The Succinate-SUCNR1 Axis and Its Impact on Beta-Cell Function: An Integrative Study Uncovering Novel Insights into Insulin Secretion Regulation and Diabetes Pathogenesis

Identifier:  TDX:4299

Handle: https://hdl.handle.net/20.500.11797/TDX4299

Authors:  Sabadell i Basallote, Joan-Martí

Abstract:
Pancreatic β-cell dysfunction constitutes a fundamental characteristic of type 2 diabetes (T2D), and novel regulators of insulin secretion are desirable. Succinate, a tricarboxylic acid cycle substrate, has emerged as a signaling metabolite with broader functions beyond energy metabolism, especially when engaging its cognate receptor SUCNR1. In this doctoral thesis, we report that SUCNR1 is prominently expressed in β-cells and exhibits up-regulation in hyperglycemic states, including elevated SUCNR1 levels in human islets during obesity and T2D. Succinate, acting as a hormone-like metabolite associated with food intake, significantly influences insulin secretion through SUCNR1 engagement. β-cells effectively sense extracellular succinate under high glucose, thereby enhancing insulin release through a SUCNR1-Gq-PKC-dependent mechanism. To further elucidate the significance of SUCNR1, we conducted a comprehensive examination of β-cell-specific Sucnr1 knockout mice and observed glucose tolerance impairment and insulin secretion deficiency in the context of a high-fat diet. These alterations occurred independently of any changes in β-cell mass or insulin sensitivity, highlighting the essential nature of SUCNR1 in preserving insulin secretion in the face of diet-induced insulin resistance. Moreover, our investigation extended to subjects with prediabetes who exhibited concurrent hyperinsulinemia. These individuals demonstrated an enhanced nutritional-related succinate response, assessed through oral glucose challenges and isoglycemic intravenous glucose infusions. Importantly, this augmented succinate