In obesity, chronically elevated circulating free fatty acids (FFA) potentially cause ß-cell dysfunction which leads to type 2 diabetes (T2D). In vitro data have identified various cellular mechanisms leading to FFA-induced ß-cell dysfunction including activation of inflammatory kinase c-Jun N-terminal kinase (JNK). In the ß-cell, JNK1 responds to oxidative stress or ER stress, which can both be caused by FFA. Previous in vitro studies from our group have demonstrated that islets of JNK1-null mice are protected from the effect of palmitate but not oleate on inducing ß-cell dysfunction, suggesting that activation of JNK1 is specific to saturated FFA. Thus, we hypothesized that saturated FFA-induced ß-cell dysfunction is mediated in part by JNK.

Due to its detergent effects, palmitate cannot be infused directly into circulation. Thus, ethylpalmitate was used, as the ethyl group reduces the toxic effect. Mice can hydrolyze the ethyl group in circulation, producing palmitate and ethanol. JNK1-null (KO) mice and their littermate controls (WT) were infused with ethylpalmitate or ethanol vehicle for 48 hours, after which their pancreatic islets were isolated for ex vivo determination of insulin secretion.

We confirmed that ethylpalmitate infusion does significantly increase plasma FFA as compared to vehicle infusion. We found that WT mice infused with ethylpalmitate demonstrated significantly decreased insulin secretion as compared with WT mice infused with vehicle, whereas JNK1-null mice infused with ethylpalmitate had similar insulin secretion as controls. These data suggest that JNK1 plays a causal role in saturated FFA-induced ß-cell dysfunction in vivo.


J. Yung: None. L. Yeung: None. A. Nahle: None. K. Koulajian: None. A. Giacca: Research Support; Self; Jazz Pharmaceuticals.


Canadian Institutes of Health Research

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