Frontiers in Endocrinology最新文献

[This corrects the article DOI: 10.3389/fendo.2025.1711369.].

Ectopic adrenocorticotropic hormone (ACTH)-dependent Cushing's syndrome (EAS) is a rare complication of neuroendocrine tumors (NETs). Severe hypercortisolism (SH) requires urgent medical intervention due to its life-threatening consequences. We report a 74-year-old female patient with an ACTH-secreting pancreatic NET (pNET) who presented with rapidly progressive cognitive decline, muscle weakness, severe hypokalemia, and hyperglycemia. Laboratory evaluation confirmed ACTH-dependent Cushing's syndrome with loss of diurnal cortisol rhythm and panhypopituitarism. Surgical treatment was contraindicated because of significant comorbidities. The initial management included intravenous etomidate infusion. Subsequently, osilodrostat was introduced as long-term oral therapy. Marked clinical and hormonal improvements were observed, including the normalization of potassium and cortisol levels, resolution of neuropsychiatric symptoms, and restoration of mobility. After 19 months of osilodrostat therapy, endoscopic ultrasound-guided ethanol ablation of the pancreatic lesion was performed, and medical therapy was discontinued. This case demonstrates the effectiveness of dual steroidogenesis blockade with etomidate and osilodrostat in both the acute and chronic management of severe ectopic Cushing's syndrome due to pNET. It also highlights the role of endoscopic ethanol ablation as a minimally invasive curative option for patients who are unfit for surgery.

Diabetic peripheral neuropathy (DPN), a debilitating diabetic complication, has a complex pathological mechanism involving oxidative stress, mitochondrial dysfunction, and endoplasmic reticulum stress, and there are no effective disease-mitigating treatments. Current management is restricted to glycaemic control and symptomatic analgesia, both of which offer only modest benefit and carry appreciable adverse-effect profiles. Heat Shock Proteins (HSP) are stress-inducible chaperones that counteract protein misfolding and aggregation. Through suppression of apoptosis, cytoskeletal stabilisation and immune modulation they exert neuroprotective effects relevant to DPN onset and progression. Studies have shown that HSP90 regulates neuronal plasticity and that its inhibitors restore mitochondrial function in diabetic neurons, whereas HSP70 and HSP27 exert context-dependent positive or negative regulation. Subsequent work has evaluated covalent HSP90 inhibitors, novel HSP70 agonists, Trans-activator of transduction-Heat shock protein 27 (TAT-HSP27) mediates suppression of mitochondrial apoptosis and the utility of HSP27 as a circulating biomarker. Here we synthesise recent advances in HSPs biology and DPN pathogenesis, highlight the therapeutic potential of targeting HSPs and outline translational strategies that may expedite disease-modifying therapy.

Metabolic dysfunction-associated steatotic liver disease (MASLD) has evolved from a hepatic-centric condition to a systemic metabolic disorder, with multisystem complications driving clinical outcomes. This review comprehensively examines the pathogenesis and extrahepatic manifestations of MASLD, focusing on interorgan crosstalk. We first delineate the hepatic progression from steatosis to fibrotic metabolic dysfunction-associated steatohepatitis (MASH), emphasizing lipotoxicity, mitochondrial dysfunction, and inflammatory cascades. Subsequently, we analyze key extrahepatic axes (1): the liver-brain axis, where neuroinflammation and cognitive impairment are linked to hepatic metabolic disturbances (2); the gut-liver axis, highlighting roles of gut microbiota dysbiosis and intestinal permeability in disease progression; and (3) the liver-kidney axis, exploring shared fibrotic mechanisms and functional decline. Common pathways-including chronic inflammation, oxidative stress, and immune-metabolic dysregulation-underpin these systemic complications. Therapeutically, we advocate a shift from isolated liver-targeted approaches to integrated multisystem strategies. This review underscores the imperative to reconceptualize MASLD as a systemic disease, necessitating collaborative efforts to refine diagnostic frameworks and therapeutic paradigms for improving patient outcomes.

Long COVID, or post-acute sequelae of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection (PASC), refers to a range of persistent health effects associated with SARS-CoV-2 infection. Long COVID is a complex, multisystem disorder that can affect nearly every organ system and is strongly linked with the incidence of diabetes and other chronic conditions. Increasing evidence also connects persistent SARS-CoV-2 infection with the development of new-onset diabetes and other metabolic disorders. In this review, we assess the current evidence and discuss the incidence of new-onset diabetes, along with the pathobiological mechanisms by which SARS-CoV-2 may contribute to the progression of both new-onset type 1 and type 2 diabetes mellitus (T1DM and T2DM). We summarize the latest understanding of the molecular and cellular mechanisms underlying SARS-CoV-2-associated new-onset diabetes. Potential mechanisms include direct damage to pancreatic β-cells, inflammation, insulin resistance, and autoimmune responses. Dysregulation of the ACE2/renin-angiotensin system (RAS) pathway has been linked to multiple inter-organ pathologies, and increased inflammatory cytokines together with dysregulation of interferon regulatory factors (IRFs)-such as overexpression of IRF1-appear to represent key mechanistic links to widespread tissue damage and metabolic alterations. Moreover, the presence of viral RNA or viral RNA fragments may directly damage pancreatic islets, contributing to insulin resistance and β-cell dysfunction that, in turn, may promote the development of new-onset diabetes. In light of these findings, this review further examines evidence supporting the persistence of SARS-CoV-2 RNA in PASC reservoir tissues, including the pancreas, and its potential association with the development of new-onset diabetes mellitus.

Classic Congenital Adrenal Hyperplasia (CAH) due to 21-hydroxylase deficiency is typically diagnosed in early life. We report a 46,XX completely virilized 46,XX patient who was diagnosed with classic CAH at the age of 73 years. He was under follow-up for prostate hyperplasia and referred after the finding of giant bilateral adrenal myelolipomas. He presented with hormonal values initially interpreted as suggestive of hypogonadotropic hypogonadism, prompting further biochemical and genetic analysis. Next-generation sequencing identified heterozygous variants in X-linked genes, uncovering a 46,XX difference of sex development (DSD). Then, CYP21A2 molecular analysis revealed compound heterozygosity for two pathogenic variants (p.I173N, p.R357W), confirming simple virilizing CAH. The patient's reticent attitude contributed to the diagnostic delay. However, this unique case reveals the challenges generated by the paraurethral glands hyperplasia - mimicking a prostate due to prolonged untreated hyperandrogenism - as well as the repeated failure to recognize Müllerian remnants on imaging and the critical issues related to diagnostic communication.

Objective: To determine if combining PET-derived beta-cell mass (BCM) estimates with MRI-based morphology metrics improves the prediction of beta-cell functional mass in type 2 diabetes (T2D).

Methods: We performed a retrospective analysis of 40 participants-19 T2D individuals, 16 healthy obese volunteers (HOVs), and five prediabetes individuals-who underwent [¹⁸F]FP-(+)-DTBZ PET to quantify vesicular monoamine transporter type 2 (VMAT2) density [standardized uptake value ratio (SUVR-1)], T1-weighted MRI for 3D morphology metric analysis, and an arginine stimulation test to measure acute (AIRarg) and maximum (AIRargMAX) insulin responses. Least Absolute Shrinkage and Selection Operator (LASSO) regression models identified the optimal combination of positron emission tomography (PET), MRI, and clinical variables to predict beta-cell function for the whole pancreas and its subregions.

Results: Compared to HOVs, individuals with T2D exhibited significantly reduced AIRarg and AIRargMAX. Only the pancreas body volume was significantly smaller in the T2D cohort. For the whole pancreas, a model including PET-derived SUVR-1 and a subset of clinical covariates best predicted acute beta-cell function (AIRarg). However, predicting maximum functional reserve (AIRargMAX) required the addition of MRI-based morphology metrics in combination with SUVR-1 and a subset of clinical covariates.

Conclusion: We combined PET imaging of BCM and MRI morphology metrics with a robust machine learning-based variable selection method to extract useful PET- and MRI-based metrics for predicting acute and maximum insulin responses. This synergistic approach offers a novel combination of biomarkers for staging disease and evaluating therapeutic interventions.

Background: 48,XXYY is a sex chromosome aneuploidy (SCA) occurring in 1:18,000-50,000 male births, characterized by androgen deficiency in conjunction with hypogonadism, hypertelorism, clinodactyly, pes planus, radioulnar synostosis, increased height velocity, hypotonia, and a suspected increased incidence of autism spectrum disorder (ASD). The neurodevelopmental phenotype includes motor dysfunction, speech/language disturbance, and intellectual deficits.

Aim: This series will compare the neurodevelopmental profile of five patients with 48,XXYY during early childhood.

Methods: Five cases of male patients with 48,XXYY were followed beginning at the time of diagnosis. Each case underwent a combination of neurodevelopmental, oral motor, speech/language, physical therapy, medical genetics, and/or neurology evaluations.

Results: In the five cases presented, there was an increased incidence of torticollis, with the right side more common. Abnormal muscle tonus was noted in all cases, characterized by hypotonia of the trunk, upper extremities, and oral motor musculature. Four of the patients exhibited an increased head circumference (≥ 79th percentile) by 7 months of age. All cases had speech/language and motor delays evident in the first 12 months of life and showed no signs of ASD prior to 3 years of age.

Conclusions: The presentation of 48,XXYY is varied, including oral motor deficits, hypotonia, positional and congenital muscular torticollis, respiratory issues, and inner-ear dysfunction. Early presentations of infantile developmental dyspraxia are evident by 18 months, specifically as discrepancies between fine and gross motor and expressive and receptive language skills. This series provides additional insight into the phenotypic presentation of male patients with 48,XXYY during infancy and early childhood and identifies common complications.

Background: Intrinsic capacity (IC)is closely associated with cardiometabolic health in middle-aged and older adults. The purpose of this study was to determine the associations of baseline IC, cumulative IC scores, and their dynamic changes with the risk of incident cardiometabolic multimorbidity (CMM).

Methods: Using data from three prospective cohorts, the China Health and Retirement Longitudinal Study (CHARLS), the English Longitudinal Study of Ageing (ELSA), and the Health and Retirement Study (HRS), participants who met the eligibility criteria were included in this study. Kaplan-Meier curves and Cox models analyzed risk trends and associations.

Results: A total of 11,916 participants were included based on the inclusion and exclusion criteria. At baseline, the risk of CMM in the injured group was significantly higher than that in the non-injured group(Pooled: HR = 1.40, 95% CI 1.30-1.52, P < 0.001); Cumulative IC scores showed a graded association with CMM risk: individuals with moderately reduced scores (≈1 SD below intact) had higher risk (HR = 1.22, 95% CI 1.09-1.36), and those with substantially reduced scores (>1 SD below intact) had even higher risk (HR = 1.61, 95% CI 1.47-1.78). For dynamic changes, CMM risk was significantly higher in persistent impairment and decline groups; even the improvement group had higher risk than the no-decline group (Decline: HR = 1.25, 95% CI 1.10-1.42, P < 0.001; Improvement: HR = 1.28, 95% CI 1.13-1.45, P < 0.001; Persistent impairment: HR = 1.63, 95% CI 1.48-1.80, P < 0.001).

Conclusions: IC and its changes relate to CMM risk. Even with IC improvement, risk remains higher than in those with intact IC. Precise strategies to delay IC decline and individualized interventions are needed for CMM control.

Inborn metabolic diseases (IMDs) represent a diverse and complex group of rare disorders, typically resulting from variants in genes that encode specific enzymes or cofactors, leading to reduced or absent enzymatic activity. These conditions commonly disrupt one or more metabolic pathways, often impacting multiple organ systems from early childhood. Clinicians should consider the possibility of an IMD when an endocrine abnormality is accompanied by other unexplained clinical signs or in presence of combined endocrinopathies. While some IMDs associated with endocrine dysfunction in children and adolescents are well-documented and supported by established treatment guidelines, others lack clear recommendations or are characterized by inconsistent data. This narrative review aims to summarize the main IMDs that present with endocrine abnormalities in pediatric patients, organized according to affected organ systems and underlying pathophysiological mechanisms. Furthermore, we reviewed the latest recommendations, when available, for monitoring endocrine function in children with these disorders and eventually for providing a tailored treatment, where applicable.