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Thyroid hormones, primarily triiodothyronine (T3) and thyroxine (T4), are critical regulators of metabolic rate, mitochondrial function, and cellular repair mechanisms. Emerging evidence suggests that thyroid status may significantly influence aging trajectories and longevity through modulation of key cellular pathways. This review explores the role of thyroid hormones in aging biology, with a focus on their interaction with longevity-associated signaling pathways and the hallmarks of aging. Both physiological and subclinical thyroid states in the context of healthspan, cognitive preservation, metabolic resilience, and mitochondrial integrity are explored. A narrative synthesis of human and animal studies was conducted, including mechanistic, epidemiologic, and clinical data, to evaluate how thyroid hormone levels affect aging pathways such as mechanistic target of rapamycin, AMP-activated protein kinase, IGF-1, sirtuins, FOXO transcription factors, and mitochondrial biogenesis. Thyroid hormones modulate several hallmarks of aging, including mitochondrial dysfunction, genomic instability, epigenetic drift, and deregulated nutrient sensing. T3 enhances mitochondrial respiration and autophagy while interacting with mechanistic target of rapamycin and AMP-activated protein kinase to regulate energy balance. Altered thyroid function-particularly subclinical hypothyroidism-has been paradoxically associated with increased longevity in some centenarian cohorts, possibly due to reduced oxidative metabolism. However, overt thyroid dysfunction is linked to increased metabolic risk in aging populations. Thyroid hormones serve as metabolic gatekeepers that influence both cellular aging and organismal longevity. A deeper understanding of their role in aging pathways may inform novel strategies for promoting healthy aging, including thyroid hormone modulation and personalized endocrine optimization.
The aim of this cross-sectional study was to compare and test associations between inflammatory profiles and liver steatosis/fibrosis in individuals with different degrees of adiposity with or without metabolic syndrome. Forty-six patients (82.6% females, aged 38.3±7.8 yr, body mass index of 32.6±5.1 kg/m2) were allocated into three groups according to body adiposity and the presence or absence of metabolic syndrome: normal-weight controls, patients with obesity or with obesity and metabolic syndrome. Between-group comparisons were performed for clinical history, anthropometry, biochemical, metabolic, and inflammatory profiles, and degree of liver stiffness and steatosis by transient elastography. As expected, obesity and obesity and metabolic syndrome had greater body mass index and waist circumference than controls. No significant differences between groups in lipid profile, aspartate aminotransferase, ferritin, adiponectin, and retinol-binding protein-4 were noted. Obesity and metabolic syndrome had significantly higher fasting glucose levels compared to controls and obesity. A more significant proportion of patients with hypertension, higher insulinemia, HOMA-IR, glycated hemoglobin, aspartate aminotransferase, gamma-glutamyltransferase, tumor necrosis factor-alpha, interleukin-6, and leptin were observed in obesity and metabolic syndrome compared to controls. Obesity had higher alkaline phosphatase, interleukin-6, and leptin levels than controls. Liver stiffness and steatosis were higher in obesity and metabolic syndrome than in controls, while hepatic fibrosis degree F2 occurred more frequently in obesity and metabolic syndrome (p≤0.03). No associations were detected between liver stiffness and steatosis and inflammatory biomarkers in the studied groups (p≥0.07). Our findings highlight the impact of metabolic conditions on liver health but also suggest that systemic inflammation might not be directly linked to liver stiffness and steatosis.
Adrenalectomy and conservative management are therapeutic approaches for mild autonomous cortisol secretion; however, their comparative clinical impact in routine practice remains uncertain. We aimed to evaluate real-world hormonal, clinical, and metabolic outcomes according to the treatment strategy in patients with mild autonomous cortisol secretion. This single-center retrospective observational study included consecutive patients with adrenal incidentaloma fulfilling guideline-based diagnostic criteria for mild autonomous cortisol secretion between January 2015 and December 2024. Sixty-five patients with complete hormonal evaluation and follow-up data were analyzed and classified into surgery (n=23) and conservative (n=42) groups. Demographic characteristics, adenoma features, comorbidities, hormonal parameters, and metabolic outcomes were assessed at baseline and at the final follow-up. The median follow-up duration was approximately 3 years and similar between groups (p>0.05). At baseline, the body mass index, adenoma size, and cortisol levels after the 1-mg dexamethasone suppression test were significantly higher, while adrenocorticotropic hormone levels were lower in the surgery group (p=0.02, p=0.02, p=0.036, and p<0.01, respectively). During the follow-up, adrenocorticotropic hormone levels increased and post-dexamethasone suppression test cortisol levels significantly decreased after adrenalectomy (p=0.001 and p=0.036, respectively), whereas metabolic parameters and comorbidity profiles remained largely unchanged. In the conservative group, total cholesterol increased modestly over time (p=0.048), with no significant changes in other clinical outcomes. No significant difference in comorbidity progression was observed between treatment strategies. In this real-world cohort, adrenalectomy resulted in clear hormonal improvement without parallel short-term metabolic or clinical benefits compared with conservative management. These findings highlight the heterogeneous clinical expression of mild autonomous cortisol secretion and underscore the importance of individualized patient selection for surgery.
Metabolic dysfunction-associated steatotic liver disease and metabolic dysfunction-associated steatohepatitis are increasingly concerning health issues, especially in people with type 2 diabetes mellitus, where metabolic problems drive liver disease progression. While lifestyle changes remain essential, new drug strategies-particularly sodium-glucose cotransporter-2 inhibitors and glucagon-like peptide-1 receptor agonists-have gained growing interest for their potential to protect the liver. This review examines how sodium-glucose cotransporter-2 inhibitors and glucagon-like peptide-1 receptor agonists might help treat metabolic dysfunction-associated steatotic liver disease and metabolic dysfunction-associated steatohepatitis, focusing on their mechanisms of action, study evidence, and results from meta-analyses. A thorough search of the literature found studies on how these drugs affect insulin sensitivity, liver fat, and inflammation. Preclinical models show that they can lower liver fat, reduce oxidative stress, and decrease fibrosis markers. Clinical trials and meta-analyses support their potential to improve liver enzyme levels, decrease liver fat, and slow fibrosis growth. Overall, sodium-glucose cotransporter-2 inhibitors and glucagon-like peptide-1 receptor agonists appear promising in the management of metabolic dysfunction-associated steatotic liver disease and metabolic dysfunction-associated steatohepatitis, especially in type 2 diabetes mellitus patients. Still, more long-term research studies are needed to confirm how well they work, how safe they are, and the best way to use them, either alone or in combination with other treatments. These drugs may represent important advances in the treatment of liver diseases linked to metabolic problems.
The metabolic score for visceral fat was a newly developed surrogate marker for evaluating visceral fat. This study aimed to investigate the relationship between the metabolic score for visceral fat and the mortality risk in US adults with diabetes or prediabetes. A cohort of 12,992 individuals with diabetes or prediabetes was identified from the US National Health and Nutrition Examination Survey (1999-2018). Baseline metabolic score for visceral fat measurements were recorded, and mortality outcomes were assessed by linking participants to the National Death Index records up to December 31, 2019. Multivariate Cox regression and restricted cubic spline models were employed to examine the relationship between the metabolic score for visceral fat and both all-cause mortality and cardiovascular mortality. Over a median follow-up of 97 months, a total of 2,438 all-cause deaths and 662 cardiovascular deaths were recorded. Multivariate Cox regression analysis indicated that individuals in the highest metabolic score for visceral fat quartile exhibited adjusted hazard ratios of 2.857 (95% confidence interval: 2.348-3.477) for all-cause mortality and 3.290 (95% confidence interval: 2.218-4.881) for cardiovascular mortality, compared to those in the lowest quartile. Additionally, a nonlinear relationship between the metabolic score for visceral fat and the mortality risk was observed, with inflection points identified at 7.093 for all-cause mortality and 7.220 for cardiovascular mortality. Elevated metabolic score for visceral fat levels are strongly associated with heightened risks of mortality among diabetic or prediabetic population, underscoring their potential utility as a prognostic indicator.
Thyrotropin (thyroid-stimulating hormone)-secreting pituitary adenomas are a rare cause of hyperthyroidism that frequently presents diagnostic and therapeutic challenges. This study characterizes the clinical, biochemical, radiological, and histopathological features of thyrotropin-secreting pituitary adenomas, evaluates long-term outcomes, and identifies factors influencing remission and recurrence. We retrospectively analysed 12 patients with thyrotropin-secreting pituitary adenomas treated between January 2003 and February 2025 at a tertiary endocrine referral centre. Clinical presentation, hormonal profiles, imaging characteristics, histopathology, management, and follow-up were reviewed. Diagnostic criteria included inappropriately normal or elevated thyroid-stimulating hormone levels with increased free thyroid hormones and pituitary imaging confirming an adenoma. Remission was defined as clinical and biochemical normalization without ongoing therapy. Subgroup analysis examined the impact of diagnostic delay on tumour size, invasiveness, and outcome. The cohort comprised nine men (75%) and three women (25%) with a mean age at diagnosis of 47.8±17.2 years. Excluding one multiple endocrine neoplasia type 1 case with early detection, the mean diagnostic delay was 42.5 months (range: 4-156). Magnetic resonance imaging revealed macroadenomas in 75% of patients and Knosp grade 3-4 invasion in 41.7%. Longer diagnostic delay was correlated with significantly larger tumours (17.9±3.6 mm vs 9.8±1.0 mm; p=0.004). All patients underwent surgery; 50% achieved remission, while 33.3% required additional therapy (somatostatin analogues and/or radiotherapy). At a median 7.8-year follow-up, 66.7% remained in sustained remission. No patient experienced thyroid storm; transient postoperative hypothyroidism occurred in 25%. Thyrotropin-secreting pituitary adenomas often present with heterogeneous and misleading biochemical profiles leading to diagnostic delay, larger and more invasive tumours, and a greater need for multimodal therapy. Early recognition of discordant thyroid function tests-elevated free T3/T4 with non-suppressed thyroid-stimulating hormone-is critical to avoid unnecessary thyroid ablation and improve surgical outcomes.
This retrospective study aimed to evaluate hematological and inflammatory markers as predictors of thyroid cancer in patients with atypia of undetermined significance thyroid nodules. A total of 174 patients with atypia of undetermined significance who underwent thyroidectomy were included. Pre- and postoperative immature granulocyte counts, neutrophil-to-lymphocyte ratio, and platelet-to-lymphocyte ratio were analyzed after achieving euthyroid status. Propensity score matching for age and gender resulted in a final cohort of 128 patients (64 benign and 64 malignant). Static preoperative and postoperative immature granulocyte values did not differ significantly between the benign and malignant groups; however, the delta immature granulocyte value, defined as the change between pre- and postoperative measurements, was significantly lower in malignant cases (p=0.007). Receiver operating characteristic analysis demonstrated an area under the curve of 0.651 at a cut-off value of≤- 0.01, with a sensitivity of 46.2% and a specificity of 79.2%. Univariate logistic regression revealed that delta immature granulocytes independently predicted malignancy in the overall cohort (odds ratio=3.273 and p=0.007) and in patients younger than 55 years (odds ratio=5.082 and p=0.007), whereas this association was not observed in patients aged 55 years and older. The neutrophil-to-lymphocyte and platelet-to-lymphocyte ratios were not significant predictors. These findings suggest that dynamic changes in immature granulocyte levels between the pre- and postoperative periods, rather than single-time-point measurements, may serve as a cost-effective and accessible complementary tool for malignancy prediction in atypia of undetermined significance thyroid nodules.
The interplay between liver fibrosis and thyroid function remains incompletely understood, particularly regarding thyroid hormone sensitivity. Thus, this study aims to explore the relationship between liver fibrosis and thyroid hormone sensitivity in euthyroid US individuals. This study involved 4,678 euthyroid participants from the National Health and Nutrition Examination Survey 2007-2012. Key clinical parameters were extracted, including thyroid-stimulating hormone, free and total thyroxine, and liver function-related data. Thyroid hormone sensitivity was assessed by three indices: the Thyroid Function Quotient Index, Thyroid-Stimulating Hormone Index, and Thyrotrophic Thyroxine Resistance Index. Multiple regression analyses and machine learning models were performed to evaluate the relationships between liver fibrosis and thyroid sensitivity indices. Participants with advanced liver fibrosis indicated by fibrosis index 4 (FIB-4) demonstrated significantly impaired thyroid hormone sensitivity indicated by Thyroid Function Quotient Index, Thyrotrophic Thyroxine Resistance Index, and Thyroid-Stimulating Hormone Index. Then, the logistic regression and restricted cubic spline analysis indicated that Thyroid Function Quotient Index, Thyrotrophic Thyroxine Resistance Index, and Thyroid-Stimulating Hormone Index were risk factors for liver fibrosis (odds ratio>1, p<0.05). Furthermore, we developed machine learning models using random forest and Boruta's algorithm identifying thyroid hormone sensitivity indices, Thyroid-Stimulating Hormone Index, Thyrotrophic Thyroxine Resistance Index, and Thyroid Function Quotient Index as key predictors for liver fibrosis. Mediation analysis indicates that uric acid is a weak mediator between thyroid hormone sensitivity and liver fibrosis. This study reveals that impaired thyroid hormone sensitivity is a risk factor for liver fibrosis progression in euthyroid individuals. These findings uncover a potential molecular link between thyroid hormone signaling and the development of liver fibrosis, warranting further investigation.
Zoledronate is most effective when bone turnover is elevated, as in postmenopausal women. Individuals with type 2 diabetes mellitus show lesser bone mineral density gains compared to non-diabetes mellitus individuals with zoledronate, and fractures often occur despite preserved bone mineral density. It is unclear whether zoledronate reduces fracture risks in type 2 diabetes mellitus. This study aimed to evaluate skeletal outcomes, including fracture incidence, over 5 years in postmenopausal osteoporotic women with and without type 2 diabetes mellitus. This prospective cohort included postmenopausal women with bone mineral density T-scores of≤-2.5 at the lumbar spine, femoral neck, or hip. Participants were classified as type 2 diabetes mellitus or non-diabetes mellitus. All received annual zoledronate (4 mg), daily calcium (1000 mg), and cholecalciferol (500 IU), with standardized fall-prevention measures. Fracture history was recorded at follow-up visits, and annual spine radiographs were performed to detect morphometric vertebral fractures. Women completing≥5 years of follow up were included in the final analysis. The primary end point was fracture incidence; secondary end points were changes in bone mineral density and bone turnover markers. Of 221 women enrolled, 150 completed 5 years (63 type 2 diabetes mellitus and 87 non-diabetic mellitus; median age 59 y). The baseline bone mineral density was similar, but bone turnover markers were lower in type 2 diabetes mellitus. At a minimum of 60 months follow up, 20 new fractures occurred in 15 women: 8 (12.7%) with type 2 diabetes mellitus and 7 (8.0%) without. The relative risk (RR) was 1.58 (95% confidence interval: 0.60-4.13; p=0.2). Both groups showed comparable bone mineral density improvements. Despite differences in baseline bone turnover, fracture incidence did not differ significantly between postmenopausal women with and without type 2 diabetes mellitus treated with annual zoledronate over a 5-year follow-up. However, the low number of fracture events and wide confidence intervals limit definitive inference.
Thyroid nodules are among the most frequently encountered endocrine abnormalities, affecting up to two-thirds of adults in iodine-sufficient regions. Although thyroid-stimulating hormone and genetic mutations have long been implicated in their pathogenesis, emerging evidence reveals a multifactorial interplay among inflammatory, hormonal, toxic, and micronutrient influences that extends beyond the classical model. This narrative review examines the converging biological pathways that contribute to thyroid nodule formation, emphasizing the integrative roles of inflammation, estrogen signaling, environmental endocrine disruptors, and micronutrient imbalance in altering thyroid cellular homeostasis. Chronic low-grade inflammation and oxidative stress create a permissive microenvironment for thyrocyte proliferation and clonal expansion. Estrogen receptor activation-amplified by insulin and insulin-like growth factor 1 signaling-enhances vascular and proliferative responses within thyroid tissue, contributing to the female predominance of nodular disease. Exposure to heavy metals and xenoestrogens disrupts thyroid peroxidase activity, deiodinase regulation, and immune tolerance, while deviations in iodine, selenium, zinc, and vitamin D status further impair redox balance and DNA repair mechanisms. Together, these factors promote a spectrum of structural changes ranging from microscopic hyperplasia to clinically significant nodules. Thyroid nodules represent a visible manifestation of intersecting metabolic and environmental stressors rather than a single endocrine defect. Integrating insights from molecular endocrinology, environmental toxicology, and nutritional science may advance early detection and preventive strategies targeting the inflammatory-hormonal-toxic axis of thyroid disease.
The non-insulin-based metabolic score for insulin resistance (METS-IR) is a recently developed index aimed at being a practical and efficient alternative biomarker of insulin resistance (IR). This study aimed to investigate the association between METS-IR in euthyroid women in the first trimester of pregnancy and pregnancy outcomes. A total of 1810 participants who gave birth at Fujian Maternity and Child Health Hospital from November 2018 to November 2019 were included in this study. Thyroid function, fasting blood glucose (FPG) levels, lipid profiles, and anthropometric parameters were collected during the first trimester of pregnancy. METS-IR was calculated by FPG, total triglyceride, high-density lipoprotein cholesterol, and body mass index. Pregnancy outcomes were collected. There were 75 (4.1%) cases of macrosomia and 433 (23.9%) cases of gestational diabetes mellitus (GDM). Participants were divided into four groups based on METS-IR, with a median and interquartile range of METS-IR levels of 23.91 (22.83, 24.67), 26.53 (25.88, 27.17), 29.13 (28.47, 30.00), and 33.59 (32.10, 36.21), respectively. The higher METS-IR quartile was significantly associated with macrosomia and GDM (p<0.05). The risk of macrosomia and GDM increased with the increased METS-IR levels when METS-IR was a continuous variable, particularly METS-IR levels reaching 27.84 and higher (overall p<0.05). We found no correlation between METS-IR and low birth weight, cesarean section, and preterm delivery (p>0.05). Increasing METS-IR in euthyroid women in the first trimester of pregnancy may predict macrosomia and GDM.
We conducted this study to compare the anthropometric and metabolic outcomes and nutritional status, after sleeve gastrostomy (SG) and gastric bypass (GB) in adolescents with severe obesity. We selected 219 adolescents with severe obesity (Body Mass Index>99th percentile or 95th≤BMI<99th percentile) among the participants of Tehran Obesity Treatment Study and assessed them for anthropometric and metabolic outcomes and nutritional status at baseline and during 1 year follow up after the surgery. Out of the total, 182 participants were in the SG group and 37 were in the GB group. BMI was lower in SG patients compared to GB group (38.5±4.8 kg/m 2 vs. 36.1±4.0 kg/m 2, p-value<0.05), 3 months after surgery. Metabolic profiles such as aspartate transaminase and alanine transaminase were lower in SG group compared to GB after 6 months of follow up, while high-density lipoprotein was higher in SG patients compered to GB patients (41.6±8.4 mg/dl vs. 48.0±9.2 mg/dl, p-value<0.05). After one year, total cholesterol and low-density lipoprotein were higher in adolescents who underwent SG compared to those in GB group. There was no significant difference in micronutrient status between SG and GB groups. It seems that SG in adolescents with obesity and fatty liver disease, is more appropriate but GB may be preferred in patients with a history of lipid profile abnormalities. More studies are needed to draw conclusions about nutritional status and long-term outcomes after surgery.
Metabolic syndrome is a complex condition characterized by central obesity, hyperglycemia, insulin resistance, inflammation, dyslipidemia and hypertension which predispose individuals toward diabetes and cardiovascular disorder. The aim of this review is to investigate some selected novel adipokines, myokines, and hepatokines whose secretion is affected by exercise and improves metabolic syndrome. According to epidemiological studies, the incidence of metabolic syndrome is expected to increase every year, which predisposes health organizations with big challenges. Regular exercise stands as a preventive tool for metabolic syndrome, not only by improving blood circulation, but also through alterations in exerkines. The proteins are secreted by adipose tissue (adipokines), skeletal muscles (myokines), liver (hepatokines) or other tissues during exercise. Interestingly, adipo-myo-hepatokines are categorized into inflammatory and anti-inflammatory peptides, and exercise either reduces or elevates them. The beneficial effects of exercise for various physiological systems, and more importantly prevention and treatment of metabolic syndrome, still have remained mysterious. According to the literature, some of the anti-inflammatory exerkines cooperate in the metabolic homeostasis of organisms by increasing blood flow, muscle mass, and glucose utilization and improving insulin sensitivity and fatty acid oxidation.
Hyperparathyroidism has been associated with an increased risk of stroke in several previous studies; but the findings have not been consistent, which prompts further investigation. This study aimed to elucidate the association between high serum parathyroid hormone levels and stroke through a systematic review and meta-analysis. PubMed, Embase, Scopus and Google Scholar were systematically searched up to May 2025 for relevant and original observational studies. Pooled odds ratios and hazard ratios were calculated with corresponding 95% confidence intervals, along with heterogeneity and publication bias. The combined search yielded 2,063 unique articles, and 14 studies were included in statistical analysis. Two associations were analysed: nine studies focused on comparing the risk of stroke between populations with normal and high parathyroid hormone levels and the remaining five studies focused on comparing the rate of hyperparathyroidism between populations with stroke and normal population. In the first group, subgroup analyses of studies reported that both hazard ratios and odds ratios demonstrated stroke to be more likely in groups with hyperparathyroidism (odds ratio: 1.49 and 95% confidence interval: 1.38-1.61; hazard ratio: 1.38 and 95% confidence interval: 1.09-1.75). In the second group, analysis demonstrated that groups with stroke are more likely to have higher level of parathyroid hormone (mean difference of parathyroid hormone levels: 10.30 pg/mL and 95% confidence interval: 1.60-19.00). There were no significant publication biases in any of the analyses (p> 0.05). This review is supportive of the association between hyperparathyroidism and stroke but does not establish a conclusive causal relationship.
Steroidogenesis in the human adrenal cortex follows a distinct anatomical and functional zonation, which is essential for maintaining electrolyte balance, stress response, and metabolic homeostasis. Dysregulation of this tightly controlled system leads to endocrine disorders causing hypertension, such as primary aldosteronism and glucocorticoid excess. The aim of this study was to analyze the zonal distribution and expression levels of enzymes involved in steroidogenesis and correlate these findings with hypertension, body mass index and previous administration of corticosteroids while correcting severe acute respiratory syndrome coronavirus 2 infection as a potential confounder. Tissue microarrays were constructed from 99 formalin-fixed paraffin-embedded adrenal glands obtained from adult human autopsies, with clinical information on hypertension status. As controls, 14 normal adrenal glands derived from surgical specimens were included. Protein expression of CYP11B2, CYP11B1, CYP17, HSD3B1, and HSD3B2 was assessed semi-quantitatively and evaluated with respect to their localization within specific adrenal cortical zones using immunohistochemistry. The expression of CYP17, CYP11B1, CYP11B2, and HSD3B2 was inversely correlated with the presence of hypertension (p<0.001 and p=0.0149), higher body mass index (p=0.026 and p=0.001), and the administration of corticosteroids (p=0.0012, p=0.001, and p=0.002). CYP11B2 showed reduced expression in the zona glomerulosa only in the non-COVID-19 hypertension group (p=0.031). Tissue microarray-based tissue analysis is a reliable method in a research setting to detect consistent downregulation of CYP11B1, CYP11B2, and CYP17 in patients with hypertension, independent of concomitant underlying infections. The positive correlation between the body mass index and CYP11B1 expression, and the negative correlation between glucocorticoid administration and CYP11B1, may reflect clinical factors such as obesity-associated hypertension and altered aldosterone production and its relationship with metabolic syndrome.
An independent association between insulin resistance and cancer has been consistently reported in humans. Patients with cancer display insulin resistance or its clinical manifestations, and this metabolic adaptation precedes the clinical diagnosis of cancer. Insulin resistance in cancer patients is associated with a metabolic switch from oxidative metabolism toward glycolysis that spares oxygen to be used in anabolic processes and facilitates the fast production of energy and intermediate metabolites required for the rapid proliferation of cancer cells. In malignant cells, glucose consumption via glycolysis occurs under normoxic conditions (aerobic glycolysis). Pathogenic mechanisms underlying insulin resistance in cancer patients include hypoxia-inducible factor-1 upregulation and overproduction of cytokines, such as interferon, interleukin-6, interleukin-18, and interleukin-1β. Deficit of 2-oxoglutarate (α-ketoglutarate) has been detected in cancer cells and may facilitate hypoxia-inducible factor-1 assembly and activity. Overproduction of cytokines in cancer patients follows activation of the immune system by abnormal nucleic acid variants. Anomalous DNA or RNA structures are recognized by immune sensors and stimulate signaling pathways that ultimately increase cytokine production. Likewise, interferon overproduction occurs in congenital disorders that feature ineffectively repaired DNA lesions, such as Werner syndrome, Bloom syndrome, mutations in DNA polymerase-δ1, and ataxia telangiectasia. These diseases cause simultaneous insulin resistance and a high tendency to develop cancer, highlighting the relationship between the two processes. Defectively repaired DNA injury endangers genomic integrity, predisposing to cancer, and activates the immune system to increase interferon production and subsequent insulin resistance. Hypoxia-inducible factor-1 and cytokines induce insulin resistance by suppressing peroxisome proliferator-activated-γ in the subcutaneous adipose tissue.
Metyrapone and osilodrostat are both steroidogenic inhibitors targeting the 11β-hydroxylase, yet their safety profile has not been comprehensively analyzed. The objective of this study is to compare the adverse events (AEs) associated with osilodrostat and metyrapone based on the Food and Drug Administration Adverse Event Reporting System (FAERS). AEs were classified according to the System Organ Class (SOC) in the Medical Dictionary for Regulatory Activities (MedDRA) version 26.1. Adverse event (AE) signals of osilodrostat and metyrapone were determined by calculating reporting odds ratios (ROR). A total of 1380 and 449 AE reports were retrieved from osilodrostat and metyrapone, respectively, involving 26 and 27 SOC categories. Unexpected AEs such as asthenia, decrease of blood potassium, myalgia, increase of blood pressure, abdominal distension, increase of blood testosterone, nephrolithiasis, and hunger were associated with osilodrostat. while metyrapone was linked with respiratory failure, deep vein thrombosis, interstitial lung disease, liver function test abnormal, and respiratory distress. Among osilodrostat-treated patients, those aged between 18 to 65 years old were more likely to develop adrenal insufficiency, fatigue, tachycardia, than those older than 65. Male patients treated with metyrapone have the significantly higher incidence of the increased blood corticotrophin, muscular weakness and acute respiratory distress syndrome compared to females. During treatment with osilodrostat and metyrapone, clinicians need to monitor the effects of AEs varied by gender and age and to pay more attention to new AE signals.
Thyrotoxicosis is associated with heightened adrenergic activity, arrhythmogenic susceptibility, and procoagulant alterations; yet, its contribution to sudden death outside overt thyroid storm remains incompletely understood. We retrospectively screened 975 consecutive autopsies and identified 7 cases with biochemical evidence of thyroid hormone excess defined by elevated free T3 and/or free T4 levels. Clinical background, medication exposure, thyroid-related biomarkers, including thyroglobulin, thyroid autoantibodies, and interleukin-6, together with detailed histopathological examination of the thyroid gland and the cardiovascular system, were integrated to assess the potential contribution of thyroid hormone excess to the fatal outcome. Targeted genetic analysis was additionally performed in selected cases. Two cases fulfilled clinicopathological criteria for thyroid storm and showed markedly elevated IL-6 concentrations, suggesting severe systemic decompensation. In the remaining cases, death was attributed to structural cardiovascular or cerebrovascular pathology, including intracerebral hemorrhage, acute coronary thrombosis with plaque rupture, hydrocephalus, or presumed arrhythmic mechanisms. Biochemical thyrotoxicosis was observed even in the absence of thyroid-stimulating hormone suppression, and exogenous or treatment-associated thyrotoxicosis was sometimes accompanied by thyroid atrophy rather than hyperplasia. These findings indicate that thyroid hormone excess detected at autopsy represents a clinicopathological spectrum ranging from primary thyroid-driven death to contexts in which thyrotoxicosis functions as a physiological modifier that lowers the threshold for fatal cardiovascular events. Integrative interpretation of biochemical, pathological, and clinical findings may improve the understanding of thyroid hormone-mediated vulnerability in sudden death.
Hypoestrogenism causes an imbalance in bone homeostasis, which can affect bone microarchitecture and result in loss of tissue strength and increased risk of fractures. Physical training and melatonin can act on bone formation; however, in a state of hypoestrogenism, the potential effect of the combination of both interventions is not understood. The aim of this study was to investigate the effect of 12 weeks of swimming physical training associated with melatonin administration on the mineral content and biomechanical parameters in bone tissue under hypoestrogenism conditions. The animals (Wistar rats) performed an incremental swimming test to determine the individual anaerobic lactacidemic threshold and underwent bilateral ovariectomy. The interventions consisted of physical training (30 min, 5 d/wk, 90% of individual anaerobic lactacidemic threshold) and melatonin administration (10 mg/kg/d via gavage). After 12 weeks, the femur was collected for the analysis of calcium and phosphorus contents and the three-point flexion test to obtain biomechanical parameters. Data were expressed as mean±standard deviation, subjected to factorial analysis of variance and the Newman-Keuls post hoc test (a significance level of 5%). The association of endurance physical training with melatonin administration resulted in a significant increase in calcium and phosphorus contents, while presenting a significant increase in the capacity to support a greater maximum load and promote rigidity to bone tissue. Considering the detrimental impact of hypoestrogenism on bone tissue, both interventions, endurance physical training and melatonin administration, were able to generate beneficial results regarding the bone mineral content, influencing the improvement of biomechanical parameters that determine tissue strength, which can prevent bone fracture.
Empagliflozin, a sodium-glucose cotransporter 2 inhibitor, is approved for the treatment of type 2 diabetes mellitus and heart failure. Its known ability to enhance mitochondrial adenosine triphosphate production and improve cardiac function led us to investigate whether blood adenosine triphosphate levels could serve as a predictive biomarker for treatment response. This prospective study included 120 patients from Kyrgyzstan: 49 with type 2 diabetes mellitus, 43 with heart failure, and 28 with both type 2 diabetes mellitus and heart failure. The mean age of the study population was 63.9±7.1 years, with no significant age difference between groups. Patients received oral empagliflozin at a dose of either 10 or 25 mg daily for 12 weeks. Adenosine triphosphate activity was measured in erythrocytes from whole blood samples before and after treatment. In vitro assays were also performed, incubating patient blood samples with empagliflozin at concentrations of 0.1, 1, and 10 µM. In patients with type 2 diabetes mellitus, empagliflozin significantly reduced body mass index (p=0.001), though HbA1c levels remained unchanged. Among heart failure patients, treatment resulted in a significant increase in left ventricular ejection fraction (p=0.028) and a decrease in B-type natriuretic peptide levels (p=0.01). Blood adenosine triphosphate concentrations increased significantly following empagliflozin treatment in both type 2 diabetes mellitus and heart failure groups. Proteomic analysis identified 12 differentially expressed proteins-ADIPOQ, ARG1, CST3, CPPED1, GSTO1, FN1, ITIH4, LCN2, LCP1, MIF, PCMT1, and SERPINA3-that are functionally linked to type 2 diabetes mellitus and/or heart failure pathophysiology. Our data suggest that blood adenosine triphosphate activity may serve as a potential biomarker for clinical response to empagliflozin in patients with type 2 diabetes mellitus and heart failure. Further studies are warranted to validate these exploratory findings and to evaluate the sensitivity, specificity, and predictive value of blood adenosine triphosphate as a biomarker in these populations.