Chronic elevation of free fatty acids (FFA) in obesity may cause ß-cell dysfunction leading to type 2 diabetes (T2D). Recent studies have focused on innate immunity receptors due to evidence implicating inflammation in obesity-induced T2D. While several of these receptors have been implicated in FFA-induced ß-cell dysfunction, the nucleotide-binding oligomerization domain (NOD) receptors have not been investigated. Our previous work showed that whole-body NOD1-null mice were protected from palmitate-induced ß-cell dysfunction in vivo. This may be due to lack of NOD1 in ß-cells and/or macrophages infiltrating islets. Also, islets of whole-body NOD1-null and JNK1-null mice were protected from ß-cell dysfunction induced by palmitate but not oleate in vitro, suggesting NOD1 activation is likely in ß-cells, is specific to saturated FFA and may cause ß-cell dysfunction via JNK1. Thus, we hypothesized that ß-cell NOD1 mediates palmitate-induced ß-cell dysfunction in vivo, and that JNK1 is downstream of NOD1 activation. Addition of an ethyl group on palmitate reduces toxicity of unbound palmitate, thus ethylpalmitate (EtPAL) was used. Ethyl esterases in mouse plasma hydrolyze EtPAL into palmitate and ethanol. ß-cell specific NOD1-null (ßKO) mice (using Ins1- and RIP-Cre) and their controls were infused with EtPAL or ethanol vehicle (Veh) for 48 hours, followed by a hyperglycemic clamp to evaluate ß-cell function in vivo from the disposition index (DI). Islets of JNK1-null and wildtype (WT) mice were isolated and treated with a NOD1 activator to investigate the NOD1-JNK1 axis. As expected, EtPAL infusion elevated plasma FFA. EtPAL decreased DI in control mice, while EtPAL-infused ßKO mice had similar DI to Veh-infused mice. Further, the NOD1 activator reduced insulin secretion in WT islets but not in JNK1-null islets. These data implicate ß-cell NOD1-JNK1 axis in palmitate-induced ß-cell dysfunction and reveal a novel pathway that could be targeted for manipulation in order to preserve ß-cell function.
J. Yung: None. A. Ivovic: None. I. Clark: None. F. Li: None. B. Lin: None. Y. Tan: None. A. Giacca: None.
Canadian Institutes of Health Research (CIHR50748)