulsive eaters' had a higher fat mass. Irregular eaters were predominantly male (41.0%), while disordered eaters were predominantly female (39.9%) ( p = 0.0016)., Conclusions: Gender-specific eating patterns influence obesity outcomes. Structured eating was associated with healthier profiles, whereas impulsive or irregular patterns were related to higher fat mass. The retrospective design and non-validated questionnaire for dietary behaviour assessment limit generalisability, warranting further research for tailored interventions., Registration: ClinicalTrials.gov (NCT06654674)., Competing Interests: The authors declare no conflicts of interest.

Introduction: This study investigates the interplay between body composition, dietary patterns, and physical activity across genders, focusing on gender-specific differences in food preferences and eating behaviors. Understanding these interactions is crucial for developing targeted nutritional and lifestyle interventions., Methods: A cross-sectional study was conducted with 1,333 participants (58.7% female, 41.3% male), aged 18-65 years. Participants were categorized into tertiles based on their fat mass to fat-free mass (FM-to-FFM) ratio. Data on dietary choices, eating behaviors, and physical activity were collected and analyzed to identify gender-specific trends., Results: Significant gender-specific differences were observed in food preferences and eating behaviors. Males experienced greater hunger in the late afternoon, while females felt more hunger in the morning. Males showed a preference for processed and red meats, whereas females preferred cooked vegetables. Eating behaviors such as meal skipping, uncontrolled eating, nocturnal eating, and taste preferences (sweet or salty) varied distinctly between FM-to-FFM tertiles and genders. Higher FM-to-FFM ratios correlated with lower physical activity levels, particularly in strength training and general sports engagement., Discussion: These findings highlight the complex interactions between body composition, dietary habits, and lifestyle factors, emphasizing gender-specific differences. The results suggest that body composition and BMI significantly impact health-related behaviors, necessitating tailored interventions to address these differences and promote healthier lifestyles., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2024 Lombardo, Feraco, Armani, Camajani, Gorini, Strollo, Padua, Caprio and Bellia.)

In this case report, we describe an uncommon case of neuroendocrine cancer of unknown origin began with cauda equina syndrome in a patient affected by Paget disease of bone (PDB). A 76-year-old man with diagnosis of PDB, without history of pain or bone deformity, developed sudden severe low back pain. Bone alkaline phosphatase was increased and MRI and whole-body scintigraphy confirmed the localization of the disease at the third vertebra of the lumbar spine. Treatment with Neridronic Acid was started, but after only 2 weeks of therapy anuria and bowel occlusion occurred together with lower limb weakness and walking impairment. Cauda equina syndrome consequent to spinal stenosis at the level of L2-L3 was diagnosed after admission to Emergency Department and the patient underwent neurosurgery for spinal medulla decompression. The histologic results showed a complete subversion of bone structure in neoplastic tissue, consistent with metastatic neuroendocrine carcinoma of unknown origin. In conclusion, low back pain in the elderly may require deep investigation to individuate rare diseases. In asymptomatic patients with apparently stable PDB, the sudden appearance of pain or neurologic symptoms may alert the clinician for the possibility of other superimposing diseases, like bone metastases., (© 2024. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

Type 2 diabetes (T2D) is associated with higher fracture risk, despite normal or high bone mineral density. We reported that bone formation genes ( SOST and RUNX2 ) and advanced glycation end-products (AGEs) were impaired in T2D. We investigated Wnt signaling regulation and its association with AGEs accumulation and bone strength in T2D from bone tissue of 15 T2D and 21 non-diabetic postmenopausal women undergoing hip arthroplasty. Bone histomorphometry revealed a trend of low mineralized volume in T2D (T2D 0.249% [0.156-0.366]) vs non-diabetic subjects 0.352% [0.269-0.454]; p=0.053, as well as reduced bone strength (T2D 21.60 MPa [13.46-30.10] vs non-diabetic subjects 76.24 MPa [26.81-132.9]; p=0.002). We also showed that gene expression of Wnt agonists LEF-1 (p=0.0136) and WNT10B (p=0.0302) were lower in T2D. Conversely, gene expression of WNT5A (p=0.0232), SOST (p<0.0001), and GSK3B (p=0.0456) were higher, while collagen ( COL1A1 ) was lower in T2D (p=0.0482). AGEs content was associated with SOST and WNT5A (r=0.9231, p<0.0001; r=0.6751, p=0.0322), but inversely correlated with LEF-1 and COL1A1 (r=-0.7500, p=0.0255; r=-0.9762, p=0.0004). SOST was associated with glycemic control and disease duration (r=0.4846, p=0.0043; r=0.7107, p=0.00174), whereas WNT5A and GSK3B were only correlated with glycemic control (r=0.5589, p=0.0037; r=0.4901, p=0.0051). Finally, Young's modulus was negatively correlated with SOST (r=-0.5675, p=0.0011), AXIN2 (r=-0.5523, p=0.0042), and SFRP5 (r=-0.4442, p=0.0437), while positively correlated with LEF-1 (r=0.4116, p=0.0295) and WNT10B (r=0.6697, p=0.0001). These findings suggest that Wnt signaling and AGEs could be the main determinants of bone fragility in T2D., Competing Interests: GL, FC, MF, CP, VV, FT, NP, GV, AP, RS, FZ, AB, ES, ST, RC, MM, RP, NN No competing interests declared, (© 2023, Leanza et al.)

Aims/hypothesis: Type 1 diabetes is an autoimmune disorder that is characterised by destruction of pancreatic beta cells by autoreactive T lymphocytes. Although islet autoantibodies (AAb) are an indicator of disease progression, specific immune biomarkers that can be used as target molecules to halt development of type 1 diabetes have not been discovered. Soluble immune checkpoint molecules (sICM) play a pivotal role in counteracting excessive lymphocyte responses, but their role in type 1 diabetes is unexplored. In this longitudinal study, we measured sICM levels in AAb-positive (AAb + ) children to identify molecules related to type 1 diabetes progression., Methods: We measured the levels of 14 sICM in the sera of AAb + children (n=57) compared to those with recent-onset type 1 diabetes (n=79) and healthy children (n=44), obtained from two cohorts. AAb + children were followed up and divided based on their progression to type 1 diabetes (AAb P ) or not (AAb NP ) (if they lost islet autoimmunity and did not develop disease in subsequent years). sICM were also measured in the sample taken at the visit closest to disease onset in AAb P children., Results: We found that AAb + children had a distinct sICM profile compared with healthy children and those with recent-onset type 1 diabetes. In addition, AAb + children who progressed to type 1 diabetes (AAb P ) had higher sICM concentrations than non-progressors (AAb NP ). Further, sICM levels decreased in AAb P children close to disease onset. Application of Cox regression models highlighted that high concentrations of soluble programmed cell death protein 1 (sPD-1) are associated with type 1 diabetes progression (HR 1.71; 95% CI 1.16, 2.51; p=0.007)., Conclusions/interpretation: This study reveals an sICM profile that is dysregulated during the preclinical stage of type 1 diabetes, and identifies sPD-1 as a pathophysiologically-relevant molecule that is associated with disease progression, offering a potential target for early interventions in autoimmune diabetes., (© 2024. The Author(s).)

Background: Visceral adiposity has been associated with an increased risk of critical illness in COVID-19 patients. However, if it also associates to a poor survival is still not well established. The aim of the study was to assess the relationship between abdominal fat distribution and COVID-19 mortality., Methods: In this six-month longitudinal cohort study, abdominal visceral (VAT) and subcutaneous adipose tissues (SAT) were measured by computed tomography in a cohort of 174 patients admitted to the emergency department with a diagnosis of COVID-19, during the first wave of pandemic. The primary exposure and outcome measures were VAT and SAT at hospital admission, and death at 30 and 180 days, respectively., Results: Overall survival was not different according to VAT (p = 0.94), SAT (p = 0.32) and VAT/SAT ratio (p = 0.64). However, patients in the lowest SAT quartile (thickness ≤ 11.25 mm) had a significantly reduced survival compared to those with thicker SAT (77 vs. 94% at day 30; 74 vs. 91% at day 180, p = 0.01). Similarly, a thinner SAT was associated with lower survival in Intensive Care Unit (ICU) admitted patients, independently of sex or age (p = 0.02). The VAT/SAT ratio showed a non-linear increased risk of ICU admission, which plateaued out and tended for inversion at values greater than 1.9 (p = 0.001), although was not associated with increased mortality rate., Conclusions: In our cohort, visceral adiposity did not increase mortality in patients with COVID-19, but low SAT may be associated with poor survival., (© 2023. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

Introduction: Food preferences are influenced by various factors, such as culture, age, and gender. The relationship between food tastes, meal preferences, and eating habits has been studied extensively in recent years; however, research on gender differences in these fields still needs to be addressed. The aim of this study was to investigate gender differences in food preferences and eating habits through self-administered questionnaires in a large Italian population sample., Methods: The online survey included questions on food tastes, meal preferences, eating habits, and sport involvement., Results: The results of the study underline significant gender-specific dietary tendencies among the 2198 participants (1314 females and 884 males, average age 41.1 ± 12.7 yrs). The majority of subjects were in the annual income range between €20,000 and €40,000. Our analysis reveals significant gender differences in dietary preferences and eating habits. Men prefer red and processed meat, with significantly higher consumption rates than women. Women, on the other hand, show a greater inclination towards vegetables, whole grains, tofu, and high-cocoa-content dark chocolate, aligning with healthier food choices. The study also found differences in eating behaviors, including the frequency of meals, snacking habits, and hunger patterns: women tend to eat more frequently and report higher levels of hunger in the morning, while men tend to skip snacks. Furthermore, differences extend to eating contexts, such as the speed of eating, eating out, and eating alone, with men more likely to eat quickly and dine out. Episodes of uncontrolled eating without hunger also differ, with women reporting these behaviors more frequently than men. In addition, the analysis of sports preferences showed distinct patterns, with a lower percentage of women playing sports and those who do play sports preferring endurance and strength training, while men prefer strength training and endurance sports., Discussion: These findings elucidate the complex interplay of biological, cultural, and gender-based factors in shaping dietary preferences and eating behaviors. In particular, our study reveals that gender dynamics significantly influence food choice and eating habits: women tend to choose healthier foods and eat regular meals, while men show preferences for specific tastes and meal-related behaviors. This analysis underscores the nuanced differences between male and female dietary patterns, influenced not only by inherent biological factors such as genetics and hormonal responses but also by societal norms and cultural contexts. Taken together, our results highlight the importance of integrating different perspectives, thus providing valuable insights into the development of public health strategies and tailored nutrition interventions aimed at chronic disease prevention., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2024 Feraco, Armani, Amoah, Guseva, Camajani, Gorini, Strollo, Padua, Caprio and Lombardo.)

This cross-sectional study analyses differences in dietary habits, taste preferences, variety of protein sources and body composition (BC) profiles among individuals following omnivorous, flexitarian, lacto-ovo-vegetarian and pescatarian diets. Furthermore, it assesses the correlations between these dietary patterns and various sports, classified by exercise intensity, in relation to BC parameters. The study analysed the eating habits and BC data of 1342 participants aged 18-65 years, classified into four diet groups based on their 7-day food diaries and questionnaire responses. Our analysis revealed gender- and age-related differences in weekly food consumption and protein source variety, with men generally consuming more meat, processed meat and fish than women, especially in younger age groups. Differences in dairy and soy consumption were also noted between age groups, while legume and soy preferences showed no gender disparity across all ages. Among non-sporting individuals, vegetarians exhibited lower fat mass (FM%) compared to other diets, while among athletes, vegetarians and pescatarians in in endurance and strength sports, respectively, displayed lower FM%, with flexitarians and omnivores in endurance sports showing higher FM%. Non-athletic omnivores and vegetarians demonstrated a greater proportion of body protein, while among athletes, those engaged in strength training exhibited a higher body protein content across all dietary groups compared to those in endurance training. Among non-athletic groups, vegetarians exhibited the lowest FM/FFM (fat mass/fat-free mass) ratio, while among athletes, vegetarians in endurance sports and participants in strength training across other diets showed lower FM/FFM ratios. The results emphasise the complex interaction between diet, BC and lifestyle choices, revealing how different combinations of diet and sport are associated with optimised BC.

In this retrospective study, we evaluated the efficacy of a personalised low-calorie Mediterranean Diet (MD) in promoting fat mass (FM) reduction while preserving fat-free mass (FFM). This study involved 100 Caucasian adults aged 18-65 years who followed a tailored low-calorie MD for two months. The total energy expenditure was assessed using a multi-sensor armband. The change in body composition (BC) was evaluated using the Δ% FM-to-FFM ratio, calculated as the difference in the FM to FFM ratio before and after the diet, divided by the ratio before the diet, and multiplied by 100. A negative value indicates a greater decrease in FM than FFM, while a positive value suggests a greater increase in FM than FFM. This study demonstrated a significant FM reduction, with an average decrease of 5% ( p < 0.001). However, the relationship between caloric reduction and the Δ% FM-to-FFM ratio showed a weak negative correlation (r = -0.03, p > 0.05). This suggests that the calorie deficit had a minimal direct impact on the BC changes. Subjects over the age of 30 showed an increase in muscle mass, while younger subjects showed no significant changes. Moreover, a direct correlation was observed between the changes in MET (Metabolic Equivalent of Task) values and the Δ% FM-to-FFM ratio, indicating that improved average physical activity intensity positively influences BC. In the female subgroup, high protein intake, exercise intensity, and the duration of physical activity were positively correlated with an improvement in the Δ% FM-to-FFM ratio. However, for individuals with BMI 20-25 kg/m 2 , high fibre intake was surprisingly negatively correlated with the Δ% FM-to-FFM ratio. This study underscores the intricate interplay between calorie restriction, physical activity intensity, and BC changes. It also suggests that individual factors, including age, gender, and BMI, may influence the response to a low-calorie MD. However, further prospective studies with larger sample sizes are necessary to confirm and expand upon these findings.

Purpose: The aim of this study was to evaluate the relationships between health literacy, unrealistic optimism, and adherence to glycometabolic disease management related to erectile dysfunction (ED) in male patients with type 2 diabetes (T2D) or preDM., Materials and Methods: This prospective observational study enroled 167 consecutive patients with T2D and ED. All patients underwent the following examinations: (a) medical history collection; (b) Body Mass Index (BMI) determination; (c) hormonal and biochemical assessment; (d) duration of T2D, complications and treatment; (e) International Index of Erectile Function-5 questionnaire to assess ED; and (f) validated questionnaire to evaluate health literacy, unrealistic optimism, and treatment adherence., Results: Overall, mean age was 62.5 ± 9.4 years (range: 20-75) and mean BMI was 28.4 ± 4.8 kg/m 2 (range: 18.4-46.6). The mean IIEF-5 score was 15.4 ± 5.2 (range: 5-25). The majority of patients showed high health literacy. However, low health literacy was found in patients with higher IIEF-5 scores and high BMI. Unrealistic optimism was low in most patients. Higher adherence to treatment was found in patients who reported regular physical activity, who followed a diet, and in patients with a family history of T2D. Regarding anti-diabetic treatment, patients treated with insulin showed higher health literacy than patients not treated with other medications, whereas higher adherence was found in patients using SGLT2-i., Conclusions: This study highlighted the close relationship between metabolic compensation, BMI, ED, and psychological attitudes, including health literacy and unrealistic optimism., (© 2023 The Authors. Diabetes/Metabolism Research and Reviews published by John Wiley & Sons Ltd.)

Context: Poor glucose control has been associated with increased mortality in COVID-19 patients with type 1 diabetes (T1D)., Objective: This work aimed to assess the effect of prevaccination glucose control on antibody response to the SARS-CoV-2 vaccine BNT162b2 in T1D., Methods: We studied 26 patients with T1D scheduled to receive 2 doses, 21 days apart, of BNT162b2, followed prospectively for 6 months with regular evaluation of SARS-CoV-2 antibodies and glucose control. Immunoglobulin G (IgG) to spike glycoprotein were assessed by enzyme-linked immunosorbent assay, and serum neutralization by a live SARS-CoV-2 assay (Vero E6 cells system). Glycated hemoglobin A1c (HbA1c) and continuous glucose monitoring (CGM), including time in range (TIR) and above range (TAR), were collected. The primary exposure and outcome measures were prevaccination glucose control, and antibody response after vaccination, respectively., Results: Prevaccination HbA1c was unrelated to postvaccine spike IgG (r = -0.33; P = .14). Of note, the CGM profile collected during the 2 weeks preceding BNT162b2 administration correlated with postvaccine IgG response (TIR: r = 0.75; P = .02; TAR: r = -0.81; P = .008). Patients meeting the recommended prevaccination glucose targets of TIR (≥ 70%) and TAR (≤ 25%) developed stronger neutralizing antibody titers (P < .0001 and P = .008, respectively), regardless of HbA1c. Glucose control along the study time frame was also associated with IgG response during follow-up (TIR: r = 0.93; P < .0001; TAR: r = -0.84; P < .0001)., Conclusion: In T1D, glucose profile during the 2 weeks preceding vaccination is associated with stronger spike antibody binding and neutralization, highlighting a role for well-controlled blood glucose in vaccination efficacy., (© The Author(s) 2023. Published by Oxford University Press on behalf of the Endocrine Society. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

Oxidative stress, a key mediator of cardiovascular disease, metabolic alterations, and cancer, is independently associated with menopause and obesity. Yet, among postmenopausal women, the correlation between obesity and oxidative stress is poorly examined. Thus, in this study, we compared oxidative stress states in postmenopausal women with or without obesity. Body composition was assessed via DXA, while lipid peroxidation and total hydroperoxides were measured in patient's serum samples via thiobarbituric-acid-reactive substances (TBARS) and derivate-reactive oxygen metabolites (d-ROMs) assays, respectively. Accordingly, 31 postmenopausal women were enrolled: 12 with obesity and 19 of normal weight (mean (SD) age 71.0 (5.7) years). Doubled levels of serum markers of oxidative stress were observed in women with obesity in women with obesity compared to those of normal weight (H 2 O 2 : 32.35 (7.3) vs. 18.80 (3.4) mg H 2 O 2 /dL; malondialdehyde (MDA): 429.6 (138.1) vs. 155.9 (82.4) mM in women with or without obesity, respectively; p < 0.0001 for both). Correlation analysis showed that both markers of oxidative stress increased with an increasing body mass index (BMI), visceral fat mass, and trunk fat percentage, but not with fasting glucose levels. In conclusion, obesity and visceral fat are associated with a greater increase in oxidative stress in postmenopausal women, possibly increasing cardiometabolic and cancer risks.

Aims/hypothesis: Antibodies specific to oxidative post-translational modifications (oxPTM) of insulin (oxPTM-INS) are present in most individuals with type 1 diabetes, even before the clinical onset. However, the antigenic determinants of such response are still unknown. In this study, we investigated the antibody response to oxPTM-INS neoepitope peptides (oxPTM-INSPs) and evaluated their ability to stimulate humoral and T cell responses in type 1 diabetes. We also assessed the concordance between antibody and T cell responses to the oxPTM-INS neoantigenic peptides., Methods: oxPTM-INS was generated by exposing insulin to various reactive oxidants. The insulin fragments resulting from oxPTM were fractionated by size-exclusion chromatography further to ELISA and LC-MS/MS analysis to identify the oxidised peptide neoepitopes. Immunogenic peptide candidates were produced and then modified in house or designed to incorporate in silico-oxidised amino acids during synthesis. Autoantibodies to the oxPTM-INSPs were tested by ELISA using sera from 63 participants with new-onset type 1 diabetes and 30 control participants. An additional 18 fresh blood samples from participants with recently diagnosed type 1 diabetes, five with established disease, and from 11 control participants were used to evaluate, in parallel, CD4 + and CD8 + T cell activation by oxPTM-INSPs., Results: We observed antibody and T cell responses to three out of six LC-MS/MS-identified insulin peptide candidates: A:12-21 (SLYQLENYCN, native insulin peptide 3 [Nt-INSP-3]), B:11-30 (LVEALYLVCGERGFFYTPKT, Nt-INSP-4) and B:21-30 (ERGFFYTPKT, Nt-INSP-6). For Nt-INSP-4 and Nt-INSP-6, serum antibody binding was stronger in type 1 diabetes compared with healthy control participants (p≤0.02), with oxidised forms of ERGFFYTPKT, oxPTM-INSP-6 conferring the highest antibody binding (83% binders to peptide modified in house by hydroxyl radical [ ● OH] and >88% to in silico-oxidised peptide; p≤0.001 vs control participants). Nt-INSP-4 induced the strongest T cell stimulation in type 1 diabetes compared with control participants for both CD4 + (p<0.001) and CD8 + (p=0.049). CD4 + response to oxPTM-INSP-6 was also commoner in type 1 diabetes than in control participants (66.7% vs 27.3%; p=0.039). Among individuals with type 1 diabetes, the CD4 + response to oxPTM-INSP-6 was more frequent than to Nt-INSP-6 (66.7% vs 27.8%; p=0.045). Overall, 44.4% of patients showed a concordant autoimmune response to oxPTM-INSP involving simultaneously CD4 + and CD8 + T cells and autoantibodies., Conclusions/interpretation: Our findings support the concept that oxidative stress, and neoantigenic epitopes of insulin, may be involved in the immunopathogenesis of type 1 diabetes., (© 2022. The Author(s).)

Immune checkpoint inhibitors (ICIs) has revolutionized the treatment of different advanced solid tumors, but most patients develop severe immune-related adverse events (irAEs). Although a bi-directional crosstalk between bone and immune systems is widely described, the effect of ICIs on the skeleton is poorly investigated. Here, we analyze the changes in plasma levels of type I collagen C-terminal telopeptide (CTX-I) and N -terminal propeptide of type I procollagen (PINP), reference makers of bone turnover, in patients treated with ICIs and their association with clinical outcome. A series of 44 patients affected by advanced non-small cell lung cancer or renal cell carcinoma, without bone metastases, and treated with ICIs as monotherapy were enrolled. CTX-I and PINP plasma levels were assessed at baseline and after 3 months of ICIs treatment by ELISA kits. A significant increase of CTX-I with a concomitant decreasing trend towards the reduction of PINP was observed after 3 months of treatment. Intriguingly, CTX-I increase was associated with poor prognosis in terms of treatment response and survival. These data suggest a direct relationship between ICIs treatment, increased osteoclast activity and potential fracture risk. Overall, this study reveals that ICIs may act as triggers for skeletal events, and if confirmed in larger prospective studies, it would identify a new class of skeletal-related irAEs., Competing Interests: 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., (© 2022 The Authors. Published by Elsevier GmbH.)

Aims/hypothesis: We assessed the levels of blood circulating immune checkpoint molecules (ICMs) at diagnosis of type 1 diabetes, and determined their association with the risk of developing an additional autoimmune disorder over time., Methods: Children with new-onset type 1 diabetes (n = 143), without biological and/or clinical signs of additional autoimmune disorders, and healthy children (n = 75) were enrolled, and blood circulating levels of 14 ICMs were measured. The children with type 1 diabetes were divided into two groups on the basis of the development of an additional autoimmune disease in the 5 years after diabetes onset. Differences in soluble ICM levels between the groups were assessed, and a Cox regression analysis was used to evaluate their association with the risk of development of an additional autoimmune disease over time. To validate the data, circulating ICMs were measured in an independent cohort of 60 children with new-onset type 1 diabetes stratified into two groups., Results: We found that the levels of circulating ICMs were significantly higher in children with new-onset diabetes compared with healthy children. Further, we observed that children with type 1 diabetes who developed a second autoimmune disease over time (T1D-AAD + children) had higher levels of soluble ICMs than children with type 1 diabetes who did not (T1D-AAD - children). Cox regression models revealed that high circulating levels of CD137/4-1BB and PD-1 molecules at diabetes diagnosis were associated with the risk of developing an additional autoimmune disease in both type 1 diabetes cohorts., Conclusions/interpretation: Our findings suggest that soluble CD137/4-1BB and PD-1 molecules may be used as prognostic biomarkers in children with type 1 diabetes, and may pave the way for novel immunological screening at diabetes onset, allowing early identification of children at higher risk of developing other autoimmune conditions over time., (© 2022. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.)

Epidemiological evidence shows clear gender disparities in the Coronavirus 2019 Disease (COVID-19) severity and fatality. This may reflect the contribution of gender-related factors, such as sex hormones, to COVID-19 pathogenesis. However, the mechanism linking gender disparities to COVID-19 severity is still poorly understood. In this review, we will pinpoint several elements involved in COVID-19 pathogenesis that are regulated by the two main sex hormones, estrogen and androgen. These include tissue specific gene regulation of SARS-CoV2 entry factors, innate and adaptive immune responses to infection, immunometabolism, and susceptibility to tissue injury by cytopathic effect or hyper-inflammatory response. We will discuss the mechanistic link between sex hormone regulation of COVID-19 pathogenetic factors and disease severity. Finally, we will summarize current evidence from clinical studies and trials targeting sex hormones and their signalling in COVID-19. A better understanding of the role of sex hormones in COVID-19 may identify targets for therapeutic intervention and allow optimization of treatment outcomes towards gender-based personalised medicine., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2021 Tramontana, Battisti, Napoli and Strollo.)

Background and Objective: Bone fragility has been linked to COVID-19 severity. The objective of this study was to evaluate whether a diagnosis of vertebral fracture (VF) increased mortality risk in COVID-19 patients and whether this effect was greater than in those without COVID-19., Methods: We assessed VFs by computed tomography (CT) in a cohort of 501 patients consecutively admitted to the emergency department (ED) for clinical suspicion of SARS-CoV-2 infection during the first wave of pandemic emergency. Of those, 239 had a confirmed diagnosis of COVID-19., Results: VF prevalence was similar between COVID-19 and non-COVID-19 groups (22.2 vs. 19%; p = 0.458). Death rates were similar between COVID-19 and non-COVID-19 groups at both 30 (15.8 vs. 12.2%; p = 0.234) and 120 days (21.8 vs. 17.6%; p = 0.236). The mortality risk was higher in COVID-19 patients either with one or multiple fractures compared to those without VFs, at 30 and 120 days, but statistical significance was reached only in those with multiple VFs (30-day HR 3.03, 95% CI 1.36-6.75; 120-day HR 2.91, 95% CI 1.43-5.91). In the non-COVID-19 group, the 30-day mortality risk was significantly higher in patients either with one (HR 7.46, 95% CI 3.12-17.8) or multiple fractures (HR 6.2, 95% CI 2.75-13.98) compared to those without VFs. A similar effect was observed at 120 days. After adjustment for age, sex and bone density, mortality risk remained associated with VFs in the non-COVID-19 group only., Conclusions: VFs were not independently associated with short-term mortality in patients with COVID-19, but they strongly increased mortality risk in those without COVID-19., (© 2021. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

Background: A growing body of evidence suggests a potential link between bone metabolism and cardiovascular disease. Aim of this study was to investigate the relationship between levels of circulating bone turnover biomarkers and advanced atherosclerosis., Methods: Klotho (KL), sclerostin (SOST), osteopontin (OPN) and osteoprotegerin (OPG) were measured in patients undergoing elective coronary angiography and carotid Doppler ultrasound. The primary outcome was the difference in bone biomarkers levels between participants with and without advanced atherosclerosis, defined as the presence of a critical coronary (≥70%) and/or carotid (≥50%) stenosis., Results: A total of 80 subjects (32.5% females) with a mean age of 68 ± 10 years were included. Advanced atherosclerosis was detected in 55 (68.8%) patients. Subjects with advanced atherosclerosis showed higher serum levels of OPG (p = 0.0015) and SOST (p = 0.017) and similar levels of KL (p = 0.62) and OPN (p = 0.06) compared to patients without. After adjustment for age and sex, only elevated levels of OPG remained significantly associated with advanced atherosclerosis (p = 0.011)., Conclusions: Higher serum levels of OPG are independently associated with advanced atherosclerosis confirming a common bond between bone metabolism and vascular disease. Further investigations on the role of selected bone biomarkers in the pathogenesis of cardiovascular disease are needed.

High fracture rate and high circulating levels of the Wnt inhibitor, sclerostin, have been reported in diabetic patients. We studied the effects of Wnt signaling activation on bone health in a mouse model of insulin-deficient diabetes. We introduced the sclerostin-resistant Lrp5 A214V mutation, associated with high bone mass, in mice carrying the Ins2 Akita mutation (Akita), which results in loss of beta cells, insulin deficiency, and diabetes in males. Akita mice accrue less trabecular bone mass with age relative to wild type (WT). Double heterozygous Lrp5 A214V /Akita mutants have high trabecular bone mass and cortical thickness relative to WT animals, as do Lrp5 A214V single mutants. Likewise, the Lrp5 A214V mutation prevents deterioration of biomechanical properties occurring in Akita mice. Notably, Lrp5 A214V /Akita mice develop fasting hyperglycemia and glucose intolerance with a delay relative to Akita mice (7 to 8 vs. 5 to 6 weeks, respectively), despite lack of insulin production in both groups by 6 weeks of age. Although insulin sensitivity is partially preserved in double heterozygous Lrp5 A214V /Akita relative to Akita mutants up to 30 weeks of age, insulin-dependent phosphorylated protein kinase B (pAKT) activation in vitro is not altered by the Lrp5 A214V mutation. Although white adipose tissue depots are equally reduced in both compound and Akita mice, the Lrp5 A214V mutation prevents brown adipose tissue whitening that occurs in Akita mice. Thus, hyperactivation of Lrp5-dependent signaling fully protects bone mass and strength in prolonged hyperglycemia and improves peripheral glucose metabolism in an insulin independent manner. Wnt signaling activation represents an ideal therapeutic approach for diabetic patients at high risk of fracture. © 2021 The Authors. Journal of Bone and Mineral Research published by Wiley Periodicals LLC on behalf of American Society for Bone and Mineral Research (ASBMR)., (© 2021 The Authors. Journal of Bone and Mineral Research published by Wiley Periodicals LLC on behalf of American Society for Bone and Mineral Research (ASBMR).)

Aims: Microvascular complications' risk differs between people with latent autoimmune diabetes in adults (LADA) and people with type 2 diabetes. We aimed to investigate whether the prevalence of cardiac autonomic neuropathy, a life-threatening complication of diabetes, also varies depending on diabetes type., Methods: In this cross-sectional study, 43 adults with LADA, 80 with type 1 diabetes and 61 with type 2 diabetes were screened for cardiac autonomic neuropathy with recommended tests. Logistic regression models were used to test differences between diabetes types adjusting for confounders., Results: Cardiac autonomic neuropathy was diagnosed in 17 (40%) participants with LADA, 21 (26%) participants with type 1 diabetes and 39 (64%) participants with type 2 diabetes (p < 0.001). The odds ratio (OR) for cardiac autonomic neuropathy in type 1 diabetes and in type 2 diabetes compared to LADA were 0.54 (95% CI: 0.25-1.20, p-value: 0.13) and 2.71 (95% CI: 1.21-6.06, p-value 0.015) respectively. Smoking ( adj OR 3.09, 95% CI: 1.40-6.82, p-value: 0.005), HDL cholesterol ( adj OR 0.29, 95% CI: 0.09-0.93, p-value: 0.037) and hypertension ( adj OR 2.11, 95% CI: 1.05-4.24, p-value: 0.037) were independent modifiable risk factors for cardiac autonomic neuropathy. Differences among diabetes types did not change after correction for confounders., Conclusions: This is the first study offering a comparative evaluation of cardiac autonomic neuropathy among LADA, type 1 and type 2 diabetes, showing a lower risk of cardiac autonomic neuropathy in LADA compared to type 2 diabetes and similar compared to type 1 diabetes. This disparity was not due to differences in age, metabolic control or cardiovascular risk factors., (© 2020 Diabetes UK.)

In a nationwide study of 3818 charts from patients with fatal COVID-19, we found that geographical differences in Dipeptidyl peptidase 4 (DPP4) inhibitors use did not correlate with diabetes prevalence among COVID-19 deaths, thus not supporting the hypothesis of a clinically relevant involvement of DPP4 inhibition in COVID-19 development and progression., Competing Interests: Conflict of interests RS, MD and CP have no conflict of interest to declare for the preparation of this manuscript. EM has received speaker fees from Astra-Zeneca and Lilly and research grants from scientific societies with the unrestricted support from AstraZeneca. PP has received speaker fees from AstraZeneca, MSD and Lilly. RB has received speaker fees from AstraZeneca, MSD and Lilly, (Copyright © 2020 Elsevier B.V. All rights reserved.)

Increased circulating sclerostin and accumulation of advanced glycation end-products (AGEs) are two potential mechanisms underlying low bone turnover and increased fracture risk in type 2 diabetes (T2D). Whether the expression of the sclerostin-encoding SOST gene is altered in T2D, and whether it is associated with AGEs accumulation or regulation of other bone formation-related genes is unknown. We hypothesized that AGEs accumulate and SOST gene expression is upregulated in bones from subjects with T2D, leading to downregulation of bone forming genes (RUNX2 and osteocalcin) and impaired bone microarchitecture and strength. We obtained bone tissue from femoral heads of 19 T2D postmenopausal women (mean glycated hemoglobin [HbA1c] 6.5%) and 73 age- and BMI-comparable nondiabetic women undergoing hip replacement surgery. Despite similar bone mineral density (BMD) and biomechanical properties, we found a significantly higher SOST (p = .006) and a parallel lower RUNX2 (p = .025) expression in T2D compared with non-diabetic subjects. Osteocalcin gene expression did not differ between T2D and non-diabetic subjects, as well as circulating osteocalcin and sclerostin levels. We found a 1.5-fold increase in total bone AGEs content in T2D compared with non-diabetic women (364.8 ± 78.2 versus 209.9 ± 34.4 μg quinine/g collagen, respectively; p < .001). AGEs bone content correlated with worse bone microarchitecture, including lower volumetric BMD (r = -0.633; p = .02), BV/TV (r = -0.59; p = .033) and increased trabecular separation/spacing (r = 0.624; p = .023). In conclusion, our data show that even in patients with good glycemic control, T2D affects the expression of genes controlling bone formation (SOST and RUNX2). We also found that accumulation of AGEs is associated with impaired bone microarchitecture. We provide novel insights that may help understand the mechanisms underlying bone fragility in T2D. © 2020 American Society for Bone and Mineral Research (ASBMR)., (© 2020 American Society for Bone and Mineral Research (ASBMR).)

Aims/hypothesis: We aimed to analyse the association between plasma circulating microRNAs (miRNAs) and the immunometabolic profile in children with type 1 diabetes and to identify a composite signature of miRNAs/immunometabolic factors able to predict type 1 diabetes progression., Methods: Plasma samples were obtained from children at diagnosis of type 1 diabetes (n = 88) and at 12 (n = 32) and 24 (n = 30) months after disease onset and from healthy control children with similar sex and age distribution (n = 47). We quantified 60 robustly expressed plasma circulating miRNAs by quantitative RT-PCR and nine plasma immunometabolic factors with a recognised role at the interface of metabolic and immune alterations in type 1 diabetes. Based on fasting C-peptide loss over time, children with type 1 diabetes were stratified into the following groups: those who had lost >90% of C-peptide compared with diagnosis level; those who had lost <10% of C-peptide; those showing an intermediate C-peptide loss. To evaluate the modulation of plasma circulating miRNAs during the course of type 1 diabetes, logistic regression models were implemented and the correlation between miRNAs and immunometabolic factors was also assessed. Results were then validated in an independent cohort of children with recent-onset type 1 diabetes (n = 18). The prognostic value of the identified plasma signature was tested by a neural network-based model., Results: Plasma circulating miR-23~27~24 clusters (miR-23a-3p, miR-23b-3p, miR-24-3p, miR-27a-3p and miR-27b-3p) were upmodulated upon type 1 diabetes progression, showed positive correlation with osteoprotegerin (OPG) and were negatively correlated with soluble CD40 ligand, resistin, myeloperoxidase and soluble TNF receptor in children with type 1 diabetes but not in healthy children. The combination of plasma circulating miR-23a-3p, miR-23b-3p, miR-24-3p, miR-27b-3p and OPG, quantified at disease onset, showed a significant capability to predict the decline in insulin secretion 12 months after disease diagnosis in two independent cohorts of children with type 1 diabetes., Conclusions/interpretations: We have pinpointed a novel miR-23a-3p/miR-23b-3p/miR-24-3p/miR-27b-3p/OPG plasma signature that may be developed into a novel blood-based method to better stratify patients with type 1 diabetes and predict C-peptide loss.

Dipeptidyl peptidase 4 (DPP4), also known as cluster of differentiation 26 (CD26), is a serine exopeptidase expressed ubiquitously in several tissues, including but not limited to lung, kidney, liver, gut, and immune cells. The question has been raised on whether DPP4 modulation or inhibition may prevent infection and/or progression of the COVID-19. A docked complex model of the SARS-CoV-2 spike glycoprotein and DPP4 has been proposed, showing a large interface between the proteins and proposing close similarity with other coronaviruses using DPP4 as functional receptor. In absence of experimental validation, these data should be interpreted with caution. Nevertheless, this observation may rise the question on whether DPP4 is directly involved in SARS-CoV-2 cell adhesion/virulence, and whether DPP4 inhibition might be a therapeutic strategy for preventing infection. Although a direct involvement of DPP4 in SARS-CoV-2 infection needs to be clarified, there is also evidence suggesting that DPP4 inhibitors modulate inflammation and exert anti-fibrotic activity. These properties may be of potential use for halting progression to the hyperinflammatory state associated with severe COVID-19. Taken together these findings may suggest a potential role for DPP4 inhibition or modulation in one or more steps of COVID-19 immunopathogenesis., (© 2020 John Wiley & Sons Ltd.)

Coronavirus 2019 disease (COVID-19) mostly adversely affects the elderly, a population at higher risk for low serum 25-hydroxyvitamin D (25(OH)D) levels. In this viewpoint, we highlight the well-known musculoskeletal properties of vitamin D, which are particularly relevant in the context of COVID-19, suggesting further potential benefits through extra-skeletal effects. Maintaining optimal 25(OH)D is crucial to prevent falls, frailty and fractures in elderly patients, with low activity levels due to lockdown, or who are relatively immobilized during hospitalization and after discharge for prolonged periods of time. Hypovitaminosis D is also associated with susceptibility to respiratory infections, admissions to the intensive care unit, and mortality. We underscore the importance of achieving desirable serum 25(OH)D in COVID-19 elderly patients, to ensure beneficial musculoskeletal effects and possibly respiratory effects of vitamin D, in the context of COVID-19.

Objectives: The discovery of diseased tissue-specific neoantigens offers the opportunity to develop important disease tissue-specific biomarkers that can help in the prediction, diagnosis, and stratification of diseases. This opportunity is specifically significant for autoimmune diseases where diagnostic biomarkers are not available. Inflammatory autoimmune diseases are commonly associated with local generation of large amounts of reactive oxidants. We have previously identified oxidative post-translationally modified (oxPTM) tissue-specific neoantigens in rheumatoid arthritis (RA) and type 1 diabetes that elicit an immune response. In the current study, we studied the presence and clinical significance of antibodies to oxPTM collagen type II (CII) in patients with spondyloarthritis (SpA)., Method: Levels of antibodies specific to native CII and oxPTM-CII were assessed by enzyme-linked immunosorbent assay., Results: Immunoglobulin G (IgG) binding to oxPTM-CII was observed in 52%, 83%, and 28% of serum samples from patients with axial spondyloarthritis (axSpA), RA, and psoriatic arthritis (PsA), respectively. Importantly, while strong IgA anti-oxPTM-CII responses were detected in axSpA and PsA patients, with 47% and 84% respective binders, no IgA anti-oxPTM-CII was detected in RA patients. IgA anti-oxPTM-CII reactivity in axSpA patients treated with biologics was higher and more frequent, with 85% binders compared to 9% binders in patients treated with synthetic disease-modifying anti-rheumatic drugs., Conclusion: Our data imply that SpA and PsA are associated with the presence of antibodies to oxPTM-CII, suggesting that there may be a humoral component that may distinguish patients with SpA from RA. Our approach could be adapted to other diseases, particularly to inflammatory autoimmune diseases.

Objective: To determine clinical diabetes-related risk factors for fragility fractures in type 1 diabetes (T1D)., Research Design and Methods: History of bone fragility fractures occurring after T1D diagnosis was assessed by questionnaire in this cross-sectional study in 600 T1D subjects. Glycated hemoglobin A1c (HbA1c) over the previous 5 years was used as an index of long-term glycemic control; complications were adjudicated by physician assessment. Multinomial logistic regression models were used to assess the associations between diabetes-related risk factors and fracture history., Results: One-hundred-eleven patients (18.5%) reported at least one fracture; of these 73.8% had only one and 26.2% had more than one fracture. Average age was 41.9 ± 12.8 years, with even gender distribution; disease duration was 19.9 ± 12.0 years; and BMI was 24.4 ± 3.7 kg/m 2 . The 5-year average HbA1c was 7.6 ± 1.0% (60 mmol/mol). In adjusted models, reduced risk for 1 fracture was found in those with higher creatinine clearance rate (CCr) (RRR 0.22 [95% CI: 0.06-0.83] for 1 unit increase in lnCCr, p = 0.03) and increased risk in those with neuropathy (RRR 2.57 [1.21-5.46], p = 0.01). Increased risk for ≥2 fractures was found in subjects in the highest tertile of HbA1c (≥7.9%) compared with the lowest tertile (≤7.17%) (RRR 3.50 [1.04-11.7], p = 0.04) and of disease duration (≥26 years versus <14 years) (RRR 7.59 [1.60-35.98], p = 0.01)., Conclusions: Poor glycemic control and long exposure to the disease are independent diabetes-related risk factors for multiple bone fractures in T1D., (Copyright © 2019 Elsevier Inc. All rights reserved.)

Background: Antibodies to posttranslationally modified insulin (oxPTM-INS-Ab) are a novel biomarker of type 1 diabetes (T1D). Here, we evaluated whether oxPTM-INS-Ab can improve T1D prediction in children with positive standard islet autoantibodies (AAB)., Methods: We evaluated sensitivity, specificity, accuracy, and risk for progression to T1D associated with oxPTM-INS-Ab and the standard islet AAB that include insulin (IAA), GAD (GADA), and tyrosine phosphatase 2 (IA-2A) in a cohort of islet AAB-positive (AAB + ) children from the general population (median follow-up 8.8 years)., Results: oxPTM-INS-Ab was the most sensitive and specific autoantibody biomarker (74% sensitivity, 91% specificity), followed by IA-2A (71% sensitivity, 91% specificity). GADA and IAA showed lower sensitivity (65% and 50%, respectively) and specificity (66% and 68%, respectively). Accuracy (AUC of ROC) of oxPTM-INS-Ab was higher than GADA and IAA (P = 0.003 and P = 0.017, respectively), and similar to IA-2A (P = 0.896). oxPTM-INS-Ab and IA-2A were more effective than IAA for detecting progr-T1D when used as second-line biomarker in GADA + children. Risk for diabetes was higher (P = 0.03) among multiple AAB + who were also oxPTM-INS-Ab + compared with those who were oxPTM-INS-Ab - . Importantly, when replacing IAA with oxPTM-INS-Ab, diabetes risk increased to 100% in children with oxPTM-INS-Ab + in combination with GADA + and IA-2A + , compared with 84.37% in those with IAA + , GADA + , and IA-2A + (P = 0.04)., Conclusions: Antibodies to oxidized insulin (oxPTM-INS-Ab), compared with IAA which measure autoantibodies to native insulin, improve T1D risk assessment and prediction accuracy in AAB + children., (© 2019 John Wiley & Sons, Ltd.)

Purpose: Bone formation is impaired in both type 1 diabetes and type 2 diabetes (T2D), whereas sclerostin, an antagonist of bone formation, is increased in T2D only. No data are available on latent autoimmune diabetes in adults (LADA), an autoimmune type of diabetes that may clinically resemble T2D at diagnosis. We evaluated serum sclerostin and bone turnover markers in LADA compared with those in T2D and whether metabolic syndrome (MetS) affects sclerostin in T2D or LADA., Methods: This cross-sectional study included 98 patients with T2D and 89 with LADA from the Action LADA and Non Insulin Requiring Autoimmune Diabetes cohorts. Patients were further divided according to MetS status. Nondiabetic participants (n = 53) were used as controls. Serum sclerostin, bone formation (pro-collagen type 1 N-terminal propeptide [P1NP]), and bone resorption (C-terminal telopeptide of type I collagen [CTX]) were analyzed., Results: Patients with T2D had higher sclerostin than did those with LADA [P = 0.0008, adjusted for sex and body mass index (BMI)], even when analysis was restricted to patients with MetS (adjusted P = 0.03). Analysis of T2D and LADA groups separately showed that sclerostin was similar between those with and those without MetS. However, a positive trend between sclerostin and number of MetS features was seen with T2D (P for trend = 0.001) but not with LADA. Patients with T2D or LADA had lower CTX than did controls (P = 0.0003) and did not have significantly reduced P1NP. Sclerostin was unrelated to age or hemoglobin A1c but was correlated with BMI (ρ = 0.29; P = 0.0001), high-density lipoprotein (ρ = -0.23; P = 0.003), triglycerides (ρ = 0.19; P = 0.002), and time since diagnosis (ρ = 0.32; P < 0.0001)., Conclusions: Patients with LADA presented lower bone resorption than did controls, similar to patients with T2D. Sclerostin is increased in T2D but not in LADA, suggesting possible roles on bone metabolism in T2D only.

Aims/hypothesis: We have shown that autoimmunity to insulin in type 1 diabetes may result from neoepitopes induced by oxidative post-translational modifications (oxPTM). Antibodies specific to oxPTM-insulin (oxPTM-INS-Ab) are present in most newly diagnosed individuals with type 1 diabetes and are more common than autoantibodies to native insulin. In this study, we investigated whether oxPTM-INS-Ab are present before clinical onset of type 1 diabetes, and evaluated the ability of oxPTM-INS-Ab to identify children progressing to type 1 diabetes., Methods: We used serum samples collected longitudinally from the 'All Babies in Southeast Sweden (ABIS)' cohort tested for the gold standard islet autoantibodies to insulin (IAA), GAD (GADA), tyrosine phosphatase 2 (IA-2A) and zinc transporter 8 (ZnT8A). We studied 23 children who progressed to type 1 diabetes (progr-T1D) and 63 children who did not progress to type 1 diabetes (NP) after a median follow-up of 10.8 years (interquartile range 7.7-12.8). Of the latter group, 32 were positive for one or more islet autoantibodies (NP-AAB + ). oxPTM-INS-Ab to insulin modified by • OH or HOCl were measured by our developed ELISA platform., Results: Antibodies to at least one oxPTM-INS were present in 91.3% of progr-T1D children. oxPTM-INS-Ab co-existed with GADA, IA-2A, IAA or ZnT8A in 65.2%, 56.5%, 38.9% and 33.3% progr-T1D children, respectively. In addition, oxPTM-INS-Ab were present in 17.4%, 26.1%, 38.9% and 41.6% of progr-T1D children who were negative for GADA, IA-2A, IAA and ZnT8A, respectively. • OH-INS-Ab were more common in progr-T1D children than in NP-AAB + children (82.6% vs 19%; p < 0.001) and allowed discrimination between progr-T1D and NP-AAB + children with 74% sensitivity and 91% specificity. None of the NP-AAB - children were positive for oxPTM-INS-Ab., Conclusions/interpretation: oxPTM-INS-Ab are present before the clinical onset of type 1 diabetes and can identify children progressing to type 1 diabetes.

Background: Sclerostin has been directly related to bone turnover increase in dietary-induced weight loss in non-diabetics. This has not been studied in type 2 diabetes, a condition characterized by increased circulating sclerostin and impaired bone turnover., Purpose: To study the effect of dietary weight loss and quality of the dietary intervention on changes of sclerostin and bone turnover markers in type 2 diabetes., Methods: This was a post-hoc analysis of the MADIAB trial, a 21-day randomized controlled trial on overweight/obese type 2 diabetes patients. Patients were randomly assigned 1:1 to the Ma-Pi2 macrobiotic diet or a control diet based on dietary guidelines for type 2 diabetes. Serum sclerostin and circulating markers of bone resorption and formation (P1NP) were measured by enzyme linked immunosorbent assay in 40 subjects (1:1) at baseline and after 21 days treatment., Results: Both Ma-Pi2 and the control diet groups had significant decreases in body weight (6.0 ± 0.2 vs. 3.2 ± 0.1 %, p < 0.001). Sclerostin increased significantly in the two groups (all p < 0.001) but Ma-Pi2 diet group experienced a greater increase in sclerostin (34.5 vs. 15 %; p = 0.024). Serum circulating markers of bone resorption increased in the two groups (all p < 0.001); circulating markers of bone resorption at the end of the treatment tended to be higher in Ma-Pi2 diet than the control diet group (p = 0.06). P1NP did not change significantly in the two group compared to baseline. Sclerostin changes were related to body mass index reduction (r = -0.37; p = 0.02)., Conclusions: Diet-induced weight loss may induce significant and rapid changes in bone turnover and sclerostin levels. These changes may further impair bone health in subjects with type 2 diabetes.

Aims: Charcot neuroarthropathy (CN) is a disabling complication, culminating in bone destruction and involving joints and articular cartilage with high inflammatory environment. Its real pathogenesis is as yet unknown. In autoinflammatory diseases, such as rheumatoid arthritis, characterized by inflammation and joint involvement, autoantibodies against oxidative post-translationally modified (oxPTM) collagen type I (CI) and type II (CII) were detected. Therefore, the aim of our study was to assess the potential involvement of autoimmunity in charcot neuroarthropathy, investigating the presence of autoantibodies oxPTM-CI and oxPTM-CII, in participants with charcot neuroarthropathy., Methods: In this case-control study, we enrolled 124 participants with type 2 diabetes mellitus (47 with charcot neuroarthropathy, 37 with diabetic peripheral neuropathy without charcot neuroarthropathy, and 40 with uncomplicated diabetes), and 32 healthy controls. The CI and CII were modified with ribose and other oxidant species, and the modifications were evaluated with sodium dodecyl sulfate-polyacrylamide gel electrophoresis. Binding of sera from the participants was analyzed with enzyme-linked immunosorbent assay., Results: Age, body mass index, waist and hip circumferences, and lipid profile were similar across the 4 groups, as well as glycated hemoglobin and duration of diabetes among people with diabetes. An increased binding to both native and all oxidation-modified forms of CII was found in participants with CN and diabetic neuropathy. Conversely, for CI, an aspecific increased reactivity was noted., Conclusions: Our results detected the presence of autoantibodies against oxidative post-translational modified collagen, particularly type 2 collagen, in participants with charcot neuroarthropathy and diabetic neuropathy, suggesting the possible involvement of autoimmunity. Further studies are required to understand the role of autoimmunity in the pathogenesis of charcot neuroarthropathy., (Copyright © 2016 John Wiley & Sons, Ltd.)

Aim/hypothesis: Insulin is the most specific beta cell antigen and a potential primary autoantigen in type 1 diabetes. Insulin autoantibodies (IAAs) are the earliest marker of beta cell autoimmunity; however, only slightly more than 50% of children and even fewer adults newly diagnosed with type 1 diabetes are IAA positive. The aim of this investigation was to determine if oxidative post-translational modification (oxPTM) of insulin by reactive oxidants associated with islet inflammation generates neoepitopes that stimulate an immune response in individuals with type 1 diabetes., Methods: oxPTM of insulin was generated using ribose and various reactive oxygen species. Modifications were analysed by SDS-PAGE, three-dimensional fluorescence and MS. Autoreactivity to oxPTM insulin (oxPTM-INS) was observed by ELISA and western blotting, using sera from participants with type 1 or type 2 diabetes and healthy controls as probes. IAA was measured using the gold-standard radiobinding assay (RBA)., Results: MS of oxPTM-INS identified chlorination of Tyr16 and Tyr26; oxidation of His5, Cys7 and Phe24; and glycation of Lys29 and Phe1 in chain B. Significantly higher binding to oxPTM-INS vs native insulin was observed in participants with type 1 diabetes, with 84% sensitivity compared with 61% sensitivity for RBA. oxPTM-INS autoantibodies and IAA co-existed in 50% of those with type 1 diabetes. Importantly 34% of those with diabetes who were IAA negative were oxPTM-INS positive. Altogether, 95% of participants with type 1 diabetes presented with autoimmunity to insulin by RBA, oxPTM-INS or both. Binding to oxPTM-INS was directed towards oxPTM-INS fragments with slower mobility than native insulin., Conclusion/interpretation: These data suggest that oxPTM-INS is a potential autoantigen in individuals with new-onset type 1 diabetes.