Elovl6 Deficiency Improves Glycemic Control in Diabetic <i>db</i>/<i>db</i> Mice by Expanding β-Cell Mass and Increasing Insulin Secretory Capacity.

Abstract

Dysfunctional fatty acid (FA) metabolism plays an important role in the pathogenesis of β-cell dysfunction and loss of β-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 <i>Elovl6</i> deletion in leptin receptor-deficient C57BL/KsJ <i>db</i>/<i>db</i> mice, a model of T2D. The <i>db</i>/<i>db</i>;<i>Elovl6</i>^-/- mice had a markedly increased β-cell mass with increased proliferation and decreased apoptosis, an adaptive increase in insulin, and improved glycemic control. <i>db</i>/<i>db</i> 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 <i>Elovl6</i>^-/- mice exhibited reduced susceptibility to palmitate-induced inflammation, endoplasmic reticulum stress, and β-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 β-cell dysfunction, islet inflammation, and β-cell apoptosis in T2D, highlighting oleate as the potential culprit of β-cell lipotoxicity.