BACKGROUND:Evidence regarding thyroid function changes with ageing remains inconsistent and the implications of potential changes are unclear. We aimed to investigate ageing-related thyroid function changes and their associations with mortality. METHODS:In this individual participant data (IPD) analysis, prospective population-based cohorts were eligible for inclusion when data on thyroid function measurements and mortality were available in individuals aged 18 years and older. Eligible datasets were identified through a systematic search of PubMed. We excluded cohorts of participants with only thyroid disease or thyroid-altering medications, or pregnant individuals. We requested data from all eligible cohorts that agreed to participate in the study. Linear mixed models were used to investigate associations between age and thyroid function, stratified for sex and regional iodine status. Annual changes in thyroid-stimulating hormone (TSH) and free thyroxine (FT4) were estimated per individual and categorised into quintiles, with the highest and lowest quintiles defined as increasing and decreasing, respectively, and the rest as stable. Patterns of thyroid function change were identified based on combined TSH and FT4 evolution. We used cohort-stratified Cox models to assess associations between changing patterns and all-cause mortality. This study is registered with PROSPERO, CRD42023408086. FINDINGS:In this IPD analysis, we analysed data collected between Jan 1, 2011, and Oct 13, 2022, from 31 cohorts across Europe (n=19), the USA (n=5), Asia (n=3), Brazil (n=2), and Australia (n=2; 137 488 participants; 68 322 [49·7%] were female and 69 166 [50·3%] were male; median age 60 years [range 18-106]). Cross-sectionally, older age was associated with higher TSH in iodine-sufficient regions and with lower TSH in iodine-insufficient regions. Longitudinal analyses showed that TSH increased with increasing age regardless of iodine status. The overall increase in TSH from age 18 years to 100 years was 0·61 mIU/L (0·52 SD) for female participants and 0·99 mIU/L (0·76) for male participants from iodine-sufficient regions. Greater variability in population distribution and longitudinal TSH changes was observed in adults aged 65 years or older. Higher FT4 with older age was suggested cross-sectionally, but longitudinally FT4 increased in iodine-sufficient regions and decreased in iodine-insufficient regions. Compared with stable thyroid function, all changing patterns were associated with increased all-cause mortality: hazard ratios of 1·80 (95% CI 1·57-2·06) for increasing TSH with stable or decreasing FT4; 2·45 (2·01-2·97) for increasing TSH and increasing FT4; 2·45 (1·99-3·01) for decreasing TSH with decreasing FT4; and 1·94 (1·68-2·24) for decreasing TSH with stable or increasing FT4. INTERPRETATION:Ageing-related changes in thyroid function varied by sex and iodine status. Most individuals had stable thyroid function during ageing with a slight increase in TSH, although older adults displayed greater variability. Patterns of changing thyroid function were associated with an increased all-cause mortality risk, warranting further exploration of the underlying mechanisms and clinical management. FUNDING:None.

AIMS:To investigate the association of post-oral glucose tolerance test (OGTT) hypoglycaemia with clinical features, incident diabetes and mortality. MATERIALS AND METHODS:This population-based cohort study included 2924 adults (median age 49 years, 1680 women) without known diabetes who underwent a 75-g OGTT as part of the Di@bet.es Study. Metabolic, demographic and lifestyle variables were collected. Serum glucose and insulin concentrations at 0, 30 and 120 min during the OGTT were obtained, allowing insulin resistance estimation using the HOMA-IR and the Matsuda Index. Participants were grouped according to serum glucose at 120 min: < 70 mg/dL (post-OGTT hypoglycaemia), 70 to < 140 mg/dL (normal result), 140 to < 200 mg/dL, and ≥ 200 mg/dL. The incidence of diabetes (median follow-up, 7.5 years) and mortality (median follow-up, 14.5 years) were assessed. RESULTS:Participants with post-OGTT hypoglycaemia (n = 327, 11.1%) were younger, leaner, less insulin resistant and more frequently active smokers. Despite having the lowest serum glucose at 0, 30 and 120 min, and the lowest serum insulin at 0 and 120 min, these participants tended to have the highest serum insulin concentrations at 30 min. Participants with post-OGTT hypoglycaemia had the lowest incidence of diabetes and mortality, although these associations were attenuated after adjusting for confounders (such as age, sex, body mass index and physical activity) and when compared specifically with the normal result group. CONCLUSIONS:Post-OGTT hypoglycaemia is more frequent in smokers, younger individuals, and those with a favourable metabolic profile. Post-OGTT hypoglycaemia acts as a marker of protection for incident diabetes and mortality. Preserved early insulin secretion together with good insulin sensitivity could explain post-OGTT hypoglycaemia.

AIMS:Cardiovascular disease (CVD) remains the leading cause of mortality. New biomarkers are needed to improve CVD risk prediction. Several studies have reported associations between surfactant protein D (SP-D), an innate immune system component, and CVD; however, general population studies remain scarce. The main aim of this study was to investigate the association between SP-D and CVD events incidence in the Spanish general adult population. METHODS:Socio-demographic, lifestyle (including smoking status) and clinical data from 1707 participants of the di@bet.es cohort without previous CVD events were collected and analysed. CVD events (including both morbidity and mortality) were reported at baseline and after 7.5 years of follow-up. SP-D serum levels were measured by ELISA and categorized in quartiles. RESULTS:SP-D categories are associated with CVD events incidence, independently from other strong risk factors such as cardiovascular risk scores (SCORE2 and SCORE2-OP), BMI, hs-CRP, or eGFR. Although SP-D has been linked to smoking, SP-D categories predicted CVD events incidence even among non-smokers. The addition of SP-D to multivariate models improved performance in the assessment, predicting 83% of the events with a specificity of 74% and a sensitivity of 84% in the overall population. CONCLUSIONS:SP-D may be considered as a promising biomarker of CVD events in combination with other well established factors in clinical practice.

It is well known that environmental factors influence the risk of type 2 diabetes mellitus (T2DM). Several studies have linked the xenobiotics present in tobacco or air pollutants to T2DM development, although the underlying mechanisms remain unclear. Surfactant protein D (SP-D), an immune component released into the bloodstream after lung injury, has been associated with metabolic diseases. The aim of this study was to investigate whether SP-D mediates the effects of smoking or air pollution exposure on T2DM risk in the Spanish adult population. Socio-demographic, lifestyle (including smoking status) and clinical data from 2155 participants from the Di@bet.es cohort were analyzed. Annual concentrations of PM10, PM2.5, SO2, CO and NO2 according to participants’ residential address codes were used to study air pollution exposure. T2DM was diagnosed at baseline and after 7.5 years of follow-up. SP-D serum levels were measured by ELISA and categorized as above or below the 25th percentile. Our results revealed a higher percentage of smokers in the high SP-D category; however, no associations were observed between air pollutants (PM10, PM2.5, SO2, CO) and SP-D categories. Both smoking and elevated SP-D levels were found to increase the risk of T2DM independently. Mediation analysis indicated that SP-D mediates 14% of the effect of smoking on T2DM incidence in the Spanish adult population.

OBJECTIVE:The association of thyroid peroxidase antibodies (TPOAb) status with cardiovascular disease (CVD) risk, independent of thyroid function, remains unclear. We aimed to determine whether positive TPOAb is associated with increased CVD risk, overall and among individuals with subclinical hypothyroidism. METHODS:We conducted a 2-stage individual participant data analysis including cohort studies identified through the Thyroid Studies Collaboration and systematic database searches (MEDLINE, EMBASE, Cochrane Library) through November 2024. Primary outcomes were coronary heart disease (CHD) events, CHD mortality, stroke events, and stroke mortality. We used Cox proportional hazards models, adjusted for age, sex, and thyroid-stimulating hormone (TSH) within each cohort, followed by a random-effects meta-analysis to assess cardiovascular outcomes by TPOAb status, overall and in the subclinical hypothyroidism subgroup. RESULTS:Among 100 250 adults from 14 cohort studies (median age 55 years, 56.7% women), 11.9% were TPOAb-positive, and 5.4% had subclinical hypothyroidism. In the overall population, we found no evidence of increased CVD risk in TPOAb-positive compared to TPOAb-negative individuals: Hazard ratio (HR) 1.00 (95% CI 0.90-1.11) for CHD events; HR 0.95 (95% CI 0.78-1.16) for CHD mortality; HR 0.98 (95% CI 0.87-1.11) for stroke events; and HR 1.06 (95% CI 0.81-1.40) for stroke mortality. In subclinical hypothyroidism, positive TPOAb was similarly not associated with increased risk for any of the CVD outcomes. CONCLUSIONS:Positive TPOAb status was not associated with increased risk of CHD or stroke. These findings do not support the use of TPOAb testing for cardiovascular risk assessment in the overall population or among individuals with subclinical hypothyroidism.

Obesity and type 2 diabetes mellitus (DM2) are interrelated global problems affecting 988 and 537 million people, respectively, figures that are continuously increasing. Obesity is a key factor in DM2, as it intensifies insulin resistance and β-cell dysfunction, accelerating disease progression. Weight loss improves glycemic control, reduces the occurrence of comorbidities and, in some cases, induces diabetes remission. In this regard, GLP-1 receptor agonists have revolutionized the treatment of DM2. Since the introduction of exenatide in 2005, more effective drugs have been developed that improve glycemic control, reduce weight, and decrease the occurrence of cardiovascular events. This article discusses the mechanisms of action and efficacy of these agents, highlighting recent advances such as polyagonists and oral formulations.

Background/Objectives: Although evidence suggests that miR-484 and several fruit components are involved in glucose metabolism and insulin resistance metabolic pathways, the relationship between serum miR-484 levels and fruit consumption in relation to the risk of Type 2 diabetes (T2DM) remains elusive. The aim of this study was to evaluate the possible association between serum miR-484 levels and fruit intake frequency with the risk of T2DM in the Spanish adult population. Methods: 2234 subjects from the Di@bet.es cohort study without T2DM at baseline were studied. Socio-demographic, anthropometric and clinical data were recorded, as well as responses to a questionnaire on habits, including frequency of fruit consumption (daily vs. occasional). T2DM was diagnosed at baseline and after 7.5 years of follow-up. Baseline serum miR-484 levels were measured using real-time qPCR and categorized based on the 25th percentile. Association analyses were performed using logistic regression models adjusted for potential confounders. Interaction effects were evaluated on the multiplicative and additive scales. Results: There was no association between miR-484 levels and fruit intake frequency. Categorized miR-484 levels and fruit consumption were inversely and independently associated with the likelihood of incident T2DM. Analysis of the interaction effect suggests the presence of both positive multiplicative and additive interactions between miR-484 categories and fruit consumption frequency. Conclusions: Our study demonstrates a protective effect of daily fruit intake and high miR-484 levels regarding the risk of T2DM and supports the nutritional recommendations advocating daily fruit consumption. This study also suggests that the combined effect of low miR-484 levels and occasional fruit intake may increase the risk of T2DM beyond their independent effects.

Thyroid dysfunction is a common health disorder. However, data on its incidence remain scarce and geographically limited. This study aimed to assess the incidence of thyroid dysfunction in the Spanish adult population and factors associated with its onset. A nationwide observational population‑based cohort study was conducted, including 1,629 euthyroid individuals (not receiving levothyroxine/thionamides, and TSH levels of 0.2-5.0mIU/mL) at baseline (2008–2010), who were re-evaluated in 2016–2017. Multivariable logistic regression analysis assessed the association between incident thyroid dysfunction and potential exposure factors. ROC analysis identified optimal TPOAb and TSH cut-offs for predicting incident hypothyroidism. The age- and sex-adjusted incidence of hypothyroidism was 13.38cases/1,000persons-year (CI95

La obesidad y la diabetes mellitus tipo 2 (DM2) son problemas globales interrelacionados, y que afectan a 988 y 537 millones de personas, respectivamente, cifras en continuo aumento. La obesidad es un factor clave en la DM2, ya que intensifica la resistencia a la insulina y la disfunción de las células β, acelerando la progresión de la enfermedad. La pérdida de peso mejora el control glucémico, reduce la aparición de comorbilidades y, en algunos casos, induce la remisión de la diabetes. En este sentido, los agonistas del receptor de GLP-1 han revolucionado el tratamiento de la DM2. Desde la introducción de exenatida en 2005, se han desarrollado medicamentos más eficaces que mejoran el control glucémico, reducen el peso y disminuyen la aparición de eventos cardiovasculares. Este artículo analiza los mecanismos de acción y eficacia de estos agentes, destacando avances recientes como los poliagonistas y formulaciones orales.

Background:Type 2 diabetes (T2D) is increasing its burden worldwide; therefore, research focused on its prediction and prevention is essential. Methods:We performed an untargeted metabolomics analysis using ultra high-performance liquid chromatography-mass spectrometry to discover metabolic biomarkers and biological pathways associated with incident T2D with a nested case-control design, followed by validation with targeted metabolomics in an independent cohort. In the discovery phase, plasma samples from 352 subjects (209 controls and 143 incident cases) were analyzed, collected with a mean (standard deviation) of 7.40 (0.76) years before they acquired the condition. Using this discovery phase cohort, six metabolites were identified using standards and were subsequently quantified in an independent validation phase cohort of 2,044 subjects (167 incident cases). Additionally, pathway enrichment was conducted in the discovery cohort. Results:Guanine, ecgonine, adenine, pregnenolone sulfate, phenyl sulfate, and citrulline were significantly associated with incident T2D in at least one of the analyses performed in the discovery phase. Among these, guanine, pregnenolone sulfate, and citrulline maintained their significant associations with incident T2D in the validation cohort. Additionally, several pathways were significantly altered, with nucleotide metabolism and ABC transporter pathways among the most consistently affected. Conclusion:We identified significant associations of guanine, pregnenolone sulfate, and citrulline with incident T2D.

The CORDELIA Study (Collaborative Cohorts Reassembled Data to Study Mechanisms and Long-term Incidence of Chronic Diseases) combines 35 Spanish population cohorts to investigate the clinical, environmental, genetic, and omics determinants of cardiovascular disease in the Southern European population. It aims to conduct the largest genome-wide association study to date on cardiovascular disease in this population, improve predictions of cardiovascular incidence using genomic and clinical data, and identify subgroups that would benefit most from targeted pharmacological and lifestyle interventions. CORDELIA includes 196,632 individuals (ages 18–84, 54

Type 2 diabetes (T2D) is becoming one of the leading health problems in Western societies, diminishing quality of life and consuming a significant share of healthcare resources. This study presents machine learning models for T2D diagnosis and prognosis, developed using heterogeneous data from a Spanish population dataset (Di@bet.es study). The models were trained exclusively on individuals classified as controls and undiagnosed diabetics, ensuring that the results are not influenced by treatment effects or behavioral changes due to disease awareness. Two data domains are considered: environmental (patient lifestyle questionnaires and measurements) and clinical (biochemical and anthropometric measurements). The preprocessing pipeline consists of four key steps: geospatial data extraction, feature engineering, missing data imputation, and quasi-constancy filtering. Two working scenarios (Environmental and Healthcare) are defined based on the features used, and applied to two targets (diagnosis and prognosis), resulting in four distinct models. The feature subsets that best predict the target have been identified based on permutation importance and sequential backward selection, reducing the number of features and, consequently, the cost of predictions. In the Environmental scenario, models achieved an AUROC of 0.86 for diagnosis and 0.82 for prognosis. The Healthcare scenario performed better, with an AUROC of 0.96 for diagnosis and 0.88 for prognosis. A partial dependence analysis of the most relevant features is also presented. An online demo page showcasing the Environmental and Healthcare T2D prognosis models is available upon request.

BACKGROUND:Obesity is a complex, diverse and multifactorial disease that has become a major public health concern in the last decades. The current classification systems relies on anthropometric measurements, such as BMI, that are unable to capture the physiopathological diversity of this disease. The aim of this study was to redefine the classification of obesity based on the different H-NMR metabolomics profiles found in individuals with obesity to better assess the risk of future development of cardiometabolic disease. MATERIALS AND METHODS:Serum samples of a subset of the Di@bet.es cohort consisting of 1387 individuals with obesity were analyzed by H-NMR. A K-means algorithm was deployed to define different H-NMR metabolomics-based clusters. Then, the association of these clusters with future development of cardiometabolic disease was evaluated using different univariate and multivariate statistical approaches. Moreover, machine learning-based models were built to predict the development of future cardiometabolic disease using BMI and waist-to-hip circumference ratio measures in combination with H-NMR metabolomics. RESULTS:Three clusters with no differences in BMI nor in waist-to-hip circumference ratio but with very different metabolomics profiles were obtained. The first cluster showed a metabolically healthy profile, whereas atherogenic dyslipidemia and hypercholesterolemia were predominant in the second and third clusters, respectively. Individuals within the cluster of atherogenic dyslipidemia were found to be at a higher risk of developing type 2 DM in a 8 years follow-up. On the other hand, individuals within the cluster of hypercholesterolemia showed a higher risk of suffering a cardiovascular event in the follow-up. The individuals with a metabolically healthy profile displayed a lower association with future cardiometabolic disease, even though some association with future development of type 2 DM was still observed. In addition, H-NMR metabolomics improved the prediction of future cardiometabolic disease in comparison with models relying on just anthropometric measures. CONCLUSIONS:This study demonstrated the benefits of using precision techniques like H-NMR to better assess the risk of obesity-derived cardiometabolic disease.

Background/Objectives: Metabolic Dysfunction-Associated Fatty Liver Disease (MAFLD) increases the risk of Type-2 Diabetes (T2DM). The Mediterranean diet (MD) has shown advantages in the management of MAFLD and preventing co-morbidities; however, its relationship with T2DM development in MAFLD has been less investigated. We aimed to evaluate the association of MD adherence with the risk of incident T2DM in the Spanish adult population with MAFLD and according to their weight gain at 7.5 years follow-up. Methods: A cohort of 714 participants (without weight increment: 377; with weight increment: 337) from the Di@bet.es cohort study with MAFLD and without T2DM at baseline were investigated. Anthropometric, sociodemographic, clinical data, and a survey on habits were recorded. OGTT and fasting blood biochemistry determinations were made. Baseline adherence to MD was estimated by the adapted 14-point MEDAS questionnaire and categorized as high and low adherence. Results: In total, 98 people developed T2DM at follow-up. The high adherence to MD was inversely associated with the development of T2DM in both the overall population (0.52 [0.31-0.87]) and subjects without weight gain at follow-up (0.35 [0.16-0.78]). Conclusions: Our results suggest the protective effect of high adherence to MD regarding the risk of T2DM in subjects with MAFLD, with this health benefit being more evident in men with the absence of weight gain. These results support the recommendations for MD use in these patients.

Obesity is frequently accompanied by non-alcoholic fatty liver disease (NAFLD). These two diseases are associated with altered lipid metabolism, in which reverse cholesterol transport (LXRα/ABCA1/ABCG1) and leptin response (leptin receptor (Ob-Rb)/Sam68) are involved. The two pathways were evaluated in peripheral blood mononuclear cells (PBMCs) from 86 patients with morbid obesity (MO) before and six months after Roux-en-Y gastric bypass (RYGB) and 38 non-obese subjects. In the LXRα pathway, LXRα, ABCA1, and ABCG1 mRNA expressions were decreased in MO compared to non-obese subjects (p < 0.001, respectively). Ob-Rb was decreased (p < 0.001), whereas Sam68 was increased (p < 0.001) in MO. RYGB did not change mRNA gene expressions. In the MO group, the LXRα pathway (LXRα/ABCA1/ABCG1) negatively correlated with obesity-related variables (weight, body mass index, and hip), inflammation (C-reactive protein), and liver function (alanine-aminotransferase, alkaline phosphatase, and fatty liver index), and positively with serum albumin. In the Ob-R pathway, Ob-Rb and Sam68 negatively correlated with alanine-aminotransferase and positively with albumin. The alteration of LXRα and Ob-R pathways may play an important role in NAFLD development in MO. It is possible that MO patients may require more than 6 months following RYBGB to normalize gene expression related to reverse cholesterol transport or leptin responsiveness.

Thyroid dysfunction is a common endocrine disorder in the general population, with a reported prevalence of 10-15%. However, this rate is even higher in older adults, with an estimated prevalence of ≈25% in some populations. Since elderly patients usually present more comorbidities than younger individuals, thyroid dysfunction may carry a synergistic negative health impact, mainly due to increased cardiovascular disease risk. Moreover, thyroid dysfunction in the elderly can be more difficult to diagnose due to its subtle or even asymptomatic clinical presentation, and the interpretation of thyroid function tests may be affected by drugs that interfere with thyroid function or by the coexistence of several diseases. On the other hand, thyroid nodules are also a prevalent condition in older adults, and its incidence increases with age. The assessment and management of thyroid nodules in the ageing patient should take into account several factors, as risk stratification, thyroid cancer biology, patient´s overall health, comorbidities, treatment preferences, and goals of care. In this review article, we summarize the current knowledge on the pathophysiology, diagnosis, and therapeutic management of thyroid dysfunction in elderly patients and we also review how to identify and manage thyroid nodules in this population.

Aims: The aim of this study was to combine nuclear magnetic resonance-based metabolomics and machine learning to find a glucose-independent molecular signature associated with future type 2 diabetes mellitus development in a subgroup of individuals from the Di@bet.es study.Methods: The study group included 145 individuals developing type 2 diabetes mellitus during the 8-year followup, 145 individuals matched by age, sex and BMI who did not develop diabetes during the follow-up but had equal glucose concentrations to those who did and 145 controls matched by age and sex. A metabolomic analysis of serum was performed to obtain the lipoprotein and glycoprotein profiles and 15 low molecular weight metabolites. Several machine learning-based models were trained.Results: Logistic regression performed the best classification between individuals developing type 2 diabetes during the follow-up and glucose-matched individuals. The area under the curve was 0.628, and its 95% confidence interval was 0.510-0.746. Glycoprotein-related variables, creatinine, creatine, small HDL particles and the Johnson-Neyman intervals of the interaction of Glyc A and Glyc B were statistically significant.Conclusions: The model highlighted a relevant contribution of inflammation (glycosylation pattern and HDL) and muscle (creatinine and creatine) in the development of type 2 diabetes as independent factors of hyperglycemia.

Searchable abstracts of presentations at key conferences in endocrinology ISSN 1470-3947 (print) | ISSN 1479-6848 (online)

Oleocanthal and oleacein are olive oil phenolic compounds with well known anti-inflammatory and anti-oxidant properties. The main evidence, however, is provided by experimental studies. Few human clinical trials have examined the health benefits of olive oils rich in these polyphenols. Our aim was to assess the health properties of rich oleocanthal and oleacein extra virgin olive oil (EVOO), compared to those of common olive oil (OO), in people with prediabetes and obesity. This was a randomised, double-blind, crossover trial done in people aged 40-65 years with obesity (BMI 30-40 kg/m2) and prediabetes (HbA1c 5.7-6.4%). The intervention consisted in substituting for 1 month the oil used for food, both raw and cooked, by EVOO or OO. No hypocaloric diet or changes in physical activity were recommended. The primary outcome was the inflammatory status. Secondary outcomes were the oxidative status, body weight, metabolic status and lipid profile. An ANCOVA model adjusted for age, sex and treatment administration sequence was used for the statistical analysis. 91 patients were enrolled (33 men and 58 women) and finished the trial. A decrease in interferon-{gamma} was observed after EVOO treatment, reaching inter-treatment differences (P=0.041). Total antioxidant status increased and lipid and organic hydroperoxides decreased after EVOO treatment, the changes reaching significance compared to OO treatment (P<0.05). Decreases in weight, BMI and blood glucose (p<0.05) were found after treatment with EVOO and not with OO. In conclusion, treatment with EVOO rich in oleocanthal and oleacein differentially improved oxidative and inflammatory status in people with obesity and prediabetes