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

Identifier:  imarina:9374039

Handle: https://hdl.handle.net/20.500.11797/imarina9374039

Authors:  Sabadell-Basallote, J; Astiarraga, B; Castaño, C; Ejarque, M; Repollés-de-Dalmau, M; Quesada, I; Blanco, J; Núñez-Roa, C; Rodríguez-Peña, MM; Martínez, L; Jesus, DFD; Marroqui, L; Bosch, R; Montanya, E; Sureda, FX; Tura, A; Mari, A; Kulkarni, RN; Vendrell, J; Fernández-Veledo, S

Abstract:
Pancreatic beta 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 beta 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-GqPKC-dependent mechanism in human beta cells. Mice with beta 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.