Elovl6 deficiency improves glycemic control in diabetic db/db mice by expanding beta;-cell mass and increasing insulin secretory capacity

Dysfunctional fatty acid (FA) metabolism plays an important role in the pathogenesis of beta;-cell dysfunction and loss of beta;-cell mass in type 2 diabetes (T2D). Elovl6 is a microsomal enzyme that is responsible for converting C16 saturated and monounsaturated FAs into C18 species.We previously showed that Elovl6 played a critical role in the development of obesity-induced insulin resistance by modifying FA composition. To further define its role in T2D development, we assessed the effects of Elovl6 deletion in leptin receptor-deficient C57BL/KsJ db/db mice, a model of T2D. The db/db;Elovl6^-/- mice had a markedly increased beta;-cell mass with increased proliferation and decreased apoptosis, an adaptive increase in insulin, and improved glycemic control. db/db islets were characterized by a prominent elevation of oleate (C18:1n-9), cell stress, and inflammation, which was completely suppressed by Elovl6 deletion. As a mechanistic ex vivo experiment, isolated islets from Elovl6^-/- mice exhibited reduced susceptibility to palmitate-induced inflammation, endoplasmic reticulum stress, and beta;-cell apoptosis. In contrast, oleate-treated islets resulted in impaired glucose-stimulated insulin secretion with suppressed related genes irrespective of the Elovl6 gene. Taken together, Elovl6 is a fundamental factor linking dysregulated lipid metabolism to beta;-cell dysfunction, islet inflammation, and beta;-cell apoptosis in T2D, highlighting oleate as the potential culprit of beta;-cell lipotoxicity.