SUCNR1 regulates insulin secretion and glucose elevates the succinate response in people with prediabetes
Joan Sabadell-Basallote, … , Joan Vendrell, Sonia Fernández-Veledo
Joan Sabadell-Basallote, … , Joan Vendrell, Sonia Fernández-Veledo
Published May 7, 2024
Citation Information: J Clin Invest. 2024;134(12):e173214. https://doi.org/10.1172/JCI173214.
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Research Article Endocrinology Metabolism

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

Abstract

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.

Authors

Joan Sabadell-Basallote, Brenno Astiarraga, Carlos Castaño, Miriam Ejarque, Maria Repollés-de-Dalmau, Ivan Quesada, Jordi Blanco, Catalina Núñez-Roa, M-Mar Rodríguez-Peña, Laia Martínez, Dario F. De Jesus, Laura Marroquí, Ramon Bosch, Eduard Montanya, Francesc X. Sureda, Andrea Tura, Andrea Mari, Rohit N. Kulkarni, Joan Vendrell, Sonia Fernández-Veledo

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Figure 3

The succinate/SUCNR1 axis enhances glucose-stimulated insulin secretion in β cells.

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The succinate/SUCNR1 axis enhances glucose-stimulated insulin secretion ...
(A) Succinate quantification in the conditioned medium (CM) of MIN6 cells cultured in low- or high-glucose conditions (n = 6). (B) Sucnr1 mRNA expression in MIN6 cells stimulated with different concentrations of glucose for 3 or 24 hours (n = 4). (C) SUCNR1 protein levels in EndoC-βH1 cells stimulated with different concentrations of glucose for 24 hours (n = 6). (D) Insulin quantification in the CM of MIN6 cells stimulated with succinate or cis-epoxysuccinic acid (cESA) at 2.8 mM or 16.7 mM glucose (n = 4). (E) Insulin secretion in glucose-stimulated insulin secretion assays in EndoC-βH5 cells stimulated with 500 μM succinate or 50 μM cESA at 0 mM or 20 mM glucose, determined in the CM by ELISA (n = 4). (F) Insulin secretion in EndoC-βH5 cells incubated with a human-specific SUCNR1 antagonist (1 μM NF-56-EJ40) and 500 μM succinate or 50 μM cESA (n = 4). Data are presented as mean ± SEM. *P < 0.05, **P < 0.01, ***P < 0.001 vs. basal conditions; ###P < 0.001 vs. succinate (Student’s t test in A, ANOVA with Dunnett’s test for multiple comparisons in B–E, or ANOVA with Tukey’s test for multiple comparisons in F).