Iodothyronine deiodinases (DIOs) are key regulators of thyroid hormone action. Three types of DIOs, including type 1 (D1), 2 (D2), and 3 (D3), coordinate the local and systemic availability of T3. D2 primarily catalyzes the activating conversion of T4 to T3, whereas D3 mainly catalyzes the inactivating conversion of T4 to reverse T3 (rT3) and T3 to diiodothyronine (T2). D1 has a relatively low affinity for T4 and contributes less to T4 activation but preferentially catalyzes the conversion of rT3 to T2. Thyroid hormones promote D1 and D3 expression, whereas D2 activity is transcriptionally regulated via several pathways such as cAMP and post-translationally through ubiquitin-dependent proteasomal degradation. Evidence from knockout and overexpressing mouse models and human genetic variants has clarified the physiological roles of DIOs in thyroid hormone economy. Reduced D1 activity increases serum rT3 levels, D2 enhances local thyroid hormone action and contributes to circulating T3 production, and D3 decreases circulating T3 and T4 levels while increasing rT3 levels. DIO dysregulation is implicated in several clinical conditions. GH-related disorders potentially alter thyroid function via D2-mediated mechanisms. In adrenal insufficiency, thyroid function may exhibit elevated serum fT3 levels without TSH suppression. Additionally, resistance to thyroid hormone β can be associated with bezafibrate-induced consumptive hypothyroidism through increased hepatic D3 expression. This review summarizes current knowledge on the biological properties and clinical implications of DIOs and highlights their significant role in the regulation of thyroid hormone action.
Immune checkpoint inhibitor (ICI)-related type 1 diabetes is a rare but potentially life-threatening immune-related adverse event, and imaging findings immediately before clinical presentation and diagnosis have rarely been documented. We report a 71-year-old woman with large cell neuroendocrine carcinoma who developed fulminant type 1 diabetes mellitus during carboplatin, nab-paclitaxel, and atezolizumab therapy. The day of clinical presentation and diagnosis was defined as Day 0. On Day -1, she developed nausea and appetite loss without abdominal pain. On Day 0, she presented with impaired consciousness and fever; laboratory evaluation showed plasma glucose 1,435 mg/dL, glycated hemoglobin (HbA1c) 6.9%, marked ketonemia, severe hyperosmolality, negative anti-glutamic acid decarboxylase (GAD) antibody, and near-complete insulin deficiency. The metabolic presentation was interpreted as diabetic ketoacidosis/hyperosmolar hyperglycemic state (DKA/HHS) overlap. Computed tomography (CT) performed on Day -2 showed radiologic enlargement of the pancreatic tail with increased peripancreatic fat attenuation, both of which had resolved on Day 0. Pancreatic volume increased from 46.0 mL at baseline to 82.5 mL on Day -2, decreased to 47.9 mL on Day 0, and further declined to 39.0 mL at 6-month follow-up. This hypothesis-generating case documents incidental transient pancreatic enlargement with peripancreatic inflammatory changes shortly before diagnosis, followed by pancreatic atrophy. This case suggests that incidental pancreatic enlargement during ICI therapy may serve as an early radiologic clue to immune-related diabetes, supporting prompt metabolic evaluation even in the absence of abdominal pain or pancreatic enzyme elevation.
This randomized controlled study aimed to clarify weight loss targets for improving obesity-related disorders in individuals with overweight or obesity. A total of 294 participants with six obesity-related conditions were assigned to either a standard or intensive treatment group, with 12-month weight loss targets of ≥3% and ≥7%, respectively. The standard group followed the Japanese Guidelines for the Management of Obesity Disease 2016. The intensive group received frequent nutritional guidance, enhanced diet and exercise therapy, and additional pharmacotherapy. The primary outcome was weight loss and improvement in at least two obesity-related disorders at 12 months. Secondary outcomes included remission of health disorders, improvement in at least one health disorder, and visceral fat reduction. At 12 months, the weight loss was -2.5% in the intensive group and -1.7% in the standard group, with no significant difference in the primary outcome. However, remission of health disorders was achieved in 16.9% of the intensive group compared with 6.2% of the standard group (adjusted odds ratio 3.079; 95% CI 1.075-8.823; p = 0.036). Visceral fat reduction was greater in the intensive group (-20.46 cm2 vs. -8.9 cm2; p = 0.039). Intensive treatment significantly improved blood pressure early and increased treatment motivation scores by 10.9% (95% CI: 1.2-20.6) at 24 months (p = 0.004). In both groups, ≥60% of the participants showed improvement in at least one disorder. Despite not achieving the target weight loss, resulting in no significant difference in the primary outcome, the intensive treatment increased remission percentages, improved early blood pressure control, and enhanced long-term treatment motivation. The study was registered at UMIN Clinical Trials Registry (UMIN ID: UMIN000031862).
Although randomized controlled trials have demonstrated the efficacy of real-time continuous glucose monitoring (rtCGM), evidence from routine clinical practice remains limited, particularly in Asian populations. This study aimed to evaluate the effectiveness and safety of rtCGM initiation in individuals with diabetes. This multicenter, single-arm, retrospective, observational study was conducted at 34 sites across Japan (Clinical trial registration: UMIN000054275). Adults ≥18 years of age with diabetes who began using the Dexcom G6 rtCGM system, had a baseline glycated hemoglobin (HbA1c) level ≥7.5%, and continued rtCGM for at least 26 weeks were included. Factors associated with changes in HbA1c levels were examined using multivariate linear regression models. Among 192 participants, the mean HbA1c levels at 26 weeks were significantly lower (8.62 ± 1.14% vs. 7.88 ± 1.16%, p < 0.001) than those at baseline, with a difference of -0.73 ± 1.03%. In the multivariate analysis, greater HbA1c reduction was independently associated with higher baseline HbA1c (β = -0.40; p < 0.001), longer CGM active time (β = -0.008; p = 0.043), and older age (β = -0.010; p = 0.012), whereas prior isCGM use was associated with smaller reductions (β = +0.28; p = 0.045). Sex was also independently associated with changes in HbA1c levels (p = 0.028). During the 26-week follow-up period, one patient (0.5%) experienced diabetic ketoacidosis and four individuals (2.1%) experienced severe hypoglycemia. rtCGM initiation was associated with significantly lower HbA1c levels after 26 weeks of rtCGM use. These findings support the efficacy and safety of the Dexcom G6 in routine clinical practice.
Hereditary adrenocortical unresponsiveness to adrenocorticotropin (HAUA) is a rare congenital disorder characterized by isolated glucocorticoid deficiency with preserved mineralocorticoid production. HAUA encompasses familial glucocorticoid deficiency (FGD) and triple A syndrome (AAAS) and is caused by autosomal recessive defects in ACTH-signaling-related genes, including MC2R, MRAP, AAAS, NNT, TXNRD2, and MCM4. To clarify the current clinical characteristics of HAUA (including FGD and AAAS) in Japan, we conducted a nationwide questionnaire-based survey. The primary survey identified the number of affected patients, and the secondary survey collected detailed clinical information. Fifteen patients were identified from 12 institutions. Detailed clinical data were obtained from nine patients (mean age, 40.6 years). Most patients developed symptoms during childhood [3.75 (0-8) years]. Seven presented with chronic adrenal insufficiency, and two experienced life-threatening events, hypoglycemia or encephalopathy. Genetic confirmation was obtained in four cases. All patients received glucocorticoid replacement therapy (mean hydrocortisone-equivalent dose, 13.0 mg/m2/day). Notably, 50% of adult patients were obese (BMI ≥25 kg/m2), although no clear association between glucocorticoid dose and BMI was observed. Despite the limited cohort size, this study provides detailed clinical information on HAUA (including FGD and AAAS) in Japan and suggests a potential risk of obesity in long-term management.
In adults, cases of dyshormonogenetic goiter (DG) that go undiagnosed during childhood may necessitate thyroidectomy due to unexplained thyroid enlargement, often presenting diagnostic challenges. This study aimed to characterize the histopathological features of the thyroid in adult DG cases, and to evaluate the feasibility of predicting subtypes from the findings. Fifty adult patients with DG confirmed by the presence of gene variants were included. All resected thyroids showed diffuse goiter with microscopically altered thyroid follicles throughout the gland. All patients with SLC5A5 abnormality (iodide transport defect) showed lobulation accentuated by interlobular fibrosis. Follicular cells were enlarged, except in patients with SLC26A4 abnormality (Pendred syndrome). A scant colloid was observed in all patients with thyroglobulin (TG) gene abnormality. Thyroid peroxidase (TPO) gene abnormality and SLC26A4 abnormality were characterized by large follicles with Sanderson's polsters. Multiple non-encapsulated nodular lesions were present except in two patients with SLC26A4 abnormality. These were mainly follicular thyroid adenoma-like nodules associated with TG gene abnormality, TPO gene abnormality, and SLC5A5 variant. With SLC26A4 abnormality, the nodules were follicular nodular disease-like. The proposed histological framework may be particularly valuable for adult patients undergoing thyroidectomy for unexplained diffuse enlargement or multinodularity, particularly when no prior diagnosis of DG is documented.
In an aging society, the establishment of safe and effective treatment strategies for older patients with type 2 diabetes is crucial. We performed a secondary analysis of the Hokkaido-TZP study (UMIN000056962), evaluating the real-world outcomes of tirzepatide in patients aged ≥65 years. Of 213 patients in the safety analysis set, 11 (5.2%) discontinued treatment because of adverse events, primarily gastrointestinal symptoms. In the effectiveness analysis set (n = 199; mean age 71.3 years, glycated hemoglobin [HbA1c] 7.79%), tirzepatide significantly reduced both HbA1c and body mass index over 6 months in the Young-old (65-74 years) and Old-old (≥75 years) groups. Notably, even among the 148 patients (74.4%) using agents associated with a risk of hypoglycemia (insulin, sulfonylureas, or glinides) at baseline, a substantial proportion (66.9%) achieved an HbA1c <7.0%. The physicians proactively adjusted these concomitant medications in 39.2% of users, but despite these preemptive reductions, this subgroup still achieved a reduction in HbA1c comparable to that of the entire cohort, and no severe hypoglycemia was reported. A significant reduction in body weight occurred, and this was more pronounced in glucagon-like peptide-1 receptor agonist-naïve patients and those taking fewer hypoglycemia-inducing agents. Furthermore, the tirzepatide dose tended to be lower in the patients who achieved greater weight loss. These findings suggest that although tirzepatide is highly effective, even in older adults, its safety must be optimized through preemptive reductions in the doses of concomitantly administered secretagogues and careful monitoring, to prevent excessive reductions in HbA1c and weight loss in this vulnerable population.
Capivasertib, an oral pan-AKT inhibitor, is a therapeutic option for hormone receptor-positive advanced breast cancer. While hyperglycemia is a recognized adverse effect of AKT inhibition, its diagnosis is often delayed in routine clinical practice. We report a case of acute-onset severe hyperglycemia with diabetic ketosis identified within 4 days of initiating capivasertib in a patient without pre-existing glucose intolerance. A 61-year-old woman developed marked hyperglycemia (random plasma glucose, 482 mg/dL) with ketosis, despite being asymptomatic. Laboratory evaluation showed markedly elevated serum insulin (591.9 μU/mL), indicating preserved pancreatic β-cell function and severe insulin resistance. Blood glucose levels improved rapidly within 2 days of admission using minimal insulin therapy and fluid replacement. Unlike previously reported cases identified after symptomatic presentation, including emergency department visits, or under intensive inpatient monitoring, this case was detected through a proactively scheduled outpatient visit on day 4-strategically timed to coincide with the end of the first dosing cycle based on the drug's pharmacological profile. This observation highlights that severe hyperglycemia can develop very early and remain asymptomatic, underscoring the importance of proactive detection. Therefore, even in patients without pre-existing glucose intolerance or with preserved insulin secretion, proactive glucose monitoring during the first week of therapy, specifically near the end of the initial dosing cycle, is essential to prevent severe metabolic complications. Appropriate patient education and early consultation with diabetes specialists are also crucial for timely management.
We report a case of severe thyroid eye disease (TED) complicated by dysthyroid optic neuropathy (DON) in a 55-year-old woman with Graves' disease. Despite insufficient response to high-dose intravenous steroid therapy, teprotumumab led to marked improvement in proptosis, orbital inflammation, and visual function. However, treatment was associated with progressive and persistent sensorineural hearing loss after completing eight infusions. Auditory symptoms began after the fifth infusion with intermittent aural fullness and sound reverberation, progressing to mild down-sloping sensorineural hearing loss. Nine days after the final infusion, the four-frequency pure-tone average (PTA4) was 21.25 dB hearing level (HL) in the right ear and 27.50 dB HL in the left ear. Despite initiation of oral prednisolone therapy (40 mg/day with tapering), progressive hearing loss was observed in the right ear, particularly in the low- to mid-frequency range (250-2,000 Hz), with thresholds worsening to 90 dB HL. At twenty days after the final infusion, PTA4 had increased to 75.00 dB HL in the right ear and 31.25 dB HL in the left ear. Serial audiometric assessments at 107, 128, and 198 days after the final infusion demonstrated no recovery. The patient's history of sudden sensorineural hearing loss suggests increased susceptibility to teprotumumab-associated ototoxicity. This case underscores the importance of individualized risk assessment, careful audiologic monitoring, and shared decision-making when balancing visual recovery against the risk of potentially irreversible auditory toxicity.
Cushing's disease (CD) is very rare in children. Nineteen children (≤18 years) with CD (median age at diagnosis: 13 [6-17] years; 12 females) were retrospectively analyzed using medical records (1994-2025) from Toranomon Hospital, Tokyo, Japan. Facial changes (88.9%), weight gain with decreased growth rate (88.9%), central obesity (88.9%) and hirsutism (94.4%) were frequently observed at diagnosis. Median time to diagnosis was 2.7 (0.25-5.8) years. Screening for endogenous hypercortisolism was assessed by 24-hour urinary free cortisol levels, serum cortisol levels at 23:00, and serum cortisol levels at 8:00 after a low-dose dexamethasone suppression test (DST), each with 100% sensitivity. Etiological diagnosis was evaluated by serum cortisol levels at 8:00 after a high-dose DST, plasma adrenocorticotropic hormone (ACTH) levels after a corticotropin-releasing hormone test, and plasma ACTH levels at 8:00, with sensitivities of 85.7%, 93.8%, and 83.3%, respectively. The actual tumor detection rate on magnetic resonance imaging (MRI) was 72.2%. Micro-pituitary neuroendocrine tumors were identified in 77.8% of patients. The total remission rate was 94.4% (median follow-up: 3.8 [0-10.4] years). The mean standard deviation scores (SDS) (SD) of height and body mass index (BMI) at onset and diagnosis were -0.45 (0.63) and -2.0 (1.1), and 0.61 (0.95) and 1.6 (0.75), respectively. Height and BMI SDS (SD) improved to -1.0 (0.80) and 0.091 (1.2) at the last visit (age: 11.4-17.5 years; follow-up: 1-8.6 years), respectively. This study revealed clinical characteristics of Japanese children with CD, including distinctive BMI SDS and a high tumor detection rate by MRI.
Endothelial dysfunction is an early feature of diabetic vascular injury. Stress-induced activation of the hypothalamic-pituitary-adrenal (HPA) axis, together with autonomic imbalance, may contribute to endothelial dysfunction. However, its clinical relevance in diabetes remains to be fully elucidated. We retrospectively analyzed 60 patients with diabetes who underwent both flow-mediated dilation (FMD) of the brachial artery and the coefficient of variation of the R-R interval (CVRR) measurements. The primary objective was to examine the association between FMD and stress-related hormones, including adrenocorticotropic hormone (ACTH) and cortisol. The secondary objective was to evaluate the association with autonomic function (CVRR) and other clinical variables. Mean FMD was 5.10 ± 2.32%. FMD correlated inversely with ACTH (r = -0.41, p = 0.0015) and cortisol (r = -0.39, p = 0.0024), and positively with CVRR (r = 0.49, p < 0.001). These relationships were stronger in patients with BMI ≥27 kg/m2, among whom the correlation between FMD and ACTH was particularly pronounced (r = -0.68, p = 0.0007). No significant associations were found between FMD and hemoglobin A1c or other lipid parameters. Given the cross-sectional design, these findings indicated associations rather than causality. Our results suggest that the HPA axis activity and autonomic function may be associated with endothelial dysfunction in diabetes, particularly in individuals with a higher BMI. This study was registered in the UMIN Clinical Trials Registry (UMIN-CTR; UMIN000060540).
Primary aldosteronism is the most common form of secondary hypertension, and aldosterone-producing adenoma (APA) is the most prevalent surgically curable subtype of primary aldosteronism. Over the past decade, the identification of recurrent somatic mutations, most notably in KCNJ5, has transformed the molecular understanding of APA and has revealed substantial heterogeneity across tumors. In parallel, advances in transcriptomic, epigenomic, and metabolomic profiling have further expanded insights into genotype-dependent differences in steroidogenic activity, cellular morphology, and clinical presentation. More recently, the application of single-cell, single-nucleus, and spatial transcriptomics technologies has revealed an additional layer of complexity, demonstrating marked heterogeneity within individual APA tissues. These studies show that APAs are composed of transcriptionally and functionally diverse cell populations with variable steroidogenic capacities, extending beyond what can be explained by the somatic mutation status alone. This review summarizes the current evidence for both intertumoral and intratumoral heterogeneity in APA, integrating findings from genomic, epigenomic, metabolomic, and single-cell-based studies. By highlighting how mutation-driven differences intersect with cell-state diversity and differentiation processes, this review aimed to provide a comprehensive framework for understanding the pathophysiology of APA and discuss the potential implications for disease classification, biomarker development, and future therapeutic strategies.
Oculo-facio-cardio-dental (OFCD) syndrome is a rare X-linked dominant disorder caused by pathogenic variants in the BCOR gene and is characterized by distinctive craniofacial, ocular, cardiac, and dental abnormalities. Although OFCD syndrome is a well-defined developmental disorder, its association with endocrine tumors has not been clearly established. We report a female patient with genetically confirmed OFCD syndrome harboring a novel heterozygous deletion in BCOR who developed metachronous multiple insulinomas. The patient presented with recurrent hypoglycemic episodes, and pancreatic neuroendocrine tumors were detected at different time points, necessitating repeated surgical interventions. Histopathological examination confirmed insulinoma in each resected lesion. Comprehensive clinical and pathological evaluations revealed no features suggestive of other known hereditary insulinoma-associated syndromes, including multiple endocrine neoplasia type 1. Previous reports have described either recurrent insulinoma without genetic confirmation of OFCD syndrome or multiple insulinomas without documented recurrence in genetically confirmed cases. In contrast, the present case uniquely demonstrates metachronous development of multiple insulinomas in association with a novel BCOR deletion. Given the role of BCOR in transcriptional repression and developmental regulation, this case suggests a potential contribution of BCOR dysfunction to pancreatic neuroendocrine tumorigenesis. Our findings expand the phenotypic and genotypic spectrum of OFCD syndrome and underscore the importance of long-term surveillance and further accumulation of cases to clarify tumor predisposition in this rare disorder.
Follicular thyroid carcinoma (FTC) is known to occasionally show distant recurrence (DR); however, no prognostic scoring system has been established. Furthermore, although prognostic factors have been identified, their weights as predictors of poor prognosis remain unclear. In this study, we aimed to establish a weighted scoring system for predicting DR in FTC using conventional prognostic factors and Ki-67 labeling index (LI). We analyzed data of 597 patients with FTC without distant metastasis at initial surgery. Tumor size >4 cm, male sex, age ≥60 years, Ki-67 LI >5%, and vascular invasion (VI) ≥4 (V2) significantly and VI 0-4 (V1) marginally affected DR. Wide capsular invasion was not significantly associated with DR. Stepwise model selection using the Akaike Information Criterion identified age ≥60 years, Ki-67 LI >5%, V1, V2, and tumor size >4 cm as suitable components of the score. According to the beta coefficient value, we assigned a score of 2 to age ≥60 years, Ki-67 LI >5%, and V2, and a score of 1 to tumor size >4 cm and V1, with the sum representing the final score. We categorized patients into three categories according to the DR rates: low-risk (score 0-2; n = 388, 65.0%), intermediate-risk (score 3-4; n = 156, 26.1%), and high-risk (score 5-7; n = 53, 8.9%). The 10-year DR-free survival rates declined from the low- to the high-risk categories (96.0% vs. 90.3% vs. 54.9%). These findings indicate that high-risk patients identified using this prognostic scoring model should be carefully monitored for DR following completion thyroidectomy.
Recurrent Cushing's disease is most commonly caused by residual or newly developed pituitary neuroendocrine tumor (PitNET) tissue within the sellar region. Extrasellar recurrence due to postoperative tumor cell seeding is exceedingly rare. We report the unique case of a 30-year-old woman who achieved endocrine remission after gross total resection of an ACTH-secreting PitNET but later developed biochemical and clinical recurrence without radiological evidence of a sellar lesion. Despite long-term medical therapy including cabergoline, metyrapone, and pasireotide, the hypercortisolism gradually progressed. Nearly 10 years after the initial surgery, a reoperation was performed to explore the occult tumor. Intraoperatively, a small soft tumor attached to the posterior surface of the anterior wall of the sphenoid sinus was discovered. Histopathological examination confirmed the presence of a recurrent corticotrophic PitNET. A retrospective review of CT, MRI, and octreotide scintigraphy revealed a subtle lesion that had previously been overlooked. Complete resection resulted in an immediate endocrine remission. This case demonstrates that recurrent Cushing's disease may, although rarely, arise from the implantation of tumor cells that drop into the sphenoid sinus during transsphenoidal surgery. Awareness of this mechanism is crucial for evaluating MRI-negative recurrences. Careful inspection of the sphenoid sinus and meticulous irrigation during surgery may help prevent iatrogenic seeding and improve long-term outcomes.
Autoimmune thyroid diseases (AITD), including Graves' disease (GD) and Hashimoto's thyroiditis (HT), may coexist with Type 1 diabetes mellitus (T1DM) as autoimmune polyglandular syndrome type 3 (APS3). Sialic acid-binding immunoglobulin-like lectin (SIGLEC) 1 is an interferon-inducible molecule implicated in autoimmune disorders, but its clinical significance across AITD, T1DM, and APS3 remains unclear. In this cross-sectional study, 219 patients with AITD, T1DM, or APS3 were enrolled. SIGLEC1 mRNA levels derived from peripheral blood cells were quantified using quantitative reverse transcription PCR. In the primary analysis, 213 patients with SIGLEC1 mRNA levels were included (AITD-only, n = 127; T1DM-only, n = 59; APS3, n = 27). SIGLEC1 mRNA levels differed significantly among the three groups (p = 0.00086). Holm-adjusted post hoc comparisons showed significantly higher SIGLEC1 mRNA levels in the T1DM-only group and APS3 group than in the AITD-only group (p = 0.0099 and p = 0.0099, respectively), whereas the T1DM-only and APS3 groups did not differ significantly (p = 0.289). Within the AITD-only cohort, thyroid autoantibody-positive patients had higher SIGLEC1 mRNA levels than antibody-negative patients (median 130.1 vs. 74.4 copies, p = 0.034). SIGLEC1 mRNA levels showed a modest positive correlation with HbA1c (r = 0.210, p = 0.0060) but not with thyroid function parameters. In multivariable models, APS3 remained independently associated with higher SIGLEC1 mRNA levels after adjustment for age, sex, and HbA1c. Elevated SIGLEC1 mRNA levels were associated with coexisting endocrine autoimmunity and thyroid autoantibody positivity in this cohort. Longitudinal studies are required to determine whether SIGLEC1 mRNA levels have prognostic or predictive utility.
Social jetlag (SJL), the misalignment between biological and social time, has been linked to adverse metabolic outcomes. However, the effect of body mass index (BMI) on this association remains unclear, particularly in Asian populations. This cross-sectional study utilized data from the Taiwan Biobank, including 65,832 adults with complete information on sleep timing and metabolic parameters. SJL was calculated as the difference in mid-sleep time between workdays and free days and categorized as <2 or ≥2 h. Metabolic syndrome (MetS) was defined using standard clinical criteria. Multivariable logistic regression models were used to examine the association between SJL and MetS, with stepwise adjustment for sociodemographic, lifestyle, and clinical factors. Additional analyses stratified participants into BMI categories (<24, 24-26.9, ≥27 kg/m2). After full adjustment including BMI, SJL ≥2 h was not significantly associated with MetS (adjusted odds ratio = 1.05, 95% confidence interval: 0.98-1.12; p = 0.180). In BMI-stratified analyses, a significant association was observed only in the overweight group (BMI 24-26.9 kg/m2; adjusted odds ratio = 1.12, 95% confidence interval: 1.01-1.24; p = 0.035), but not in normal-weight or obese groups. An association between SJL and MetS was observed only in the overweight group, suggesting a BMI-dependent association between SJL and MetS. These findings highlight the importance of considering BMI when evaluating the association between SJL and MetS and indicate that the relationship between circadian misalignment and metabolic risk may vary across BMI categories.
The meibomian glands play a central role in maintaining ocular surface homeostasis by producing meibum, which is the lipid layer of the tear film that suppresses tear evaporation. Dysregulation of the secretion of this lipid leads to meibomian gland dysfunction (MGD), the most common cause of evaporative dry eye disease. Accumulating evidence indicates that androgen signaling is a critical regulator of meibomian gland structure and function. In contrast to classical endocrine mechanisms, androgen action in this tissue is largely mediated by intracrine steroid metabolism, whereby circulating adrenal precursors are locally converted to active androgens within the gland. Key steroidogenic enzymes, including 3β-hydroxysteroid dehydrogenase (3β-HSD), are expressed in the meibomian acinar cells, thereby enabling local testosterone production. Simultaneously, the gland exhibits robust metabolic pathways that convert testosterone to downstream androstane derivatives, providing a mechanism for the spatially restricted control of androgen signaling. Recent study has revealed that the intracrine steroidogenic system is affected by circadian rhythms. In particular, 3β-HSD activity exhibits daily rhythmicity that parallels fluctuations in nicotinamide adenine dinucleotide (NAD+), suggesting that NAD+-dependent metabolic processes contribute to temporal control of local androgen production. Importantly, administration of NAD+ precursors improves meibomian gland morphology in experimental models of aging-associated MGD. This review summarizes the current knowledge on intracrine androgen metabolism in the meibomian gland and highlights emerging metabolic and circadian mechanisms that may provide novel therapeutic targets for dry eye disease.
