Sayers SR, Gesheva VS, Varghese JJ
… +8 more, Beavil R, Zhao M, Cheah Y, Hopkins D, Fine NHF, Hasib A, Hodson DJ, Caton PW
Endocrinology
· 2026 May · PMID 42271608
·
Full text
CONTEXT: Loss of functional beta-cell mass, coupled with alpha-cell dysfunction are key factors in pathophysiology of type 1 and type 2 diabetes. We have reported that extracellular nicotinamide phosphoribosyltransferase...CONTEXT: Loss of functional beta-cell mass, coupled with alpha-cell dysfunction are key factors in pathophysiology of type 1 and type 2 diabetes. We have reported that extracellular nicotinamide phosphoribosyltransferase (eNAMPT) is elevated in type 2 diabetes and that elevated eNAMPT levels promote beta-cell dysfunction. OBJECTIVE: To further investigate the effects of eNAMPT on beta-cell mass. METHODS: Islets isolated from CD1 and Ins1tm1.1(cre)Thor+/-; mTmGfl/- mice and human donors were exposed to eNAMPT (48-96 hours). CD1 mice were administered eNAMPT for 14 days. Alpha-, beta-, and delta-cell numbers were determined by glucagon, insulin, and somatostatin staining, respectively. Alpha-cell proliferation was assessed by bromodeoxyuridine (BrDU) uptake and Ki67 expression. Glucagon secretion was assessed via radioimmunoassay. Trans-differentiation was assessed by determining changes in presence of bi-hormonal cells in CD1/human islets and using Ins1tm1.1(cre)Thor+/-; mTmGfl/- islets to determine changes in GLU+/GFP+ and GLU+/TdT+ cells. RESULTS: eNAMPT treatment reduced beta-cell number and induced corresponding increases in alpha-cell number. Indicative of beta- to alpha-cell trans-differentiation eNAMPT induced increased presence of bi-hormonal INS+/GLU+ cells and PDX1+/GLU+ cells, and increased GLU+/GFP+ cells in Ins1tm1.1(cre)Thor+/-; mTmGfl/- mouse islets. In addition, eNAMPT induced alpha-cell proliferation, indicated by increased BrDU uptake. Despite marked elevation in alpha-cell number, alpha-cell function was compromised following eNAMPT exposure, indicated by impaired glucagon counterregulatory response (CCR) to low glucose levels. CONCLUSION: This data supports a role for elevated eNAMPT levels in driving increased alpha-cell mass via a combination of beta- to alpha-cell trans-differentiation and alpha-cell proliferation. When combined with observed impaired CCR, these data have implications for both type 1 and type 2 diabetes pathophysiology.
Endocrinology
· 2026 May · PMID 42269091
·
Full text
Pancreatic islets maintain glucose homeostasis through the coordinated secretion of hormones and, notably, neurotransmitters. While islet innervation has long been recognized as essential for development and function, th...Pancreatic islets maintain glucose homeostasis through the coordinated secretion of hormones and, notably, neurotransmitters. While islet innervation has long been recognized as essential for development and function, the source of these neuromodulators is variable and so is their signaling. Islet α and β cells express a broad repertoire of receptors for neurotransmitters such as acetylcholine, glutamate, GABA, and catecholamines. Emerging evidence reveals an additional layer of regulatory complexity, as a subset of these receptors localize to the primary cilium, a sensory organelle that functions as a specialized signaling hub. Disruption of primary cilia on β cells impairs glucose homeostasis in mice, and human ciliopathies commonly feature metabolic dysfunction. In this review, we synthesize recent findings on neurotransmitter signaling within the islet, with a focus on pathways that converge on the primary cilium. We discuss how compartmentalized signaling via cilia-enriched receptors represents a new dimension of islet cell regulation and offer a perspective on how targeting these ciliary pathways may provide future research directions for modulating α- and β-cell function in diabetes.
Polyendocrine metabolic ovarian syndrome (PMOS), formerly known as polycystic ovary syndrome, is a chronic condition driven by genetic, epigenetic and lifestyle factors. The resulting endocrine changes, including hyperin...Polyendocrine metabolic ovarian syndrome (PMOS), formerly known as polycystic ovary syndrome, is a chronic condition driven by genetic, epigenetic and lifestyle factors. The resulting endocrine changes, including hyperinsulinaemia and hyperandrogenism, underpin the clinical manifestations of PMOS and are amplified by overweight and obesity. Reproductive features of PMOS, including ovulatory disturbance, endometrial abnormalities, subfertility and an increased rate of pregnancy and birth complications, have long been documented in these patients, but awareness in clinical practice has only increased in the past decade. The pathophysiology of PMOS interacts with physiological changes in pregnancy, leading to pregnancy and birth complications, exacerbated by the high prevalence of pre-pregnancy overweight, obesity and increased gestational weight gain in PMOS. However, the condition is poorly recognized as an independent risk factor for pregnancy and birth complications in antenatal guidelines and clinical practice. The 2023 international evidence-based guidelines, supported by extensive meta-analyses, have advanced knowledge on PMOS and pregnancy and birth outcomes. They recommend recognition of 'higher-risk' status for individuals with PMOS in pregnancy and aim to improve antenatal prevention, awareness, screening and treatment. Here, we explore the pathophysiology of PMOS and PMOS during pregnancy as well as related pregnancy and birth complications. We also outline current guideline recommendations, implementation strategies and research priorities related to PMOS in pregnancy.
Otsuka Y, Kadoi S, Seki S
… +9 more, Yabushita R, Ariyoshi R, Noda C, Hazim S, Matsuzaki S, Yamada K, Uenoyama Y, Tsukamura H, Inoue N
Endocrinology
· 2026 May · PMID 42236284
·
Publisher ↗
Inflammatory diseases often suppress reproductive function in mammals. This study investigated whether central fractalkine-CX3CR1 signaling mediates the inhibition of luteinizing hormone (LH) release induced by intraveno...Inflammatory diseases often suppress reproductive function in mammals. This study investigated whether central fractalkine-CX3CR1 signaling mediates the inhibition of luteinizing hormone (LH) release induced by intravenous administration of lipopolysaccharide (LPS), an endotoxin, in ovariectomized rats treated with diestrous levels of estradiol-17β (E2). Double in situ hybridization (ISH) for the fractalkine gene (Cx3cl1) and fos (a cellular activation marker) revealed that LPS significantly increased the percentage of fos-positive Cx3cl1-expressing cells in the lateral mammillary nucleus (LM) and the number of Cx3cl1-expressing cells in the paraventricular nucleus (PVN). Central administration of AZD8797, an CX3CR1 antagonist significantly restored LPS-induced decreases in the mean LH concentrations and the amplitude and baseline of LH pulses. Furthermore, LPS administration significantly increased the percentage of fos-positive fractalkine receptor gene (Cx3cr1)-expressing cells in the arcuate nucleus (ARC), whereas AZD8797 treatment significantly attenuated this LPS-induced increase. ISH for Cx3cr1 and Iba1 (a microglial marker) immunohistochemistry revealed that most Cx3cr1-expressing cells were Iba1-positive. Additionally, Cx3cr1-positive signals were observed adjacent to kisspeptin gene (Kiss1)-expressing cells in the ARC, although a few ARC Kiss1-expressing cells also exhibited Cx3cr1 expression. Collectively, these findings demonstrate that central fractalkine-CX3CR1 signaling, at least in part, mediates the suppression of LH pulses induced by systemic LPS. LM and PVN fractalkine neurons might suppress ARC kisspeptin neurons-the center for gonadotropin-releasing hormone/LH pulse generation-via neighboring CX3CR1-expressing microglial cells. These findings may contribute to the development of therapeutic strategies to mitigate inflammation-associated reproductive dysfunction in both livestock and humans.
Owen CM, Lowther KM, Kaback D
… +2 more, Jaffe LA, Yee SP
Endocrinology
· 2026 May · PMID 42230292
·
Full text
To facilitate the investigation of signaling by the luteinizing hormone receptor (LHR), we created a mouse line called Lhr-COIN. This line allows for the conditional replacement of the Lhr coding sequence with enhanced g...To facilitate the investigation of signaling by the luteinizing hormone receptor (LHR), we created a mouse line called Lhr-COIN. This line allows for the conditional replacement of the Lhr coding sequence with enhanced green fluorescent protein (eGFP), resulting in both a conditional knockout line and a reporter line. By breeding these mice with mice expressing Cre recombinase, we generated mice in which either one or both Lhr alleles were replaced with eGFP. Notably, mice in which one Lhr allele in the granulosa cells was replaced with eGFP exhibited normal LH responsiveness. This enabled live imaging of LH-induced migration of LH-receptor-expressing granulosa cells within preovulatory ovarian follicles. The Lhr-COIN mouse line holds significant potential for future research on LHR function and localization in the ovary and other tissues.
Lacasse JM, Mohammad A, Montgomery KR
… +4 more, Bellaflor S, MacPherson REK, Galea LAM, McCormick CM
Endocrinology
· 2026 May · PMID 42219595
·
Full text
Oral contraceptives containing ethinyl estradiol (EE) with levonorgestrel (LNG) are common in hormonal contraceptives. EE+LNG suppresses weight gain in rodents, but the mechanisms for this remain unclear. Further, metabo...Oral contraceptives containing ethinyl estradiol (EE) with levonorgestrel (LNG) are common in hormonal contraceptives. EE+LNG suppresses weight gain in rodents, but the mechanisms for this remain unclear. Further, metabolic demands in adolescence are increased relative to adulthood. We tested the metabolic effect of a low dose of EE + LNG in adolescents and adult female Long-Evans rats. Rats were given EE (10 µg/kg) + LNG (20 µg/kg) or vehicle subcutaneous injections daily for 16 days. Body mass, food intake, whole-body oxygen consumption, respiratory exchange ratio, and energy expenditure were measured in Promethion phenotyping cages. Dual-energy X-ray absorptiometry (DXA), glucose tolerance, serum metabolic hormone levels, depot-specific adipose and reproductive tissues were collected. EE+LNG limited body-mass gain in both age groups by combining hypophagia with a marked elevation in total energy expenditure and no change in locomotion, implicating potential thermogenic pathways. Dual-energy X-ray absorptiometry scans showed curtailed fat accrual and the preservation of lean mass in EE + LNG-treated rats. White-adipose depots were smaller in all hormone-treated rats, whereas brown adipose tissue mass was reduced only in adults. EE+LNG-treated adults had lower leptin and C-peptide levels with enhanced glucose clearance, whereas adolescents had reductions in GLP-1, glucagon, and PYY levels without altered glucose clearance. Thus low-dose EE + LNG reduced caloric intake, increased energy expenditure, and limited white-adipose deposition irrespective of age. Age-specific effects on metabolic hormones and adipose depot UCP1 content were noted. Together, these results delineate an age-sensitive metabolic and endocrine profile of EE + LNG.
Endocrinology
· 2026 May · PMID 42178481
·
Full text
Enzalutamide resistance remains a key challenge in the treatment of advanced prostate cancer (PCa), as clinical efficacy is frequently hindered by acquired resistance. While reactivation of AR signaling, including AR spl...Enzalutamide resistance remains a key challenge in the treatment of advanced prostate cancer (PCa), as clinical efficacy is frequently hindered by acquired resistance. While reactivation of AR signaling, including AR splice variants, has been extensively studied, accumulating evidence indicates that metabolic reprogramming is a key adaptive response to sustained AR inhibition. As resistance advances, tumor cells exhibit metabolic plasticity, dynamically regulating glycolysis, mitochondrial respiration, lipid metabolism, and redox homeostasis to adapt to treatment pressure. In this context, phosphoglycerate kinase 1 (PGK1), a key glycolytic enzyme, has emerged as a potential mediator linking metabolic adaptation to therapy resistance. Beyond its ATP-generating function, PGK1 exhibits non-canonical functions, including regulation of mitochondrial metabolism, protein kinase activity, and stress-response signaling. These properties suggest that PGK1 may integrate AR-driven metabolic programs with downstream survival pathways under therapeutic pressure. Preclinical studies support a role for PGK1 in promoting glycolytic phenotypes and resistance-associated metabolic states. However, current evidence remains largely associative, and direct in vivo validation in prostate-specific models is limited. Moreover, whether PGK1 functions as a causal driver or downstream effector of resistance remains unresolved. This review summarizes current understanding of AR-metabolism coupling and evaluates PGK1 as a potential metabolic-signaling node in enzalutamide resistance, highlighting key knowledge gaps and future directions for metabolic targeting in PCa.
Endocrinology
· 2026 May · PMID 42175718
·
Publisher ↗
Activation of Rac1, a member of the Rho family of small GTPases and a well-established downstream effector of receptor tyrosine kinases (RTKs), has been linked to prostate cancer progression and predicts poor progression...Activation of Rac1, a member of the Rho family of small GTPases and a well-established downstream effector of receptor tyrosine kinases (RTKs), has been linked to prostate cancer progression and predicts poor progression in prostate cancer patients. Rac1 and its upstream activators, the Rac guanine nucleotide exchange factors (Rac-GEFs), act as key drivers for RTK-mediated formation of actin-rich protrusions, structures involved in cancer cell motility and invasion. Our previous study identified VAV2 as the main Rac-GEF effector of epidermal growth factor receptor in androgen-independent cellular models. An unbiased RNAi screen targeting Rac-GEFs as effectors of cMET, which is an RTK frequently overexpressed in castration-resistant prostate cancer and associated with invasion and metastasis, identified the Rac-GEF FARP1 (FERM, ARH/RhoGEF and Plekstrin Domain Protein 1) as a pivotal contributor to Rac1-mediated migration and invasion. Notably, stimulation of cMET with its ligand Hepatocyte Growth Factor (HGF) promotes the formation of actin-rich protrusions through a PI3K-FARP1-Rac1-dependent pathway and independently of VAV2. Furthermore, FARP1 relocalizes to actin-rich protrusions in PC3 cells in response to HGF stimulation. Our results shed light on the distinctive contribution of Rac-GEFs to prostate cancer cell motility via RTKs and identify FARP1 as a crucial cMET-invasive effector. The differential coupling of RTKs to Rac-GEFs underscores the complexities of signaling events leading to Rac1 activation. It provides insight into the RTK effectors that contribute to prostate cancer cell invasiveness.
Aldosterone is essential for maintaining blood pressure during hypovolaemia and/or dehydration through genomic actions mediated by the mineralocorticoid receptor and rapid signalling pathways involving the G-protein-coup...Aldosterone is essential for maintaining blood pressure during hypovolaemia and/or dehydration through genomic actions mediated by the mineralocorticoid receptor and rapid signalling pathways involving the G-protein-coupled oestrogen receptor. Inappropriate aldosterone secretion contributes to cardiovascular and renal injury in several common disorders, including resistant hypertension, primary aldosteronism and heart failure. Pharmacological blockade of the mineralocorticoid receptor has therefore become a cornerstone in the therapy of cardiovascular disease. Nevertheless, mineralocorticoid receptor antagonism does not address the pathophysiological effects that are mediated by aldosterone, and residual cardiovascular risk remains substantial in many patients. Aldosterone synthase inhibitors are a novel therapeutic strategy that have effectively lowered aldosterone concentrations and reduced blood pressure in randomized clinical trials in patients with resistant or uncontrolled hypertension and patients with chronic kidney disease. Although these findings highlight the potential therapeutic value of aldosterone synthase inhibition, data on long-term safety, effectiveness compared with mineralocorticoid receptor antagonists and effects on cardiovascular outcomes are still lacking.
Glucagon-like peptide 1 (GLP1) receptor (GLP1R) agonists and tirzepatide, a dual GLP1R and glucose-dependent insulinotropic polypeptide receptor agonist, have become fundamental in managing type 2 diabetes mellitus (T2DM...Glucagon-like peptide 1 (GLP1) receptor (GLP1R) agonists and tirzepatide, a dual GLP1R and glucose-dependent insulinotropic polypeptide receptor agonist, have become fundamental in managing type 2 diabetes mellitus (T2DM) and obesity due to their potent glycaemia-lowering and weight-lowering effects as well as their cardiovascular and renal benefits. However, data from the past 2 years suggest that real-world persistence on these drug classes is often suboptimal, with many people discontinuing these medications, even within their first year of therapy. Reasons for treatment discontinuation include, but are not limited to, gastrointestinal adverse effects, less-than-desired efficacy, high cost, and fear about uncommon or rare adverse effects. When treatment is discontinued, weight regain and the deterioration of multiple cardiometabolic risk factors are common. Repeated cycles of initiation, interruption and re-initiation of these drugs might induce body weight and HbA fluctuations - two risk factors for cardiovascular and microvascular events. These phenomena, coupled with the re-development of overweight or obesity and poor glycaemic control when not on therapy, might increase the long-term risk of complications. The lack of anti-atherosclerotic and plaque-stabilizing effects of incretin-based medications might contribute to elevated cardiovascular risk, especially acutely following their discontinuation. However, at present, few data are available regarding the incidence of hard outcomes in people discontinuing such drugs. In this Review, we discuss common reasons for GLP1R agonist and tirzepatide discontinuation and examine available evidence related to potential cardiometabolic consequences. We also discuss long-term implications for T2DM care, weight management and, ultimately, cardiorenal disease prevention in patients with T2DM and/or overweight or obesity.
Monogenic disorders of bone mass arise from variants in single genes disrupting the intricate processes of bone formation and resorption. Genes underlying bone mass disorders are involved in various intersecting molecula...Monogenic disorders of bone mass arise from variants in single genes disrupting the intricate processes of bone formation and resorption. Genes underlying bone mass disorders are involved in various intersecting molecular mechanisms in cells of the mesenchymal and haematopoietic lineages. Signalling pathways, including WNT-β-catenin, TGFβ-BMP and NF-κB, have central roles in bone metabolism, and variants in their regulators or effectors can have opposing effects on bone mass. Defects in osteoblast differentiation, collagen biosynthesis and extracellular matrix mineralization primarily drive the pathogenesis of low bone mass (LBM) conditions, exemplified by various forms of osteogenesis imperfecta. Conversely, impaired osteoclast differentiation and function, or enhanced osteoblastic activity underlie high bone mass (HBM) disorders, such as osteopetrosis and osteosclerosis. A subset of genes have pleiotropic effects, contributing to both LBM and HBM disorders depending on the genetic background. Advances in genetics have not only elucidated pathogenic mechanisms, but also enabled the development of targeted therapies, including anti-sclerostin antibodies and enzyme replacement therapies. However, most LBM and HBM conditions still have no cure. Understanding the shared and divergent mechanisms of bone mass regulation will offer insights into future therapeutic strategies.
Das P, Abubakar RA, Mojahed N
… +9 more, Abou-Jabal D, Kittu P, Brinkmeier ML, Olsen J, Sunny DA, Camper SA, Lovell-Badge R, Rizzoti K, Ellsworth BS
Endocrinology
· 2026 May · PMID 42141901
·
Full text
Glucocorticoids are an important signal for the differentiation of many types of cells. Consistent with this, several studies have demonstrated that glucocorticoids promote the somatotrope differentiation program and fun...Glucocorticoids are an important signal for the differentiation of many types of cells. Consistent with this, several studies have demonstrated that glucocorticoids promote the somatotrope differentiation program and functionality. Interestingly, we previously found that loss of the forkhead factor, FOXO1, results in delayed emergence of somatotropes and prevents glucocorticoid-induced premature differentiation of somatotropes. In the present study, we find that pituitary-specific deletion of Nr3c1, the gene encoding the glucocorticoid receptor, impairs somatotrope differentiation and increases lactotrope numbers embryonically and at 5 days after birth. The number of somatotropes remains reduced at age 7 weeks in females and males, but lactotrope cell numbers are increased only in females at this age. FOXO1 is nearly undetectable in pituitary glands from mouse embryos lacking NR3C1 and continues to be reduced in adults. These findings suggest that glucocorticoids are an important signal for determining the balance between somatotropes and lactotropes and that FOXO1 may mediate NR3C1 induction of somatotrope differentiation.