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

• Published in: The Journal of clinical investigation Vol. 134; no. 12
• Main Authors: Sabadell-Basallote, Joan, Astiarraga, Brenno, Castaño, Carlos, Ejarque, Miriam, Repollés-de-Dalmau, Maria, Quesada, Ivan, Blanco, Jordi, Núñez-Roa, Catalina, Rodríguez-Peña, M-Mar, Martínez, Laia, De Jesus, Dario F., Marroquí, Laura, Bosch, Ramon, Montanya, Eduard, Sureda, Francesc X., Tura, Andrea, Mari, Andrea, Kulkarni, Rohit N., Vendrell, Joan, Fernández-Veledo, Sonia
• Format: Journal Article
• Language: English
• Published: United States American Society for Clinical Investigation 15.06.2024
• Subjects: Animals; Cell receptors; Development and progression; Dextrose; Diabetes; Endocrinology; Female; Glucose; Glucose - metabolism; Glucose - pharmacology; Health aspects; Humans; Insulin; Insulin - metabolism; Insulin Resistance; Insulin Secretion; Insulin-Secreting Cells - metabolism; Insulin-Secreting Cells - pathology; Male; Metabolic regulation; Metabolism; Metabolites; Mice; Mice, Knockout; Pancreatic beta cells; Physiological aspects; Prediabetic state; Prediabetic State - genetics; Prediabetic State - metabolism; Prediabetic State - pathology; Receptors, G-Protein-Coupled - genetics; Receptors, G-Protein-Coupled - metabolism; Succinic Acid - metabolism; Type 2 diabetes; Spain; Beta cells; G protein-coupled receptors; Metabolism; Insulin; Endocrinology
• ISSN: 1558-8238; 0021-9738; 1558-8238
• DOI: 10.1172/JCI173214

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.