https://hdl.handle.net/11000/475 2026-04-04T19:08:16Z 2026-04-04T19:08:16Z Quesada-Candela, Cristina Tudurí, Eva Marroquí, Laura Alonso-Magdalena, Paloma Quesada, Iván Nadal, Ángel https://hdl.handle.net/11000/39000 2026-01-24T02:05:41Z 2026-01-23T09:38:28Z

Título : Morphological and functional adaptations of pancreatic alphacells during late pregnancy in the mouse Autor : Quesada-Candela, Cristina; Tudurí, Eva; Marroquí, Laura; Alonso-Magdalena, Paloma; Quesada, Iván; Nadal, Ángel Resumen : Background: Pregnancy represents a major metabolic challenge for the mother, and involves a compensatory response of the pancreatic beta-cell to maintain normoglycaemia. However, although pancreatic alpha-cells play a key role in glucose homeostasis and seem to be involved in gestational diabetes, there is no information about their potential adaptations or changes during pregnancy. Material and methods: Non-pregnant (controls) and pregnant C57BL/6 mice at gestational day 18.5 (G18.5) and their isolated pancreatic islets were used for in vivo and ex vivo studies, respectively. The effect of pregnancy hormones was tested in glucagon-secreting α-TC1.9 cells. Immunohistochemical analysis was performed in pancreatic slices. Glucagon gene expression was monitored by RT-qPCR. Glucagon secretion and plasma hormones were measured by ELISA. Results: Pregnant mice on G18.5 exhibited alpha-cell hypertrophy as well as augmented alpha-cell area and mass. This alpha-cell mass expansion was mainly due to increased proliferation. No changes in alpha-cell apoptosis, ductal neogenesis, or alpha-to-beta transdifferentiation were found compared with controls. Pregnant mice on G18.5 exhibited hypoglucagonaemia. Additionally, in vitro glucagon secretion at low glucose levels was decreased in isolated islets from pregnant animals. Glucagon content was also reduced. Experiments in α-TC1.9 cells indicated that, unlike estradiol and progesterone, placental lactogens and prolactin stimulated alpha-cell proliferation. Placental lactogens, prolactin and estradiol also inhibited glucagon release from α- TC1.9 cells at low glucose levels. Notas: Journal Pre-proof.

2026-01-23T09:38:28Z Marroquí, Laura Martínez-Pinna, Juan Castellano-Muñoz, Manuel Santos, Reinaldo S. dos Medina-Gali, Regla M. Soriano, Sergi Quesada, Iván Gustafsson, Jan-Ake Encinar, José A. Nadal, Ángel https://hdl.handle.net/11000/38949 2026-01-23T02:08:32Z 2026-01-22T09:17:33Z

Título : Bisphenol-S and Bisphenol-F alter mouse pancreatic β-cell ion channel expression and activity and insulin release through an estrogen receptor ERβ mediated pathway Autor : Marroquí, Laura; Martínez-Pinna, Juan; Castellano-Muñoz, Manuel; Santos, Reinaldo S. dos; Medina-Gali, Regla M.; Soriano, Sergi; Quesada, Iván; Gustafsson, Jan-Ake; Encinar, José A.; Nadal, Ángel Resumen : Bisphenol-S (BPS) and Bisphenol-F (BPF) are current Bisphenol-A (BPA) substitutes. Here we used pancreatic β-cells from wild type (WT) and estrogen receptor β (ERβ) knockout (BERKO) mice to investigate the effects of BPS and BPF on insulin secretion, and the expression and activity of ion channels involved in β-cell function. BPS or BPF rapidly increased insulin release and diminished ATP-sensitive K+ (KATP) channel activity. Similarly, 48 h treatment with BPS or BPF enhanced insulin release and decreased the expression of several ion channel subunits in β- cells from WT mice, yet no effects were observed in cells from BERKO mice. PaPE-1, a ligand designed to preferentially trigger extranuclear-initiated ER pathways, mimicked the effects of bisphenols, suggesting the involvement of extranuclear-initiated ERβ pathways. Molecular dynamics simulations indicated differences in ERβ ligand-binding domain dimer stabilization and solvation free energy among different bisphenols and PaPE-1. Our data suggest a mode of action involving ERβ whose activation alters three key cellular events in β-cell, namely ion channel expression and activity, and insulin release. These results may help to improve the hazard identification of bisphenols. Journal

2026-01-22T09:17:33Z Marroqui Esclapez, Laura Martinez-Pinna, Juan Castellano-Muñoz, Manuel dos Santos, Reinaldo S. Medina-Gali, Regla M. Soriano, Sergi Quesada, Ivan Gustafsson, Jan Ǻke Encinar, José Antonio Nadal, Angel https://hdl.handle.net/11000/38557 2025-12-10T13:32:27Z 2025-11-27T13:26:44Z

Título : Bisphenol-S and Bisphenol-F alter mouse pancreatic β-cell ion channel expression and activity and insulin release through an estrogen receptor ERβ mediated pathway Autor : Marroqui Esclapez, Laura; Martinez-Pinna, Juan; Castellano-Muñoz, Manuel; dos Santos, Reinaldo S.; Medina-Gali, Regla M.; Soriano, Sergi; Quesada, Ivan; Gustafsson, Jan Ǻke; Encinar, José Antonio; Nadal, Angel Resumen : Bisphenol-S (BPS) and Bisphenol-F (BPF) are current Bisphenol-A (BPA) substitutes. Here we used pancreatic b-cells from wild type (WT) and estrogen receptor b (ERb) knockout (BERKO) mice to investigate the effects of BPS and BPF on insulin secretion, and the expression and activity of ion channels involved in b-cell function. BPS or BPF rapidly increased insulin release and diminished ATP-sensitive Kþ (KATP) channel activity. Similarly, 48 h treatment with BPS or BPF enhanced insulin release and decreased the expression of several ion channel subunits in b-cells from WT mice, yet no effects were observed in cells from BERKO mice. PaPE-1, a ligand designed to preferentially trigger extranuclear-initiated ER pathways, mimicked the effects of bisphenols, suggesting the involvement of extranuclear-initiated ERb pathways. Molecular dynamics simulations indicated differences in ERb ligand-binding domain dimer stabilization and solvation free energy among different bisphenols and PaPE-1. Our data suggest a mode of action involving ERb whose activation alters three key cellular events in b-cell, namely ion channel expression and activity, and insulin release. These results may help to improve the hazard identification of bisphenols.

2025-11-27T13:26:44Z Marroqui Esclapez, Laura Perez-Serna, Atenea Alexandra Babiloni-Chust, Ignacio dos Santos, Reinaldo S. https://hdl.handle.net/11000/38556 2025-11-28T02:05:13Z 2025-11-27T13:26:06Z

Título : Type I interferons as key players in pancreatic β-cell dysfunction in type 1 diabetes Autor : Marroqui Esclapez, Laura; Perez-Serna, Atenea Alexandra; Babiloni-Chust, Ignacio; dos Santos, Reinaldo S. Resumen : Type 1 diabetes (T1D) is a chronic autoimmune disease characterized by pancreatic islet inflammation (insulitis) and specific pancreatic β-cell destruction by an immune attack. Although the precise underlying mechanisms leading to the autoimmune assault remain poorly understood, it is well accepted that insulitis takes place in the context of a conflicting dialogue between pancreatic β-cells and the immune cells. Moreover, both host genetic background (i.e., candidate genes) and environmental factors (e.g., viral infections) contribute to this inadequate dialogue. Accumulating evidence indicates that type I interferons (IFNs), cytokines that are crucial for both innate and adaptive immune responses, act as key links between environmental and genetic risk factors in the development of T1D. This chapter summarizes some relevant pathways involved in β-cell dysfunction and death, and briefly reviews how enteroviral infections and genetic susceptibility can impact insulitis. Moreover, we present the current evidence showing that, in β-cells, type I IFN signaling pathway activation leads to several outcomes, such as long-lasting major histocompatibility complex (MHC) class I hyperexpression, endoplasmic reticulum (ER) stress, epigenetic changes, and induction of posttranscriptional as well as posttranslational modifications. MHC class I overexpression, when combined with ER stress and posttranscriptional/posttranslational modifications, might lead to sustained neoantigen presentation to immune system and β-cell apoptosis. This knowledge supports the concept that type I IFNs are implicated in the early stages of T1D pathogenesis. Finally, we highlight the promising therapeutic avenues for T1D treatment directed at type I IFN signaling pathway.

2025-11-27T13:26:06Z dos Santos, Reinaldo S. Babiloni Chust, Ignacio Marroqui Esclapez, Laura Nadal, Angel https://hdl.handle.net/11000/38555 2025-12-10T13:32:27Z 2025-11-27T13:25:33Z

Título : Screening of Metabolism-Disrupting Chemicals on Pancreatic α-Cells Using In Vitro Methods Autor : dos Santos, Reinaldo S.; Babiloni Chust, Ignacio; Marroqui Esclapez, Laura; Nadal, Angel Resumen : Metabolism-disrupting chemicals (MDCs) are endocrine disruptors with obesogenic and/or diabetogenic action. There is mounting evidence linking exposure to MDCs to increased susceptibility to diabetes. Despite the important role of glucagon in glucose homeostasis, there is little information on the effects of MDCs on α-cells. Furthermore, there are no methods to identify and test MDCs with the potential to alter α-cell viability and function. Here, we used the mouse α-cell line αTC1-9 to evaluate the effects of MDCs on cell viability and glucagon secretion. We tested six chemicals at concentrations within human exposure (from 0.1 pM to 1 µM): bisphenol-A (BPA), tributyltin (TBT), perfluorooctanoic acid (PFOA), triphenylphosphate (TPP), triclosan (TCS), and dichlorodiphenyldichloroethylene (DDE). Using two different approaches, MTT assay and DNA-binding dyes, we observed that BPA and TBT decreased α-cell viability via a mechanism that depends on the activation of estrogen receptors and PPARγ, respectively. These two chemicals induced ROS production, but barely altered the expression of endoplasmic reticulum (ER) stress markers. Although PFOA, TPP, TCS, and DDE did not alter cell viability nor induced ROS generation or ER stress, all four compounds negatively affected glucagon secretion. Our findings suggest that αTC1-9 cells seem to be an appropriate model to test chemicals with metabolism-disrupting activity and that the improvement of the test methods proposed herein could be incorporated into protocols for the screening of diabetogenic MDCs.

2025-11-27T13:25:33Z Perez-Serna, Atenea Alexandra dos Santos, Reinaldo S. Ripoll, Cristina Nadal, Angel Eizirik, Decio L. Marroqui Esclapez, Laura https://hdl.handle.net/11000/38554 2025-12-10T13:32:27Z 2025-11-27T13:24:53Z

Título : BCL-XL Overexpression Protects Pancreatic β-Cells against Cytokine- and Palmitate-Induced Apoptosis Autor : Perez-Serna, Atenea Alexandra; dos Santos, Reinaldo S.; Ripoll, Cristina; Nadal, Angel; Eizirik, Decio L.; Marroqui Esclapez, Laura Resumen : Diabetes is a chronic disease that affects glucose metabolism, either by autoimmune-driven β-cell loss or by the progressive loss of β-cell function, due to continued metabolic stresses. Although both α- and β-cells are exposed to the same stressors, such as proinflammatory cytokines and saturated free fatty acids (e.g., palmitate), only α-cells survive. We previously reported that the abundant expression of BCL-XL, an anti-apoptotic member of the BCL-2 family of proteins, is part of the α-cell defense mechanism against palmitate-induced cell death. Here, we investigated whether BCL-XL overexpression could protect β-cells against the apoptosis induced by proinflammatory and metabolic insults. For this purpose, BCL-XL was overexpressed in two β-cell lines—namely, rat insulinoma-derived INS-1E and human insulin-producing EndoC-βH1 cells—using adenoviral vectors. We observed that the BCL-XL overexpression in INS-1E cells was slightly reduced in intracellular Ca2+ responses and glucose-stimulated insulin secretion, whereas these effects were not observed in the human EndoC-βH1 cells. In INS-1E cells, BCL-XL overexpression partially decreased cytokine- and palmitate-induced β-cell apoptosis (around 40% protection). On the other hand, the overexpression of BCL-XL markedly protected EndoC-βH1 cells against the apoptosis triggered by these insults (>80% protection). Analysis of the expression of endoplasmic reticulum (ER) stress markers suggests that resistance to the cytokine and palmitate conferred by BCL-XL overexpression might be, at least in part, due to the alleviation of ER stress. Altogether, our data indicate that BCL-XL plays a dual role in β-cells, participating both in cellular processes related to β-cell physiology and in fostering survival against pro-apoptotic insults.

2025-11-27T13:24:53Z dos Santos, Reinaldo S. Guzmán Llorens, Daniel Perez-Serna, Atenea Alexandra Nadal, Angel Marroqui Esclapez, Laura https://hdl.handle.net/11000/38553 2025-12-10T13:32:27Z 2025-11-27T13:24:19Z

Título : Deucravacitinib, a tyrosine kinase 2 pseudokinase inhibitor, protects human EndoC-βH1 β-cells against proinflammatory insults Autor : dos Santos, Reinaldo S.; Guzmán Llorens, Daniel; Perez-Serna, Atenea Alexandra; Nadal, Angel; Marroqui Esclapez, Laura Resumen : Introduction: Type 1 diabetes is characterized by pancreatic islet inflammation and autoimmune-driven pancreatic β-cell destruction. Interferon-α (IFNα) is a key player in early human type 1 diabetes pathogenesis. IFNα activates the tyrosine kinase 2 (TYK2)-signal transducer and activator of transcription (STAT) pathway, leading to inflammation, HLA class I overexpression, endoplasmic reticulum (ER) stress, and β-cell apoptosis (in synergy with IL-1β). As TYK2 inhibition has raised as a potential therapeutic target for the prevention or treatment of type 1 diabetes, we investigated whether the selective TYK2 inhibitor deucravacitinib could protect β-cells from the effects of IFNα and other proinflammatory cytokines (i.e., IFNγ and IL-1β). Methods: All experiments were performed in the human EndoC-βH1 β-cell line. HLA class I expression, inflammation, and ER stress were evaluated by real-time PCR, immunoblotting, and/or immunofluorescence. Apoptosis was assessed by the DNA-binding dyes Hoechst 33342 and propidium iodide or caspase 3/7 activity. The promoter activity was assessed by luciferase assay. Results: Deucravacitinib prevented IFNα effects, such as STAT1 and STAT2 activation and MHC class I hyperexpression, in a dose-dependent manner without affecting β-cell survival and function. A comparison between deucravacitinib and two Janus kinase inhibitors, ruxolitinib and baricitinib, showed that deucravacitinib blocked IFNα- but not IFNγ-induced signaling pathway. Deucravacitinib protected β-cells from the effects of two different combinations of cytokines: IFNα + IL-1β and IFNγ + IL-1β. Moreover, this TYK2 inhibitor could partially reduce apoptosis and inflammation in cells pre-treated with IFNα + IL-1β or IFNγ + IL-1β. Discussion: Our findings suggest that, by protecting β-cells against the deleterious effects of proinflammatory cytokines without affecting β-cell function and survival, deucravacitinib could be repurposed for the prevention or treatment of early type 1 diabetes.

2025-11-27T13:24:19Z Sabadell-Basallote, Joan Astiarraga, Brenno Castaño, Carlos Ejarque, Miriam Repollés de Dalmau, Maria Quesada, Ivan Blanco, Jordi Núñez-Roa, Catalina Rodríguez-Peña, M. Martínez, Laia F De Jesus, Dario Marroqui Esclapez, Laura Bosch, Ramon Montanya, Eduard Sureda, Francesc Tura, Andrea Mari, Andrea Kulkarni, Rohit N. Vendrell, Joan Fernández-Veledo, Sonia https://hdl.handle.net/11000/38552 2025-11-28T02:04:59Z 2025-11-27T13:21:33Z

Título : SUCNR1 regulates insulin secretion and glucose elevates the succinate response in people with prediabetes Autor : Sabadell-Basallote, Joan; Astiarraga, Brenno; Castaño, Carlos; Ejarque, Miriam; Repollés de Dalmau, Maria; Quesada, Ivan; Blanco, Jordi; Núñez-Roa, Catalina; Rodríguez-Peña, M.; Martínez, Laia; F De Jesus, Dario; Marroqui Esclapez, Laura; Bosch, Ramon; Montanya, Eduard; Sureda, Francesc; Tura, Andrea; Mari, Andrea; Kulkarni, Rohit N.; Vendrell, Joan; Fernández-Veledo, Sonia Resumen : Pancreatic β cell dysfunction is a key feature of type 2 diabetes, and novel regulators of insulin secretion are desirable. Here, we report that succinate receptor 1 (SUCNR1) is expressed in β cells and is upregulated in hyperglycemic states in mice and humans. We found that succinate acted as a hormone-like metabolite and stimulated insulin secretion via a SUCNR1-Gq-PKC–dependent mechanism in human β cells. Mice with β cell–specific Sucnr1 deficiency exhibited impaired glucose tolerance and insulin secretion on a high-fat diet, indicating that SUCNR1 is essential for preserving insulin secretion in diet-induced insulin resistance. Patients with impaired glucose tolerance showed an enhanced nutrition-related succinate response, which correlates with the potentiation of insulin secretion during intravenous glucose administration. These data demonstrate that the succinate/SUCNR1 axis is activated by high glucose and identify a GPCR-mediated amplifying pathway for insulin secretion relevant to the hyperinsulinemia of prediabetic states.

2025-11-27T13:21:33Z Garcia-Gutierrez, Enriqueta O'Mahony, A. Kate dos Santos, Reinaldo S. Marroqui Esclapez, Laura Cotter, Paul https://hdl.handle.net/11000/38551 2025-11-28T02:05:06Z 2025-11-27T13:20:50Z

Título : Gut microbial metabolic signatures in diabetes mellitus and potential preventive and therapeutic applications Autor : Garcia-Gutierrez, Enriqueta; O'Mahony, A. Kate; dos Santos, Reinaldo S.; Marroqui Esclapez, Laura; Cotter, Paul Resumen : Diabetes mellitus can be subdivided into several categories based on origin and clinical characteristics. The most common forms of diabetes are type 1 (T1D), type 2 diabetes (T2D) and gestational diabetes mellitus (GDM). T1D and T2D are chronic diseases affecting around 537 million adults worldwide and it is projected that these numbers will increase by 12% over the next two decades, while GDM affects up to 30% of women during pregnancy, depending on diagnosis methods. These forms of diabetes have varied origins: T1D is an autoimmune disease, while T2D is commonly associated with, but not limited to, certain lifestyle patterns and GDM can result of a combination of genetic predisposition and pregnancy factors. Despite some pathogenic differences among these forms of diabetes, there are some common markers associated with their development. For instance, gut barrier impairment and inflammation associated with an unbalanced gut microbiota and their metabolites may be common factors in diabetes development and progression. Here, we summarize the microbial signatures that have been linked to diabetes, how they are connected to diet and, ultimately, the impact on metabolite profiles resulting from host-gut microbiota-diet interactions. Additionally, we summarize recent advances relating to promising preventive and therapeutic interventions focusing on the targeted modulation of the gut microbiota to alleviate T1D, T2D and GDM.

2025-11-27T13:20:50Z Ruiz-Pino, Antonia Goncalves-Ramírez, Arianna Jiménez-Palomares, Margarita Merino, Beatriz Castellano-Muñoz, Manuel Vettorazzi, Jean F. Rafacho, Alex Marroqui Esclapez, Laura Nadal, Angel Alonso-Magdalena, Paloma Perdomo, Germán Cózar-Castellano, Irene Quesada, Ivan https://hdl.handle.net/11000/38550 2025-12-10T13:32:27Z 2025-11-27T13:20:11Z

Título : Hyperglucagonemia and glucagon hypersecretion in early type 2 diabetes result from multifaceted dysregulation of pancreatic mouse α-cells Autor : Ruiz-Pino, Antonia; Goncalves-Ramírez, Arianna; Jiménez-Palomares, Margarita; Merino, Beatriz; Castellano-Muñoz, Manuel; Vettorazzi, Jean F.; Rafacho, Alex; Marroqui Esclapez, Laura; Nadal, Angel; Alonso-Magdalena, Paloma; Perdomo, Germán; Cózar-Castellano, Irene; Quesada, Ivan Resumen : Hyperglucagonemia has been implicated in the pathogenesis of type 2 diabetes (T2D). In contrast to β-cells, studies on the function of the pancreatic α-cell in T2D are scarce. Consequently, the processes underlying hyperglucagonemia and α-cell dysfunction are largely unknown, limiting the appropriate design of specific pharmacological and therapeutic strategies. In the current study, we aimed to analyze the alterations of the pancreatic α-cell and its glucagon responses in diabetic db/db mice at early stages of the disease. In this context of glucose intolerance, hyperinsulinemia, and β-cell dysfunction, hyperglucagonemia was only present at fed conditions and was associated with insulin resistance. Yet, we found that the glucagon-to-insulin ratio in db/db mice did not change with fed or fasted states, further supporting that the metabolic regulation of glucagon release was impaired. Pancreatic β-cell dysfunction in db/db mice was manifested by increased basal secretion from isolated islets along with reduced insulin content. In contrast, α-cells from diabetic animals presented upregulated secretion and islet content of glucagon compared with controls. Electrophysiological analysis of dispersed α-cells revealed that altered secretion was not the result of impaired exocytosis. Instead, we found defective regulation of Ca2+ signaling by glucose. Besides these functional alterations, we also observed augmented α-cell mass in diabetic mice, which was accompanied by disrupted islet cytoarchitecture as well as increased α-cell size and number, without pieces of evidence of upregulated proliferation. Overall, these findings indicate that hyperglucagonemia in early T2D results from multifaceted α-cell deregulation in mice.

2025-11-27T13:20:11Z