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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 5

SUCNR1 in β cells is required for preserving insulin secretion and glucose homeostasis in HFD-fed male mice.

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SUCNR1 in β cells is required for preserving insulin secretion and gluco...
(A) IHC staining of SUCNR1 in pancreas sections of control and Sucnr1-βKO mice accompanied by serial H&E staining. Scale bars: 50 μm. (B) Body mass of control and Sucnr1-βKO mice under HFD for 8 weeks (n = 8–9). (C) Blood glucose levels in control and Sucnr1-βKO mice in fasted or random-fed conditions (n = 8). (D) Plasma insulin levels in control and Sucnr1-βKO mice in fasted or random-fed conditions (n = 7–8). (E) Morphometric analysis of control and Sucnr1-βKO mice by H&E staining (n = 3). Scale bars: 50 μm. (F) Morphometric analysis of control and Sucnr1-βKO mice by immunofluorescence staining with insulin and glucagon and counterstaining with DAPI (n = 3–4). Scale bars: 50 μm. (G) Intraperitoneal (i.p.) and oral glucose tolerance tests in control and Sucnr1-βKO mice (n = 6–7). Displayed are the blood glucose levels, AUC, plasma insulin (n = 5–6), and GLP-1 levels (n = 5). (H) Insulin tolerance test in control and Sucnr1-βKO mice (n = 6–8). (I) HOMA-IR for control and Sucnr1-βKO mice (n = 5). (J) Insulin secretion in isolated islets from control and Sucnr1-βKO mice stimulated with or without 1 mM succinate or 100 μM cESA at 2.8 or 16.7 mM glucose (n = 5 islet pools from 5–6 mice). Data are presented as mean ± SEM or as box-and-whisker plots indicating median, first and third quartiles, and maximum and minimum values. *P < 0.05, **P < 0.01, ***P < 0.001 vs. control mice, comparing experimental groups in orally administered mice, or in indicated pairwise comparisons; ##P < 0.01, ###P < 0.001 comparing experimental groups in i.p.-administered mice (Student’s t test in B, E, F, and I comparing 2 groups, or 2-way ANOVA with Bonferroni’s test for multiple comparisons in C, D, G, H, and J).

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

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