Diabetes mellitus is one of the fastest-growing chronic medical conditions worldwide. It disproportionately affects some minoritized populations, including certain racial and ethnic groups, migrant populations, and rural...Diabetes mellitus is one of the fastest-growing chronic medical conditions worldwide. It disproportionately affects some minoritized populations, including certain racial and ethnic groups, migrant populations, and rural communities. Disparities in diabetes mellitus prevalence, morbidity and mortality in minoritized populations are related to longstanding structural and social inequities and are closely tied to social factors. However, current interventions to improve diabetes mellitus outcomes among people from minoritized populations have primarily focused on trying to change individual behaviour, without sufficiently addressing the root structural barriers that drive disparities. Here, we aim to describe the structural inequities in the diagnosis, management and outcomes of minoritized people with diabetes mellitus and to discuss practical measures that can ensure equitable care for people in minoritized groups who have diabetes mellitus. Using a framework to examine diabetes mellitus disparities, we will consider interventions at system levels, including public health approaches, the endocrine healthcare workforce, care quality standards, access to high-quality care (including advanced technologies) and involvement in research. We will also discuss strategies to address intermediate factors, including food insecurity and literacy, and to improve diabetes mellitus care services among migrant and refugee populations and racial and/or ethnic minority communities.
Endocrinology
· 2026 Feb · PMID 41493221
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Polycystic ovary syndrome (PCOS) is a common reproductive disorder characterized by irregular ovulation, cyst-like follicles on the ovaries, and hyperandrogenism. PCOS is also strongly associated with increased risk of o...Polycystic ovary syndrome (PCOS) is a common reproductive disorder characterized by irregular ovulation, cyst-like follicles on the ovaries, and hyperandrogenism. PCOS is also strongly associated with increased risk of obesity and metabolic diseases such as type 2 diabetes and metabolic dysfunction-associated steatotic liver disease (MASLD). Hyperandrogenism independently associates with many of the metabolic symptoms observed in women with PCOS, and increased androgen signaling in the female brain is hypothesized to impair central homeostatic mechanisms controlling food intake and body weight. However, peripheral metabolic organs such as pancreas, liver, fat, and skeletal muscle all express the androgen receptor, suggesting that direct androgen signaling in these organs may disrupt peripheral metabolic health. Although it is difficult to separate the impacts of hyperandrogenism from hyperinsulinemia and insulin resistance, tissue explant studies and transgenic knockout models provide the ability to interrogate signaling through the androgen receptor in metabolic organs. This review will summarize and discuss recent evidence implicating hyperandrogenism as a driver of metabolic impairments in PCOS, with an emphasis on the molecular mechanisms by which androgens may alter metabolic function in the periphery in females.
Diabetes mellitus is a metabolic disease marked by chronic high blood levels of glucose (also known as hyperglycaemia), which over time can cause damage to the blood vasculature, leading to devastating complications. The...Diabetes mellitus is a metabolic disease marked by chronic high blood levels of glucose (also known as hyperglycaemia), which over time can cause damage to the blood vasculature, leading to devastating complications. The increase in global prevalence and the number of cases of type 2 diabetes mellitus continues unabated, prompting diabetes mellitus researchers to continue studying the aetiology of the disease in search of ways to improve therapeutic outcomes. Over the years, numerous in vivo and in vitro mammalian models have been developed to investigate the mechanisms underlying diabetes mellitus and its complications. The customary use or induction of high levels of glucose in vivo or in vitro to recapitulate chronic hyperglycaemia in diabetes mellitus is central to these models. However, there has never been a consensus as to how to standardize the re-creation of glucotoxicity conditions so that the pathophysiological effects in human diabetes mellitus can be accurately mimicked experimentally. In this Review, we critically discuss glucotoxicity (without lipotoxicity) in diabetes mellitus and analyse the various in vivo and in vitro models used to study the conditions created by high levels of glucose in diabetes mellitus. Efforts to standardize experimental induction or administration of high levels of glucose, and understanding the pros and cons of each model, could help harmonize findings that will benefit the diabetes mellitus research community.
Endocrinology
· 2026 Mar · PMID 41486877
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About 12% of couples worldwide are infertile. Male factor infertility causes or is contributory to a couple's ability to conceive in approximately 50% of cases. Evidence has emerged that infertile men have poor overall h...About 12% of couples worldwide are infertile. Male factor infertility causes or is contributory to a couple's ability to conceive in approximately 50% of cases. Evidence has emerged that infertile men have poor overall health and increased morbidity and mortality, yet the causes for this are poorly understood. Although these men may appear healthy, research shows that they can harbor a wide variety of systemic diseases and illnesses that may share common links with the causes of their infertility. In fact, as semen parameters decline, their risks of several health conditions increase. In the early 1990s to the present, studies revealed that 1% to 6% of unselected infertile men seeking clinical evaluation have significant and (sometimes) life-threatening pathologies ranging from endocrine abnormalities to malignancies, developmental anomalies, and genetic diseases. Yet, despite this knowledge, for couples seeking treatment of their infertility, the female partner undergoes extensive clinical evaluation but the male partner frequently is only asked to provide a specimen for a routine semen analysis. This review focuses on the current understanding of the association of the genetic causes of male infertility and a multitude of diseases that affect these men's overall health and their increased risk of mortality.
The autonomic nervous system is a crucial mediator between the central nervous system and peripheral tissues and is essential for maintaining homeostasis. In this Review, we discuss the bidirectional communication betwee...The autonomic nervous system is a crucial mediator between the central nervous system and peripheral tissues and is essential for maintaining homeostasis. In this Review, we discuss the bidirectional communication between the autonomic nervous system and metabolic tissues in humans, focusing on the coordination of systemic glucose and lipid metabolism through autonomic signalling across changing physiological states. We also discuss the crosstalk between autonomic and immune pathways and its relevance for metabolic control. An overview of current methodologies to assess autonomic function in humans shows that quantifying organ-specific autonomic outflows remains challenging. Chronic disturbances in autonomic regulation are increasingly recognized as contributors to metabolic diseases such as obesity and type 2 diabetes mellitus. Hence, emerging therapeutic strategies targeting autonomic function could offer promising opportunities to improve metabolic health. Progress will depend on the development of tools to selectively assess autonomic input to individual metabolic organs. Addressing high inter-individual variability and capturing the temporal dynamics of organ-specific autonomic regulation will be essential for advancing mechanistic insights, ultimately enabling clinical translation.
Endocrinology
· 2026 Jan · PMID 41468323
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The thyroid-stimulating hormone receptor (TSHR) and the insulin-like growth factor 1 receptor (IGF-1R) have been shown to be involved in the development and perpetuation of thyroid eye disease found in up to 40% of patie...The thyroid-stimulating hormone receptor (TSHR) and the insulin-like growth factor 1 receptor (IGF-1R) have been shown to be involved in the development and perpetuation of thyroid eye disease found in up to 40% of patients with Graves disease-a form of autoimmune hyperthyroidism. While these 2 receptors have been known for many years to interact and exhibit synergy, the exact mechanism and the role of this interaction had not been fully evaluated. Recently, the use of a monoclonal blocking antibody to the IGF-1R has been shown to be an important therapeutic tool in improving the disease in such patients, thus revealing the importance of the IGF-1R in the disease pathogenesis. Since we recently presented direct evidence that the TSHR and IGF-1R bind to form a single complex, it is likely that this conjoining contributes to the enhanced signaling of both receptors. Using molecular dynamics simulations, we have furthered our observation by showing the high strength of their association and also determined that our modeling provides no evidence that β1-arrestin is responsible for bringing the TSHR and IGF-1R together in the cell membrane. We show that it is even difficult to break up the TSHR/IGF-1R complex, and while β1-arrestin does indeed bind well it is not necessary for the conjoining to take place.
Endocrinology
· 2026 Jan · PMID 41466449
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Label-free quantification (LFQ) proteomics is growing in popularity and becoming increasingly more accessible to researchers, empowering them to compare proteome-wide changes between different treatment conditions. Howev...Label-free quantification (LFQ) proteomics is growing in popularity and becoming increasingly more accessible to researchers, empowering them to compare proteome-wide changes between different treatment conditions. However, it remains difficult to leverage the full potential of LFQ data when the researcher has limited experience in proteomics and/or bioinformatics due to the complexity of data analysis. Here, we present MetaboMiNR, an easy-to-use web application for the analysis of LFQ data with a focus on metabolism and nuclear receptors (NRs). MetaboMiNR guides users through an intuitive process with clear instructions and minimal user input to conduct statistical analysis and produce publication ready plots. Users may input a MaxQuant-generated output file and perform standard global analysis and data quality control with the click of a button. The application offers 3 additional unique features: 1) Metabolism Miner extracts a user-selected Reactome pathway from the dataset, 2) Nuclear Receptor Miner extracts the target genes of a user-selected NR, and 3) Individual Plotter produces publication-ready bar plots for a selected protein. The utility of this application was demonstrated by analyzing a previously published dataset from mice treated with LDT409, a synthetic peroxisome proliferator-activated receptor agonist. MetaboMiNR can be accessed freely at https://cumminslab.shinyapps.io/MetaboMiNR/.
Müller-Limberger E, Frederick B, Hansen S
… +12 more, Wohlfarth M, Kasper P, Janoschek R, Mahabir E, Fischer P, Mesaros A, Purrio M, Quaas A, Alejandre Alcázar MA, Dötsch J, Hucklenbruch-Rother E, Appel S
Endocrinology
· 2026 Feb · PMID 41462562
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Maternal obesity before and during pregnancy causes maladaptive fetal development with long-term effects on offspring's metabolic health, including a higher risk of metabolic dysfunction-associated steatotic liver diseas...Maternal obesity before and during pregnancy causes maladaptive fetal development with long-term effects on offspring's metabolic health, including a higher risk of metabolic dysfunction-associated steatotic liver disease. Treatment with metformin during obese pregnancy has been suggested to prevent adverse fetal programming, but its long-term effects on offspring liver metabolism remain uncertain. In wild-type C57BL/6NCrl mice, obesity was induced by feeding a high-fat/high-sucrose Western-style diet before and throughout gestation and lactation. A subset of obese dams received metformin during gestation. Offspring from control, obese (OB), and obese with metformin-treated (OB + M) dams were analyzed at postnatal days (P) 21 and 56 for their metabolic phenotype, hepatic histomorphology, and key metabolic proteins. At P21, maternal metformin treatment worsened obesity-related traits in male OB + M offspring, including increased body weight, length, and fat volume, higher plasma leptin, insulin, and resistin levels, and impaired glucose tolerance. Female OB + M offspring also showed a worsening of obesity traits, though less pronounced. Hepatic lipid accumulation displayed sex-specific patterns; male OB + M offspring exhibited reduced lipid accumulation, whereas female OB + M offspring demonstrated increased lipid accumulation. By P56, phenotypic parameters returned to normal, but molecular alterations persisted, involving shifts in hepatic fatty acid metabolism and mitochondrial respiratory chain complexes. Maternal metformin during obese pregnancy has age- and sex-specific effects on offspring, aggravating early obesity traits in a sex-dependent manner and prompting adaptations in hepatic metabolism during adolescence. These findings highlight the controversy surrounding metformin use during obese pregnancy, given its potential to induce sex-specific obesity and metabolic disturbances in offspring.
Endocrinology
· 2026 Jan · PMID 41420538
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Endocrine mediators are essential for pregnancy maintenance, and their functional withdrawal is associated with normal term and preterm birth (PTB). Therefore, the disruption to endocrine functions or agents that can dis...Endocrine mediators are essential for pregnancy maintenance, and their functional withdrawal is associated with normal term and preterm birth (PTB). Therefore, the disruption to endocrine functions or agents that can disrupt endocrine functions are naturally suspected as contributors to PTB. One of the well-studied endocrine-disrupting compounds is polybrominated diphenyl ether(s) (PBDE). PBDE is a flame-retardant compound that is contained in several products and is a ubiquitous environmental contaminant. PBDE exists in several different congeners, many harmless compounds, but a few PBDE congeners are linked as endocrine disruptors contributing to adverse pregnancy outcomes like PTB. However, data ambiguity suggests that current platforms are insufficient to conclude PBDE's mechanisms of action as an endocrine disruptor at the fetomaternal interface (FMI) (placenta/fetal membranes). The development of microfluidic-based new approach methods (NAMs) is being introduced to study PBDE and other environmental pollutants. Organs-on-a-chip (OOCs) are an emerging class of NAMs that can replicate human organ-level functions in vitro. OOCs are microfluidic systems comprising multiple cell types from an organ that mimics the environment of a physiological organ. These devices are interconnected through microchannels to maintain intercellular interactions. OOC-based testing and development have accelerated globally as regulatory agencies now emphasize the need for reliable, humanized alternatives to traditional animal models. Multiple reproduction-associated OOCs are being developed, and their utility has been tested in assessing mechanisms of action and toxicological parameters of environmental pollutants. This review provides an overview of FMI OOCs and uses PBDE as an example to demonstrate how OOCs can study endocrine-disrupting compounds.
Insulin resistance (IR) is a condition where insulin-targeted tissues (muscle, liver, and adipose tissue) fail to normally respond to insulin action, leading to impaired insulin signaling and hyperglycemia. It is common...Insulin resistance (IR) is a condition where insulin-targeted tissues (muscle, liver, and adipose tissue) fail to normally respond to insulin action, leading to impaired insulin signaling and hyperglycemia. It is common in individuals with obesity and diagnosed with type 2 diabetes mellitus (T2DM), with the most prevalent disorders being polycystic ovarian syndrome and coronary artery disease. IR is also associated with cardiovascular risk factors such as hypertension and dyslipidemia. Current methods for detecting and measuring insulin sensitivity include the oral glucose tolerance test, insulin tolerance test, hyperinsulinemic-euglycemic clamp. Therapies for treating and preventing IR includes physical activity, diet modifications, and medications like Glucagon-like peptide-1 receptor agonists, gliclazide and metformin. This review aims at deciphering the molecular mechanisms and factors contributing to IR, potential clinical practices for measuring IR, medications for treating T2DM and the physical activity and dietary measures for controlling IR.
Endocrinology
· 2025 Dec · PMID 41410097
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Gene expression profiles and the heterogeneity among hormone-producing pituitary cells remain poorly characterized in most vertebrates, especially in chicken embryos. Using single-cell RNA sequencing, the transcriptomes...Gene expression profiles and the heterogeneity among hormone-producing pituitary cells remain poorly characterized in most vertebrates, especially in chicken embryos. Using single-cell RNA sequencing, the transcriptomes of 4346 basal and 10 835 corticosterone (CORT)-treated embryonic day 11 chicken pituitary cells were sequenced. Classical endocrine cell clusters were identified, and some were shown to express previously unreported marker genes. A cluster of uncommitted cells was identified that expressed markers for multiple endocrine cell types, with ∼30% coexpressing Gh and Pomc mRNA. We named this population of cells the cortico-somatotrophs. The existence of cortico-somatotrophs were confirmed at both the mRNA and protein level. We further characterized the corticosomatotrophs by utilizing the known effect of CORT to increase somatotroph abundance. Identification of cortico-somatotrophs challenges the prevailing view that corticotrophs and somatotrophs develop from distinct cell lineages.
Shookster D, Landry T, Bunner W
… +3 more, O'Connell S, Darshan P, Huang H
Endocrinology
· 2025 Dec · PMID 41408652
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BACKGROUND: The global obesity epidemic necessitates the identification of novel therapeutic targets. Although central administration of α-Klotho improves metabolic function in rodents, its precise mechanisms of action r...BACKGROUND: The global obesity epidemic necessitates the identification of novel therapeutic targets. Although central administration of α-Klotho improves metabolic function in rodents, its precise mechanisms of action remain unclear. Since α-Klotho signals through fibroblast growth factor receptors (FGFRs), we hypothesized that FGFR1 within specific hypothalamic neuronal populations is critical for maintaining metabolic homeostasis. METHODS: We investigated the metabolic role of FGFR1 in the arcuate nucleus of adult mice using an adeno-associated virus (AAV)-mediated CRISPR/Cas9 system, in conjunction with transgenic models, to achieve cell-type-specific knockout of FGFR1 in mature glutamatergic, gamma-aminobutyric acid (GABA)ergic, and agouti-related peptide (AgRP) neurons. RESULTS: We found that FGFR1 governs distinct metabolic functions in different neuronal populations. Conditional deletion of FGFR1 in glutamatergic neurons impaired glucose tolerance. In contrast, its ablation in GABAergic neurons induced a severe energy imbalance, resulting in obesity characterized by significant weight gain and adiposity. Notably, AgRP neuron-specific deletion of FGFR1 recapitulated this obese phenotype. Furthermore, the loss of FGFR1 in AgRP neurons disrupted α-Klotho signaling, preventing its ability to modulate AgRP neuron activity and abolishing its beneficial effects on glucose and energy metabolism. CONCLUSION: Our results establish FGFR1 in hypothalamic neurons as an essential component of the pathway through which α-Klotho regulates systemic energy balance. These findings identify hypothalamic FGFR1 as a critical molecular target for developing anti-obesity therapies.
Endocrinology
· 2026 Jan · PMID 41403157
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Mutations in the SOX2 gene have been previously linked to a syndromic form of isolated hypogonadotropic hypogonadism, with additional ocular and neurodevelopmental phenotypes. Recently, we reported a functional role for...Mutations in the SOX2 gene have been previously linked to a syndromic form of isolated hypogonadotropic hypogonadism, with additional ocular and neurodevelopmental phenotypes. Recently, we reported a functional role for SOX2 in hypothalamic kisspeptin-expressing neurons and established a mechanistic relationship between SOX2 heterozygous variants and isolated hypogonadotropic hypogonadism. To further test the role of Sox2 in the hypothalamic-pituitary-gonadal axis, we generated mice with a whole-body heterozygous knockout of Sox2 (Sox2WT/KO). We found that heterozygous loss of Sox2 significantly delayed pubertal onset in both male and female Sox2WT/KO mice compared to wild-ype (WT) controls. In females, fertility was also compromised, with fewer estrous cycles and a significant delay in time to first litter of Sox2WT/KO dams compared to WT controls. Circulating levels of gonadotropins were normal in both male and female Sox2WT/KO mice, suggesting a functional pituitary. Finally, we assessed the number of kisspeptin and GnRH neurons and found that Sox2WT/KO mice do not differ from controls in the number of kisspeptin neurons but have significantly fewer GnRH neurons. This deficit occurs before birth, as by embryonic day 15.5, there are already fewer GnRH neurons in the Sox2WT/KO mice. Using luciferase assays, we determined that Sox2 increases expression of GnRH in vitro; thus, the decrease in GnRH-expressing neurons in vivo is likely the result of Sox2 haploinsufficiency. Together, these data further substantiate a critical role for SOX2 in the hypothalamic-pituitary-gonadal axis via effects on GnRH neuron development and, therefore, pubertal timing and reproductive function.