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Pancreatic ß 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 ß 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 ß cells. Mice with ß cell-specific Sucnrl 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/SUCNRI axis is activated by high glucose and identify a GPCR-mediated amplifying pathway for insulin secretion relevant to the hyperinsulinemia of prediabetic states.
Introduction
Insulin secretion by pancreatic ß cells is crucial for blood glucose homeostasis and is tightly controlled by a complex network of hormones, nutrients, and neurotransmitters. Impaired ß cell function worsened by the compensatory hyperinsulinemia associated with insulin-resistant states is a key contributing factor of type 2 diabetes (T2D), a major chronic health concern primarily linked to obesity (1-4). Two different pathways are known to interact in ß cells to ensure insulin secretion in response to glucose stimulation. The well-known "triggering" pathway involves the mitochondrial metabolism of glucose, which induces the closure of ATP-sensitive potassium channels and the activation of voltage-gated Ca2+ channels, ultimately triggering the exocytosis of insulin granules (5). However, a second or "metabolic amplifying" pathway is necessary for proper insulin secretion response, involving the external replenishment of the Krebs, or tricarboxylic acid (TCA), cycle via anaplerosis (6), and is distinct to the neurohormonal amplification pathways (e.g., incretin system) that are related to the activation of G protein-coupled receptors (GPCRs) (7). In addition to this dual and hierarchical control of insulin secretion, emerging evidence points to important roles for anaplerotic TCA cycle substrates that act as second messengers in the cytosol to drive insulin granule exocytosis (8). Within this framework, energy metabolites are increasingly recognized as signaling molecules (9).
In recent years, the TCA cycle substrate succinate has become the poster child for the concept that metabolites...