SUCNR1 regulates insulin secretion and glucose elevates the succinate response in people with prediabetes

Pancreatic beta 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 beta 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-GqPKC-dependent mechanism in human beta cells. Mice with beta 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

SUCNR1 signaling in adipocytes controls energy metabolism by modulating circadian clock and leptin expression

Adipose tissue modulates energy homeostasis by secreting leptin, but little is known about the factors governing leptin production. We show that succinate, long perceived as a mediator of immune response and lipolysis, controls leptin expression via its receptor SUCNR1. Adipocyte-specific deletion of Sucnr1 influences metabolic health according to nutritional status. Adipocyte Sucnr1 deficiency impairs leptin response to feeding, whereas oral succinate mimics nutrient-related leptin dynamics via SUCNR1. SUCNR1 activation controls leptin expression via the circadian clock in an AMPK/JNK-C/EBPα-dependent manner. Although the anti-lipolytic role of SUCNR1 prevails in obesity, its function as a regulator of leptin signaling contributes to the metabolically favorable phenotype in adipocyte-specific Sucnr1 knockout mice under standard dietary conditions. Obesity-associated hyperleptinemia in humans is linked to SUCNR1 overexpression in adipocytes, which emerges as the major predictor of adipose tissue leptin expression. Our study establishes the succinate/SUCNR1 axis as a metabolite-sensing pathway mediating nutrient-related leptin dynamics to control whole-body homeostasis.This study was supported by grants from the Spanish Ministry of Science and Innovation (MCIN)/AEI/10.13039/501100011033 (SAF2015-65019-R, RTI2018-093919-B-100, and PID2021-122480OB-I00 to S.F.-V.) and from the Instituto de Salud Carlos III (PI20/00095 to V.C.-M., and PI20/00338 to J.V.), all co-financed by the European Regional Development Fund (ERDF). This research was also supported by PID2020-119030RJ-I00 (to L. Cedó), PID2020-117640RB-I00 (to M.V.), and PID2020-117278GB-I00 (to F.V.) from MCIN/AEI/10.13039/501100011033. The project that gave rise to these results received funding from “La Caixa” Foundation under the grant agreement LCF/PR/HR20/52400013 (to S.F.-V.). N.V. is the recipient of grants “Ajuts per a projectes de recerca clínica de l’Hospital Universitari de Bellvitge (2011-PR143/11)” and the projects PI11/01960, PI14/01997, and PI17/01556 funded by the Instituto de Salud Carlos III and co-funded by “ERDF, A way to build Europe.” T.V.-C. is a recipient of an FPI fellowship (PRE2019-090360), and V.C.-M. acknowledges support from the Ramón y Cajal program (RYC2019-02649-I), both from MCIN/AEI/10.13039/501100011033 and “European Social Fund (ESF) Investing in your future.” M.R.-D.-D. is recipient of a Martí-Franquès Research Grant Programme (2021PMF-PIPF-2) from Universitat Rovira i Virgili. C.P.-L. is recipient of an FPU fellowship from the Spanish Ministry of Education. J.S.-B. is a recipient of a predoctoral contract for training in health research from the Instituto de Salud Carlos III, co-financed by the ESF (PFIS FI18/00151). S.F.-V. acknowledges support from the Miguel Servet tenue-track program (CP10/00438 and CPII16/00008) from the Fondo de Investigación Sanitaria, co-financed by the ERDF.Peer reviewe

The Succinate-SUCNR1 Axis and Its Impact on Beta-Cell Function: An Integrative Study Uncovering Novel Insights into Insulin Secretion Regulation and Diabetes Pathogenesis

La disfunció de les cèl·lules β pancreàtiques constitueix una característica fonamental de la diabetis tipus 2 (DT2) i descobrir nous reguladors de la secreció d'insulina és essencial. El succinat, un substrat del cicle dels àcids tricarboxílics, ha emergit com un metabòlit de senyalització, especialment quan activa el seu receptor SUCNR1. En aquesta tesi doctoral, demostrem que SUCNR1 s’expressa prominentment en les cèl·lules β i la seva expressió està augmentada en estats hiperglucèmics, incloent en illots humans durant l'obesitat i la DT2. Les cèl·lules β són capaces de percebre eficaçment el succinat extracel·lular en estats d’alta glucosa, potenciant així la secreció d’insulina a través d'un mecanisme dependent de SUCNR1, Gq i PKC. Per aprofundir en la importància de SUCNR1, vam examinar ratolins transgènics amb una deficiència de Sucnr1 específica en les cèl·lules β, observant un deteriorament de la tolerància a la glucosa i una deficiència en la secreció d'insulina en aquests. Malgrat això, les alteracions es van produir independentment de qualsevol canvi en la massa de cèl·lules β o a la sensibilitat a la insulina, destacant la naturalesa essencial de SUCNR1 en el manteniment de la secreció d’insulina davant la resistència a la insulina induïda per la dieta. A més, vam investigar individus amb prediabetis i hiperinsulinèmia, els quals van mostrar una resposta augmentada al succinat durant administracions de glucosa oral i infusions intravenoses de glucosa. Aquesta resposta es va associar positivament amb la potenciació de la secreció d'insulina durant l'administració intravenosa de glucosa. Col·lectivament, aquestes dades demostren que l'eix succinat-SUCNR1 és necessari per a la preservació de la secreció d'insulina en hiperglucèmia i que aquest eix està parcialment regulat per les cèl·lules β de manera autocrina. Aquestes dades confirmen una nova via d’amplificació per la secreció d’insulina, que és particularment rellevant durant la hiperinsulinèmia de les persones amb prediabetis.La disfunción de las células β pancreáticas constituye una característica fundamental de la diabetes tipo 2 (DT2) y descubrir nuevos reguladores de la secreción de insulina es esencial. El succinato, un sustrato del ciclo de los ácidos tricarboxílicos, ha emergido como un metabolito de señalización, especialmente cuando activa su receptor SUCNR1. En esta tesis doctoral, demostramos que SUCNR1 se expresa prominentemente en las células β y su expresión está aumentada en estados hiperglucémicos, incluyendo en islotes humanos durante la obesidad y la DT2. Las células β son capaces de percibir el succinato extracelular en estados de alta glucosa, potenciando así la secreción de insulina a través de un mecanismo dependiente de SUCNR1, Gq y PKC. Asimismo, examinamos ratones transgénicos con una deficiencia de Sucnr1 específica en las células β, observando un deterioro de la tolerancia a la glucosa y una deficiencia en la secreción de insulina en estos. Sin embargo, las alteraciones se produjeron independientemente de cualquier cambio en la masa de células β o a la sensibilidad a la insulina, destacando la naturaleza esencial de SUCNR1 en el mantenimiento de la secreción de insulina frente a la resistencia a la insulina inducida por la dieta. Además, investigamos individuos con prediabetes e hiperinsulinemia, los cuales mostraron una respuesta aumentada al succinato durante administraciones de glucosa oral e infusiones intravenosas de glucosa. Esta respuesta se asoció positivamente con la potenciación de la secreción de insulina durante la administración intravenosa de glucosa. Colectivamente, estos datos demuestran que el eje succinato-SUCNR1 es necesario para la preservación de la secreción de insulina en hiperglucemia y que este eje está parcialmente regulado por las células β de manera autocrina. Estos datos confirman una nueva vía de amplificación para la secreción de insulina, que es particularmente relevante durante la hiperinsulinemia de las personas con prediabetes.Pancreatic β-cell dysfunction constitutes a fundamental characteristic of type 2 diabetes (T2D), and novel regulators of insulin secretion are desirable. Succinate, a tricarboxylic acid cycle substrate, has emerged as a signaling metabolite with broader functions beyond energy metabolism, especially when engaging its cognate receptor SUCNR1. In this doctoral thesis, we report that SUCNR1 is prominently expressed in β-cells and exhibits up-regulation in hyperglycemic states, including elevated SUCNR1 levels in human islets during obesity and T2D. Succinate, acting as a hormone-like metabolite associated with food intake, significantly influences insulin secretion through SUCNR1 engagement. β-cells effectively sense extracellular succinate under high glucose, thereby enhancing insulin release through a SUCNR1-Gq-PKC-dependent mechanism. To further elucidate the significance of SUCNR1, we conducted a comprehensive examination of β-cell-specific Sucnr1 knockout mice and observed glucose tolerance impairment and insulin secretion deficiency in the context of a high-fat diet. These alterations occurred independently of any changes in β-cell mass or insulin sensitivity, highlighting the essential nature of SUCNR1 in preserving insulin secretion in the face of diet-induced insulin resistance. Moreover, our investigation extended to subjects with prediabetes who exhibited concurrent hyperinsulinemia. These individuals demonstrated an enhanced nutritional-related succinate response, assessed through oral glucose challenges and isoglycemic intravenous glucose infusions. Importantly, this augmented succinat

EndoC-βH5 cells are storable and ready-to-use human pancreatic beta cells with physiological insulin secretion

Objectives: Readily accessible human pancreatic beta cells that are functionally close to primary adult beta cells are a crucial model to better understand human beta cell physiology and develop new treatments for diabetes. We here report the characterization of EndoC-βH5 cells, the latest in the EndoC-βH cell family. Methods: EndoC-βH5 cells were generated by integrative gene transfer of immortalizing transgenes hTERT and SV40 large T along with Herpes Simplex Virus-1 thymidine kinase into human fetal pancreas. Immortalizing transgenes were removed after amplification using CRE activation and remaining non-excized cells eliminated using ganciclovir. Resulting cells were distributed as ready to use EndoC-βH5 cells. We performed transcriptome, immunological and extensive functional assays. Results: Ready to use EndoC-βH5 cells display highly efficient glucose dependent insulin secretion. A robust 10-fold insulin secretion index was observed and reproduced in four independent laboratories across Europe. EndoC-βH5 cells secrete insulin in a dynamic manner in response to glucose and secretion is further potentiated by GIP and GLP-1 analogs. RNA-seq confirmed abundant expression of beta cell transcription factors and functional markers, including incretin receptors. Cytokines induce a gene expression signature of inflammatory pathways and antigen processing and presentation. Finally, modified HLA-A2 expressing EndoC-βH5 cells elicit specific A2-alloreactive CD8 T cell activation. Conclusions: EndoC-βH5 cells represent a unique storable and ready to use human pancreatic beta cell model with highly robust and reproducible features. Such cells are thus relevant for the study of beta cell function, screening and validation of new drugs, and development of disease models