Journal of Endocrinology最新文献

Mitochondrial dysfunction is a key feature of type 2 diabetes and is closely linked to ageing, a major risk factor for the disease. This study investigated islet cell composition and mitochondrial oxidative phosphorylation protein expression in pancreatic tissue from older donors (≥62 years) with and without type 2 diabetes, matched for age, sex, and BMI. Fixed human pancreatic tissue sections were immunolabelled for insulin, glucagon, NDUFB8 (complex I), MTCO1 (complex IV), and VDAC1 (a mitochondrial mass marker) to quantify islet composition and mitochondrial protein levels. A machine learning-based single-cell segmentation pipeline enabled high-resolution profiling of individual cell populations within islets. In type 2 diabetes, islets exhibited an increased alpha:beta cell ratio, altered spatial organisation with fewer beta-beta and more alpha-alpha interactions, and a significantly higher proportion of bi-hormonal cells co-expressing insulin and glucagon. Within beta cells, we observed significant changes in mitochondrial protein expression, including reduced complex I and elevated complex IV levels. Unsupervised clustering of mitochondrial expression patterns identified three distinct beta cell expression clusters. Donors with type 2 diabetes showed a marked shift in the distribution of beta cells across clusters, with increased proportions of beta cells exhibiting low complex I and high complex IV expression. These results highlight significant alterations in islet architecture and mitochondrial protein expression associated with type 2 diabetes, providing new insights into the mechanisms underlying type 2 diabetes.

Abstract: The rs6923761 (Gly168Ser) missense variant in the glucagon-like peptide-1 receptor (GLP-1R) has been associated with favorable anthropometric and metabolic parameters in individuals with obesity but decreased responsiveness to incretin-based therapies. Here, we performed a pre-specified analysis of a randomized-controlled trial in individuals with obesity and pre-diabetes comparing treatment with the GLP-1R agonist liraglutide, the dipeptidyl peptidase 4 inhibitor sitagliptin or hypocaloric diet, and evaluated the effects of the rs6923761 variant on outcomes. We found significantly greater weight loss to liraglutide with each copy of the variant allele present, indicating a gene dose effect. In addition, individuals with the variant allele exhibited a significant reduction in the pro-thrombotic and pro-inflammatory factor plasminogen activator inhibitor-1 after liraglutide treatment. There was no effect of genotype on fasting glucose after liraglutide treatment, yet individuals with the variant allele exhibited decreased responsiveness to liraglutide and hypocaloric diet in measurements of fasting insulin, C-peptide, glucagon, and HOMA-IR. In conclusion, we found that the GLP-1R rs6923761 variant exerts a dual impact on liraglutide efficacy-enhancing weight loss while diminishing metabolic benefits. The observed associations could be consistent with the constitutive activation of the GLP-1R in the presence of this variant with reduced activation/signaling in response to pharmacologic agents, a pattern that has been observed with the rs10305492 variant in animal models. Future studies are needed to investigate the molecular mechanisms of associations with the rs6923761 variant.

Diabetes mellitus is a complex metabolic disorder characterized by hyperglycemia and the associated comorbidities. Type 2 diabetes is also associated with the dysfunction of liver, kidney and nervous system. In addition, an altered microbiota is frequently observed in subjects with type 2 diabetes. In this study, a db/db (diabetic) mouse model of type 2 diabetes was used to elucidate the beneficial effects of the probiotic Lactobacillus johnsonii N6.2. To evaluate metabolic effects, we performed metabolomics on liver samples, and RNA-seq from the liver and visceral adipose tissue, followed by qRT-PCR validation. Using L. johnsonii N6.2 extracellular vesicles, we evaluated lipid accumulation in hepatocytes. Finally, the gut microbiome of db/db mice was profiled using 16S rRNA sequencing. We observed that administration of the probiotic improved glycemic levels and decreased diabetes scores and type 2 diabetes-associated injury to the pancreas, liver and kidneys. Liver metabolomic and transcriptome analyses identified biomarkers of L. johnsonii N6.2 activity, including modulation of the vitamin K pathway, upregulation of FGF21, a key regulator of glucose and lipid metabolism, and alternations in selected circadian genes. This study elucidates the beneficial effects of L. johnsonii N6.2, against the common symptoms of type 2 diabetes, highlighting its potential as an adjuvant therapeutic agent.

TIMELESS is considered a molecular hinge linking circadian rhythms and the cell cycle. We recently identified TIMELESS as one of the upregulated core circadian clock genes during thyroid cancer dedifferentiation, but its expression and significance in thyroid cancer remain unclear. To address this, we assessed TIMELESS expression in thyroid neoplasms using bioinformatics analysis, immunoblotting, and immunohistochemistry. TIMELESS expression progressively increased from normal thyroid tissue to differentiated thyroid cancer and then to anaplastic thyroid cancer. Silencing TIMELESS expression in thyroid cancer cells reduced clonogenicity and spheroid formation, induced G2/M cell cycle arrest, and impeded xenograft growth in NOD SCID mice. In The Cancer Genome Atlas, TIMELESS expression was negatively correlated with recombination proficiency scores. Knocking down TIMELESS increased sensitivity to doxorubicin in thyroid cancer cells and upregulated the mRNA expression of NKX2-1 and SLC5A5. In conclusion, the overexpression of TIMELESS is associated with thyroid cancer dedifferentiation and may serve as a potential target for combination therapies.

Mitochondria are unique intracellular organelles that have their own DNA and are inherited intact in the oocyte. They have multiple functions, the most important of which is producing energy in the form of ATP by oxidative phosphorylation (OXPHOS) using a range of metabolic substrates. As energy requirements increase with intrauterine growth and the onset of new postnatal functions at birth, mitochondria develop structurally and functionally in utero to meet these energy demands. In part, the developmental and prepartum maturational changes in mitochondrial OXPHOS capacity depend on the endocrine environment and the natural rise in the fetal concentrations of hormones, such as cortisol and tri-iodothyronine (T3), towards term. This review discusses the development of mitochondrial respiratory function during late gestation with an emphasis on tissue OXPHOS capacity. It considers the role of cortisol and thyroid hormones, in particular, in the intrauterine development and prepartum maturation of mitochondrial OXPHOS capacity in preparation for extrauterine life. Finally, it briefly examines the potential longer-term consequences of abnormal hormonal exposure before birth on mitochondrial OXPHOS function later in postnatal life. Endocrine regulation of mitochondrial OXPHOS in the fetus is shown to be multifactorial, dynamic and tissue specific with a central role in determining functional development. It optimises energetics for survival both in utero and at birth and has implications for adult metabolic fitness and the inheritance of mitochondrial phenotype.

Cadmium is a heavy metal found widely in the environment, originating from industrial emissions, mining activities, phosphate fertilizers, and cigarette smoke. It is an endocrine-disrupting chemical that mimics essential metals such as calcium and zinc, interfering with hormone signaling. Due to its long biological half-life, cadmium bioaccumulates in organisms, raising concerns about its long-term effects on endocrine and reproductive health. Cadmium's reproductive toxicity is well documented, with studies highlighting its impact on gonadotropin regulation and testicular function. However, its specific effects on calcium (Ca2+) signaling in gonadotrophs remain poorly understood. This study aims to determine whether cadmium disrupts Ca2+-dependent signaling mechanisms essential for gonadotropin secretion. To address this, we used an adult male mouse model to assess pituitary cadmium accumulation, gonadotroph responsiveness to GnRH, and alterations in Ca2+ mobilization patterns. Our results show that cadmium exposure leads to pituitary bioaccumulation, prolonged endocrine disruption, and gonadotroph hyperplasia. Initially, gonadotroph responsiveness to GnRH declines, but over time, altered Ca2+ oscillation patterns and increased gonadotropin secretion emerge. A transition from normal oscillatory Ca2+ signaling to biphasic responses was observed, along with sustained phospholipase C-β (PLCβ) activation, suggesting persistent intracellular signaling disruptions. In addition, cadmium exposure resulted in testicular atrophy, increased apoptosis, and reduced sperm count. Testosterone levels declined, while the gonadotroph population increased, highlighting an imbalance in endocrine regulation. These findings suggest that cadmium induces reproductive toxicity through a combination of direct testicular damage and disruption of gonadotroph calcium signaling and hormone secretion, leading to testicular dysfunction that is relevant to public health.

Polycystic ovary syndrome (PCOS) is a heterogeneous endocrine disorder with diverse clinical manifestations and metabolic risks. The 2012 NIH phenotypic classification, based on the presence of hyperandrogenism (HA), ovulatory dysfunction, and polycystic ovarian morphology (PCOM), has enabled more nuanced characterization of PCOS into four phenotypes (A-D). Phenotypes A and B, both hyperandrogenic and anovulatory, are consistently associated with the highest metabolic risk, including insulin resistance, dyslipidemia, and increased prevalence of metabolic syndrome. Phenotype C, though ovulatory, still exhibits metabolic abnormalities due to androgen excess. In contrast, phenotype D, lacking hyperandrogenism, generally shows the mildest hormonal and metabolic profiles. This review outlines the evolving diagnostic landscape of PCOS, including the potential use of anti-Müllerian hormone (AMH) as a surrogate marker for PCOM. It explores hormonal and metabolic biomarkers, such as total and free testosterone, SHBG, LH/FSH ratio, HOMA-IR, and lipid parameters, in phenotype differentiation. Furthermore, emerging adipokines (e.g., adiponectin, chemerin, and ZAG) and inflammatory markers (e.g., CRP, IL-6, and TNF-α) provide additional insight into the metabolic heterogeneity of PCOS beyond obesity. Genetic and genomic studies have identified over 19 susceptibility loci involved in gonadotropin regulation, steroidogenesis, and insulin signaling, with distinct gene clusters aligning with adiposity, insulin resistance, and reproductive traits. MicroRNA signatures also show potential as phenotype-specific biomarkers. Recognizing phenotype-specific variations in PCOS is critical for individualized risk assessment and therapeutic strategies. Future research should prioritize standardized diagnostic criteria and large, diverse cohorts to validate emerging biomarkers and improve long-term outcomes for women with PCOS.

CL316,243 (CL), a beta 3 adrenergic receptor (B3-AR) agonist, has 'exercise mimetic' effects in adipose tissue. CL may also positively affect skeletal muscle (SM), yet the role of estrogen receptor beta (ERβ) in mediating SM-specific effects of CL is not known. We investigated the effects of CL on SM metabolism, as well as the role played by ERβ. High-fat diet-fed male and female wild-type (WT) and ERβ DBD knockout (KO) mice were administered CL daily for 2 weeks. Quadriceps SM protein markers of fatty acid oxidation (FatOx), protein synthesis, and protein catabolism were assessed. CL increased relative lean mass in both sexes (P = 0.012). In females, CL increased FatOx in WT, yet reduced FatOx in KO, while among males, CL reduced FatOx independent of genotype (P = 0.04). Uncoupling protein 2 (UCP2) and fatty acid synthase (FASN) abundance were higher in females (P = 0.004 and 0.037, respectively), and in both sexes, KO mice had higher SM UCP2 abundance (P = 0.022). CL increased phosphorylated acetyl-CoA carboxylase in males, yet reduced it in females (P = 0.015). Similarly, CL affected p706S kinase abundance (indicative of anabolic signaling) in a sexually dimorphic manner, increasing in males and decreasing in females. CL robustly increased SM FASN across sexes and genotypes (P < 0.001). In summary, the most salient finding was that CL increased SM FASN content independent of sex and ERβ genomic activity; additional novel sex-divergent effects of CL on SM metabolism were identified, some of which were affected by ERβ genomic activity.

Gut dysbiosis and an increased risk of respiratory infection in type 2 diabetes have been well recognised. However, the relationship between the gut and respiratory pathobiont carriage rates in the type 2 diabetic Malaysian population is understudied. To address the knowledge gap, we profiled the gut and upper respiratory tract (URT) microbial composition, and the urine metabolome of 31 type 2 diabetic adults and 14 non-diabetic adults. We showed a higher prevalence of opportunistic URT pathogens in diabetes patients. A higher abundance of pro-inflammatory bacteria Escherichia coli was detected in the gut of the diabetic subjects. This coincided with the higher levels of sorbitol and taurine in the urine. The former is produced by aldose reductase, an enzyme strongly associated with airway inflammation, while the latter is a substrate for bacterial antioxidants (i.e. H2S). Despite a small sample size, our study revealed the potential relationship between the carriage rates of URT pathobionts with the gut microbial and urine metabolomic profiles of diabetes patients.

Triclosan (TCS), an antimicrobial agent widely used in personal care products, has been associated with impaired thyroid function and reduced thyroid hormone (TH) levels. However, its potential role in the developmental programming of thyroid dysfunction remains unclear. This study investigated the long-term effects of intrauterine TCS exposure on the hypothalamic-pituitary-thyroid (HPT) axis in adult rat offspring. Pregnant Wistar rats received oral doses of corn oil (control) or TCS (10 or 30 mg/kg/day) throughout gestation. Offspring rats were euthanized on postnatal day 90 (PND90), and tissues from the hypothalamus, pituitary, thyroid, liver, and serum were collected for analysis. Gene and protein expression were evaluated by RT-qPCR and Western blotting; thyroid histology was assessed morphologically; global DNA methylation was measured by ELISA; and serum TSH and THs were quantified through immunoassays. TCS exposure altered hypothalamic TRH content, reduced Gh mRNA expression in the pituitary, and decreased serum TSH levels. In the thyroid, Slc5a5, Tg, Tpo, Tshr, Pax8, and Nkx2.1 were downregulated, accompanied by reduced NIS and TPO protein expression and decreased circulating T4 levels. Histological analyses revealed reduced follicular diameter in both sexes. Epigenetic changes included increased global DNA methylation and H3 histone methylation in both sexes, along with reduced H3 acetylation in males. In addition, TCS exposure altered hepatic enzymes involved in TH metabolism, indicating systemic endocrine disruption. Collectively, these findings demonstrate that intrauterine TCS exposure increases susceptibility to thyroid hypofunction in adulthood, highlighting its potential role as a developmental thyroid disruptor.