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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 Article has an altmetric score of 45

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

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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 6

Succinate response is heightened in patients without NGT and is associated with potentiation of insulin secretion.

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Succinate response is heightened in patients without NGT and is associat...
(A) Study cohort and study schematic. (B) Plasma glucose, insulin, and C-peptide levels during the oral glucose tolerance test (OGTT) and isoglycemic intravenous glucose infusion (IIGI) in patients with NGT (n = 12) and those without NGT (non-NGT; n = 18). (C) Fasting insulin secretion rate (ISR) in NGT and non-NGT groups. (D) ISR during OGTT and IIGI tests in NGT and non-NGT groups. (E) β Cell glucose sensitivity represented as a dose-response function between ISR and glucose concentrations for both groups. (F) Plasma GLP-1 levels during OGTT and IIGI for both groups. (G) Plasma succinate levels during OGTT and IIGI for both groups. (H) Incretin-related potentiation calculated during OGTT in relation to IIGI for both groups. (I) Potentiation calculated during IIGI for both groups. (J) Correlation between the potentiation factor mean and the AUC of succinate during IIGI for both groups (n = 30). Data are presented as mean ± SEM. ***P < 0.001 comparing OGTT and IIGI; #P < 0.05, ##P < 0.01 comparing NGT and non-NGT individuals (paired and unpaired Student’s t tests in C, D, F, and G, Mann-Whitney U test in D, F, and G, Wilcoxon’s test in D, F, and G, 2-way ANOVA tests in E–I, or Spearman’s rank correlation coefficient in J).

Copyright © 2025 American Society for Clinical Investigation
ISSN: 0021-9738 (print), 1558-8238 (online)

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