Background: Obesity and type 2 diabetes (T2D) are associated with chronic low-grade inflammation. Elevated free fatty acids (FFAs) , as seen in obesity and T2D, can act as damage associated molecular patterns (DAMPs) activating the innate immune system. Recent studies have identified nucleotide binding oligomerization domain 1 (NOD1) , an intracellular pattern recognition receptor, can be activated by saturated fatty acids (sFA) . NOD1 activates inflammatory kinase RIPK2, leading to increased cytokine production by the innate immune system. Our study aimed to determine whether wild type mice treated with GSK583, a RIPK2 inhibitor, are protected against FFA-induced glucose intolerance.

Material and Methods: C57Bl/6J mice were surgically cannulated in their jugular veins and were infused with ethylpalmitate (EtP) for 48h, which results in increased plasma palmitate levels and mimics the elevated FFA levels seen in vivo. Furthermore, mice were also infused with EtP and GSK583 for 48h. After infusion, the mice were subjected to a hyperglycemic clamp and the glucose infusion rate was measured to assess glucose tolerance that under hyperglycemic clamp conditions, is mainly determined by the beta cell ability to compensate for FFA-induced insulin resistance.

Results: Preliminary data revealed that mice infused with EtP and GSK583 had a higher glucose infusion rate (GIR; mg/kgmin) (83+20, mean+SEM) than mice infused with EtP alone (57+4) . The EtP and GSK583 was comparable to the GIR of control (EtP vehicle infused) mice (84+7) .

Conclusions: Our data indicate that pharmacological inhibition of NOD1 signaling protects against FFA-induced glucose intolerance in mice. Targeting NOD1 may be an effective strategy for treating beta cell dysfunction in T2D.


N.Tsakiridis: None. A.Ivovic: None. S.Rahman: None. Y.Tan: None. A.Giacca: None.

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