Frontiers in Endocrinology最新文献

[This corrects the article DOI: 10.3389/fendo.2025.1646643.].

Introduction: Serotonin (5-hydroxytryptamine [5-HT]) plays a fundamental role in fetal neurodevelopment. While 5-HT is synthesized in the fetal brain, the placenta contributes significantly to fetal 5-HT levels during early gestation. However, little is known about the influence of placental serotonergic components on early neurodevelopmental outcomes. In this study, we have evaluated the association between the expression of key components of the placental serotonergic system and neurodevelopmental status in infants of mother-child dyads enrolled in the Origen Bioquímico y Epigenético del Sobrepeso y la Obesidad (OBESO) perinatal cohort at the first month of life.

Methods: We analyzed 5-HT concentrations in maternal serum, umbilical cord serum, and placental tissue, and investigated the expression of key proteins of the serotonergic system in the placenta. All samples were obtained from full-term healthy pregnancies. 5-HT levels were measured by ELISA, and protein expression in placental tissue was evaluated by Western blot. Neurodevelopment was assessed at 1 month of age using the Bayley Infant Development Scale III (BSID-III). Infants with two or more BSID-III domain scores ≤ 7 were grouped as having altereded neurodevelopment.

Results: Placentas from infants with altered neurodevelopment exhibited higher expression of tryptophan hydroxylase types 1 and 2 (TPH1 and TPH2)-the rate-limiting enzymes in 5-HT synthesis-as well as the serotonin transporter (SERT), compared to those from infants with normal neurodevelopment. In contrast, expression of monoamine oxidase-A (MAO-A), the primary degrading enzyme, was significantly lower in the altered group. Interestingly, 5-HT levels and the expression of 5-HT1E and 5-HTR5A receptors were similar between groups.

Conclusion: These findings suggest that dysregulation of the placental serotonergic system, independent of total 5-HT levels, could be associated with early neurodevelopmental impairments, highlighting the importance of placental serotonin signaling in fetal brain development.

Introduction: This study evaluated 6-month effectiveness and safety of automated insulin delivery (AID) in comparison with multiple daily injections (MDI) in pediatric and adult type 1 diabetes (T1D).

Materials and methods: Individuals with T1D, aged 2-80 years, were enrolled across 32 international centers (in the United States, Europe, Canada, and New Zealand) and randomized 1:1 to AID intervention (MiniMed™ 670G or 770G system) or MDI with or without continuous glucose monitoring. Primary endpoints were change in mean HbA1c for participants with a baseline HbA1c >8.0% (Group 1) and percentage of time spent below 70 mg/dL (%TBR <70 mg/dL [<3.9 mmol/L]) for participants with baseline HbA1c ≤8.0% (Group 2), to show superiority of AID intervention versus MDI. Safety endpoints including rates of severe hypoglycemia and diabetic ketoacidosis (DKA), and difference in diabetes treatment satisfaction score were assessed.

Results: For Group 1, N = 56 participants (aged 29.4 ± 17.0 years) were randomized to AID intervention and N = 54 participants (aged 36.8 ± 19.6 years) were randomized to MDI. For Group 2, N = 73 (aged 37.4 ± 21.0 years) and N = 69 (aged 39.2 ± 19.3 years), respectively, were randomized to AID and MDI. Change in HbA1c (mean [95% CI] difference of -0.7% [-1.1, -0.3], P = 0.0002) and difference in %TBR <70 mg/dL (4.8% [-6.4, -3.1], P<0.001) favored AID intervention versus MDI. Rates of severe hypoglycemia (AID: 1.82/100 patient-years) and DKA (MDI: 3.52/100 patient-years) were low and met preestablished success criteria for safety.

Discussion: This large, international, multicenter randomized controlled trial demonstrates safety of the MiniMed™ 670G/770G systems. AID significantly improved HbA1c and time spent in hypoglycemia when compared with MDI, in both youth and adults living with T1D.

Clinical trial registration: https://clinicaltrials.gov/, identifier NCT02748018.

Background: Apolipoprotein E (ApoE) affects lipid metabolism and was associated with type 2 diabetes mellitus (T2DM) complications, including diabetic peripheral neuropathy (DPN). Despite improved glycemic control, DPN prevalence continues to rise, indicating mechanisms beyond hyperglycemia. We assessed the association between APOE genotypes and DPN susceptibility in patients with T2DM, focusing on dyslipidemia-linked pathways underlying neuropathy susceptibility distinct from glycemic effects.

Methods: The case-control study included 908 Lebanese patients with T2DM (382 with DPN, 526 without) and 695 healthy controls who underwent multimodal DPN assessment (NCS, QST, and MNSI). APOE genotyping was performed by PCR-RFLP analysis. Logistic regression models were applied to examine the associations between APOE variants and higher odds of DPN.

Results: T2DM patients showed significantly higher frequencies of ϵ2 and ϵ4 alleles than controls. Among T2DM patients, those with DPN had significantly higher ϵ2 allele frequency and lower ϵ3 allele frequency. At the genotype level, ϵ3/ϵ3 genotype demonstrated lower odds of DPN, while ϵ2/ϵ3, ϵ2/ϵ4, and ϵ3/ϵ4 were significantly associated with increased odds after adjustment for traditional risk factors. When pooled by allele, ϵ2-containing genotypes (ϵ2/ϵ3 + ϵ2/ϵ4; OR (95% CI) = 1.86 [1.38-2.51], and ϵ4-containing genotypes (ϵ3/ϵ4 + ϵ4/ϵ4 + ϵ2/ϵ4; OR (95% CI) = 1.62 [95% CI = 1.08-2.44]) showed high odds of DPN. Lipid profiles varied by genotype: ϵ4-containing genotypes displayed atherogenic patterns (elevated total cholesterol and triglycerides, reduced HDL) and were associated with a 1.6-fold higher odds of DPN, while ϵ2-containing genotypes showed increased total cholesterol and LDL among DPN patients. Genotype-specific clinical correlations were genotype-specific: ϵ3/ϵ3 was associated with retinopathy and hypertension but protective against nephropathy, while ϵ3/ϵ4 correlated with diabetic complications and dyslipidemia, and ϵ4/ϵ4 linked to a higher BMI.

Conclusion: APOE genetic variants, especially ϵ4-containing genotypes, are associated with DPN susceptibility among Lebanese T2DM patients, independent of traditional risk factors including glycemic control. These population-specific findings require validation in prospective cohorts before clinical use but indicate potential value for APOE genotyping in DPN precision-risk models.

[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.