2. Academic Validation
  3. SUCNR1 regulates insulin secretion and glucose elevates the succinate response in people with prediabetes

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

  • J Clin Invest. 2024 May 7:e173214. doi: 10.1172/JCI173214.
Joan Sabadell-Basallote 1,  Brenno Astiarraga 1,  Carlos Castaño 2,  Miriam Ejarque 1,  Maria Repollés-de-Dalmau 1,  Ivan Quesada 3,  Jordi Blanco 4,  Catalina Nuñez-Roa 2,  M-Mar Rodríguez-Peña 2,  Laia Martínez 2,  Dario F De Jesus 5,  Laura Marroqui 3,  Ramon Bosch 1,  Eduard Montanya 3,  Francesc X Sureda 5,  Andrea Tura 6,  Andrea Mari 6,  Rohit N Kulkarni 5,  Joan Vendrell 2,  Sonia Fernández-Veledo 2
Affiliations

Affiliations

  • 1 Unitat de Recerca, Hospital Universitari Joan XXIII, Insitut d'Investigació Sanitària Pere Virgili, Tarragona, Spain.
  • 2 Unitat de Recerca, Hospital Universitari Joan XXIII, Institut d'Investigació Sanitària Pere Virgili, Tarragona, Spain.
  • 3 CIBER de Diabetes y Enfermedades Metabólicas Asociadas, Instituto de Salud Carlos III, ELCHE, Spain.
  • 4 Departament de Medicina i Cirurgia, Universitat Rovira i Virgili, Reus, Spain.
  • 5 Section of Islet Cell and Regenerative Biology, Joslin Diabetes Center, Boston, United States of America.
  • 6 Institute of Neuroscience, National Research Council, Padova, Italy.
PMID: 38713514 DOI: 10.1172/JCI173214
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 the succinate receptor (SUCNR1) is expressed in β-cells and is up-regulated in hyperglycemic states in mice and humans. We found that succinate acts as a hormone-like metabolite and stimulates Insulin secretion via a SUCNR1-Gq-PKC-dependent mechanism in human β-cells. Mice with β-cell-specific Sucnr1 deficiency exhibit 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 show an enhanced nutritional-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.

Keywords

Beta cells; Endocrinology; G proteincoupled receptors; Insulin; Metabolism.

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