Endocrinology
Abstract
Insulin resistance (IR) has emerged as a risk factor for lactation insufficiency and delays the onset of milk secretion after childbirth, termed secretory activation (SA). This may cause inadequate infant weight gain and early breastfeeding cessation. However, the mechanisms underlying delayed SA in insulin resistant women are unknown. To investigate this, we characterized the mammary transcriptomes and IR-related hormones of 75 breastfeeding women with healthy term infants during postpartum days 1-5. Participants were divided into IR tertiles based on plasma leptin-to-adiponectin ratio measurements. Those in the highest tertile had later SA onset with greater neonatal weight loss during postpartum days 1-5. Transcriptomic analysis on postpartum day 2 (n=4 high IR vs. n=8 low IR participants) showed transient suppression of mammary insulin and prolactin signaling genes, increased pro-inflammatory gene expression and altered expression of >200 mammary mitochondrial genes. These alterations were absent on postpartum days 3-5. Cultured mammary epithelial cells (MECs) treated with insulin showed upregulation of prolactin signaling and oxidative phosphorylation (OXPHOS) genes, with imaging and bioenergetic studies demonstrating that insulin promotes mitochondrial biogenesis and OXPHOS. Thus, our findings delineate roles for insulin in mammary bioenergetics and highlight mitochondrial dysfunction as a mechanism for delayed SA in insulin resistant women.
Authors
Xin Meng, Taha Elajnaf, Hussam Rostom, Michelle Ma, Annalee Furst, Bryony R. Davies, Isabella R. Honess, Gaurav Pandey, Isadora C. Furigo, Craig L. Doig, Jayne F. Martin Carli, Rajesh V. Thakker, Lars Bode, Kelsey E. Johnson, Fadil M. Hannan
Abstract
Polyendocrine metabolic ovarian syndrome (PMOS), formerly known as polycystic ovary syndrome (PCOS), is the most common endocrine disorder in women and is closely associated with complex diseases such as cardiovascular disease and type 2 diabetes. However, the mechanistic links between PMOS and its comorbidities remain poorly understood. Here, we present an integrative systems genetics platform that leverages genetic diversity in both mice and humans to dissect the drivers of PMOS and its associated complications. This framework uncovers conserved genetic and environmental factors underlying PMOS, identifies susceptible cell types and organs, and elucidates mechanisms linking PMOS to subsequent pathologies. For instance, we show that increased ovarian area contributes to both PMOS susceptibility and ovarian cancer progression, while specific ovary–heart signaling circuits modulate cardiac function with aging. We further identify ovarian SF3B1-mediated alternative splicing as a key mechanistic link between PMOS and metabolic traits. Pharmacologic inhibition of SF3B1 in mice reduced circulating testosterone, insulin and glucose levels, as well as fat mass expansion. Transcriptomics analysis of ovaries from mice and experiments using human cell lines localized these effects to exon skipping events in granulosa cells. Together, this study offers a mechanistic framework for modeling the diversity of PMOS pathologies and uncovers SF3B1-mediated splicing as a link between ovary function and systemic metabolism.
Authors
Christy M. Nguyen, Leandro M. Velez, Youngseo Cheon, Cimone L. Jackson, Casey D. Johnson, Ian Tamburini, Mingqi Zhou, Erik Alvstad, Isoo Yoon, Farheen Dustagheer, Marie Li, Tvisha Gujjarlapudi, Kaitlene Ofilan, Neha Mishra, Evan G. Williams, Danica Kwan, Carlos H. Viesi, Naveena Ujagar, David G. Ashbrook, Alistair Senior, Marin E. Nelson, Nicholas R. Pannunzio, Selma Masri, Evgeny Kvon, Grant MacGregor, Cholsoon Jang, Vittorio Sebastiano, Minji Byun, Changrui Xiao, Alexander S. Kauffman, Robert W. Williams, David E. James, Ivan Marazzi, Dequina Nicholas, Marcus Seldin
Abstract
Endoplasmic reticulum (ER) stress contributes to β cell death in both Type 1 and Type 2 diabetes (T1D and T2D). However, the molecular mechanisms driving β cell death during ER stress remain insufficiently defined, limiting development of protective therapies. GRP78, an ER chaperone, is the master regulator of unfolded protein response (UPR), suppressing UPR initiators during the unstressed state and releasing them to allow UPR activation during stress. To dissect the pathways leading to ER-stress response related β cell decompensation, we engineered mice genetically lacking GRP78 in pancreatic β cells. GRP78 deletion caused acute insulin-deficient diabetes in pups before weaning, with reduced β cell mass due to increased apoptosis. Molecular studies identified deregulated UPR, specifically IRE1 activity, as driving cell death. Unbiased and targeted analyses identified a JNK-p53 axis downstream of IRE1 kinase as a key mediator of β cell death during UPR activation. In vivo JNK inhibition protected against β cell death in 2 distinct ER stress diabetes models. In human β cells, pharmacological inhibition of both JNK and p53 improved β cell survival during GRP78 knockdown–induced UPR. These findings provide insight into mechanisms causing β cell death during ER stress and outline possible therapeutic targets to preserve insulin secretory capacity in diabetes.
Authors
Rohit B. Sharma, Christine Darko, Ying Wang, Thalia A. Castro, Tara Doma Lama, Brian Gablaski, Andrew Rappa, David Redmond, Jason K. Kim, Amy S. Lee, Laura C. Alonso
Abstract
Authors
Camila L. Rossetti, Bruna L. Alves, Ernesto Bernal-Mizrachi, Joao Pedro Werneck-de-Castro
Abstract
Chronic primary pain conditions (CPPCs), such as fibromyalgia and vestibulodynia, affect over 100 million Americans, predominantly women, and pose a substantial healthcare challenge. CPPCs arise from genetic and environmental factors that enhance catecholamine tone, potentially through miRNA dysregulation following catecholamine activation of beta-adrenergic receptors. Here, we identified miR-133a-3p as a biomarker of CPPC status and investigated its functions using in vivo and in vitro approaches. Plasma levels of miR-133a-3p were consistently downregulated in humans with ≥1 CPPC and in rat and mouse models of primary pain. Our data suggest that miR-133a-3p is packaged in extracellular vesicles that are secreted by adipocytes and trafficked to the spinal cord. Activation of adrenergic receptors on white adipocytes resulted in downregulation of miR-133a-3p which negatively regulated pain-related genes in the spinal cord, such as MAP3K3, which is critical for sensory neuron activation. Adipose-specific overexpression of miR-133a-3p in a mouse model of primary pain reversed mechanical hypersensitivity in both sexes. These findings implicate miR-133a-3p dysregulation in primary pain across conditions and species and establish its role in multi-site mechanical hypersensitivity. Further, miR-133a-3p overexpression shows therapeutic potential for the millions of individuals with CPPCs.
Authors
Nathaniel P. Hernandez, Jiegen Chen, Yiling Qian, Xin Zhang, Yaomin Wang, Brittney P. Ciszek, Xianglong Gao, Marguerita E. Klein, Yun-Ling Pai, Mohamad Karaky, Carolina B. Meloto, Francesca Montagna, Matt Kanke, Clair Crewe, Luda Diatchenko, Praveen Sethupathy, Andrea G. Nackley
Abstract
BACKGROUND. In female murine models, one source of inflammation is a menopause-related increase in gut permeability. We examined whether the menopause transition (MT) in women is associated with an increase in markers of gut epithelial dysfunction and gut microbial product translocation, signals of compromised gut epithelial barrier integrity. METHODS. In 964 women, we measured markers of gut epithelial dysfunction (fatty acid binding protein 2, FABP2) and gut microbial antigen translocation (soluble CD14, sCD14) using sera collected before, during and after the MT. Multivariable mixed effects regressions fit piece-wise linear models to repeated FABP2 or sCD14 measures relative to time from final menstrual period (FMP). Covariates were age at FMP, race/ethnicity, and BMI. RESULTS. FABP2 and sCD14 did not change significantly until 2.5 years pre-FMP. At that point, FABP2 began rising; sCD14 began increasing 6 months later. FABP2 and sCD14 peaked 6 and 6.5 years post-FMP, respectively; subsequent levels remained stable. During the ~9-year interval of MT-related gain in gut barrier compromise markers, annual FABP2 and sCD14 increases were 2.6% (95% CI: 1.7 to 3.4%) and 0.8% (95% CI: 0.6 to 1.1%), respectively, among white women with sample-average BMI and age at FMP. FABP2 and sCD14 change rates did not differ significantly by race/ethnicity, BMI, or age at FMP. CONCLUSIONS. The MT is associated with a rise in markers of compromised gut barrier integrity, suggesting that this pathway of inflammation, previously described in animal models, occurs in humans. FUNDING. NIH U01NR004061, U01AG012505, U01AG012535, U01AG012531, U01AG012539, U01AG012546, U01AG012553, U01AG012554, U01AG012495, 5R01AR081794.
Authors
Albert Shieh, Marta Epeldegui, Arun S. Karlamangla, Rheinallt Jones, Roberto Pacifici, Gail A. Greendale
Abstract
Authors
Abdualrahman Mohammed Abdualkader, Xiaobei Li, Yiming Yin, Chenhao Bai, Parisa Pourfarziani, Jiaheng Guan, Sora Kwon, Kyoung-Han Kim, Rami Al Batran
Abstract
Androgen deprivation therapy (ADT), a cornerstone of advanced prostate cancer treatment, effectively suppresses androgen signaling but frequently induces systemic metabolic dysregulation. Here, we delineate an unrecognized intestinal steroid/bile acid regulatory axis that mechanistically links androgen suppression to extratumoral metabolic aberrations. HSD3B1 is the most common inherited link to prostate cancer mortality and mediates its effects by regulating steroid metabolism. Integrated metabolomic profiling of patients undergoing ADT revealed a rapid genotype-associated reduction in circulating bile acids, most pronounced in carriers of the adrenal-permissive HSD3B1 (1245C) allele. Surprisingly, analyses in human intestinal tissue and mechanistic investigations in in vitro models identified the terminal ileum as a unique site of HSD3B1 and SLC10A2 (ASBT) coexpression, where catalytically active 3βHSD1 is transcriptionally governed by liver receptor homolog-1 (LRH-1). Pharmacologic or genetic LRH-1 inhibition coordinately suppressed HSD3B1 and SLC10A2 expression and function, while inducing adaptive HSD11B2 upregulation and enhanced glucocorticoid inactivation. This LRH-1–dependent regulatory program persisted independently of androgen and glucocorticoid receptor signaling under in vitro conditions modeling androgen deprivation. These findings establish LRH-1 as a central integrator of intestinal steroidogenesis and bile acid transport and implicate the LRH-1/HSD3B1/SLC10A2 network as a mechanistic driver of ADT-associated metabolic disturbances and a potential target for therapeutic intervention.
Authors
Nikou Fotouhi, Robert Diaz, Mohammad Alyamani, Yoon-Mi Chung, Gail West, Pranab K. Mukherjee, Alireza Abdshah, Robert A. Burgess, Samreen Jatana, Rana R. McKay, Florian Rieder, Mary-Ellen Taplin, Nima Sharifi
Abstract
Interrupting glucagon signaling decreases gluconeogenesis and the fractional extraction of amino acids by liver from blood, resulting in lower glycemia. The resulting hyperaminoacidemia stimulates α cell proliferation and glucagon secretion via a liver/α cell axis. We hypothesized that α cells detect and respond to circulating amino acids’ levels via a unique amino acid transporter repertoire. We found that Slc7a2/SLC7A2 is the most highly expressed cationic amino acid transporter in α cells, with its expression being 3-fold greater in α than β cells in both mouse and human. Employing cell culture, zebrafish, and knockout mouse models, we found that the cationic amino acid arginine and SLC7A2 are required for α cell proliferation in response to interrupted glucagon signaling. Ex vivo and in vivo assessment of islet function in Slc7a2–/– mice showed decreased arginine-stimulated glucagon and insulin secretion. We found that arginine activation of mTOR signaling and induction of the glutamine transporter SLC38A5 was dependent on SLC7A2, showing that the role of both in α cell proliferation is dependent on arginine transport and SLC7A2. Finally, we identified single nucleotide polymorphisms in SLC7A2 associated with HbA1c. Together, these data indicate a central role for SLC7A2 in amino acid–stimulated α cell proliferation and islet hormone secretion.
Authors
Erick Spears, Jade E. Stanley, Matthew Shou, Linlin Yin, Xuan Li, Chunhua Dai, Amber Bradley, Katelyn Sellick, Greg Poffenberger, Katie C. Coate, Shristi Shrestha, Anna Marie R. Schornack, Taverlyn Shepard, Madushika Wimalarathne, Regina Jenkins, Kyle W. Sloop, Keith T. Wilson, Alan D. Attie, Mark P. Keller, Wenbiao Chen, Alvin C. Powers, E. Danielle Dean
Abstract
Diabetic retinopathy involves early retinal vascular barrier breakdown and pericyte loss, yet the initiating molecular events remain poorly defined. Vascular endothelial cadherin (VE-cadherin), a key regulator of endothelial integrity, is notably reduced in diabetic and prediabetic nucleoside diphosphate kinase B–deficient (NDPKB-deficient) mouse retinas, particularly in the retinal deep capillary layer, and this decline precedes pericyte loss. In vitro, high glucose (HG) and NDPKB deficiency induced VE-cadherin Y685 phosphorylation, promoting its junctional internalization, activating the hexosamine biosynthesis pathway, and increasing angiopoietin 2 (Ang2), resulting in impaired endothelial barrier function and disrupting pericyte attachment. Preventing Y685 phosphorylation through VE-cadherin Y685F mutation blocked these HG- and NDPKB-driven pathological effects. Pharmacological intervention experiments identified protein O-linked β-N-acetyl glucosamine (O-GlcNAc) modification as a mediator of Y685-dependent Ang2 upregulation. In vivo, VE-cadherin Y685F-knockin mice were protected from diabetes- and prediabetes-induced vascular hyperpermeability, exhibited reduced protein O-GlcNAcylation and Ang2 induction, and maintained neuronal function. O-GlcNAc–enriched retinal proteomics further showed that the Y685F mutation restored balanced neurovascular and mitochondrial pathways. These findings highlight the potential of targeting VE-cadherin Y685 phosphorylation as a promising therapeutic approach to maintain retinal vascular integrity and attenuate the pathological progression of diabetic and prediabetic retinopathy.
Authors
Yixin Wang, Hongpeng Huang, Feng Shao, Rachana Eshwaran, Miao Qin, Noor Karim, Yonggang Ren, Gergana Dobreva, Hans-Peter Hammes, Thomas Wieland, Yuxi Feng
Copyright © 2026 American Society for Clinical Investigation
ISSN: 0021-9738 (print), 1558-8238 (online)