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

Diabetes. 2017 Jul;66(7):1833-1846. doi: 10.2337/db16-1277. Epub 2017 May 1.


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 Elovl6 deletion in leptin receptor-deficient C57BL/KsJ db/db mice, a model of T2D. The db/db;Elovl6-/- mice had a markedly increased β-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 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.

MeSH terms

  • Acetyltransferases / deficiency*
  • Acetyltransferases / genetics*
  • Acetyltransferases / physiology
  • Animals
  • Apoptosis / genetics
  • Blood Glucose / metabolism
  • Diabetes Mellitus, Experimental / genetics*
  • Diabetes Mellitus, Experimental / metabolism
  • Diabetes Mellitus, Type 2 / genetics*
  • Diabetes Mellitus, Type 2 / metabolism
  • Endoplasmic Reticulum Stress
  • Fatty Acid Elongases
  • Fatty Acids, Nonesterified / metabolism
  • Female
  • Immunohistochemistry
  • In Vitro Techniques
  • Inflammation / chemically induced
  • Inflammation / genetics
  • Insulin / metabolism*
  • Insulin Secretion
  • Insulin-Secreting Cells / drug effects
  • Insulin-Secreting Cells / metabolism*
  • Insulin-Secreting Cells / pathology
  • Islets of Langerhans / drug effects
  • Islets of Langerhans / metabolism
  • Islets of Langerhans / pathology
  • Lipid Metabolism / genetics
  • Male
  • Mice
  • Mice, Inbred C57BL
  • Mice, Knockout
  • Oleic Acid / pharmacology
  • Organ Size
  • Palmitates / adverse effects
  • Real-Time Polymerase Chain Reaction
  • Receptors, Leptin / genetics


  • Blood Glucose
  • Elovl6 protein, mouse
  • Fatty Acids, Nonesterified
  • Insulin
  • Palmitates
  • Receptors, Leptin
  • leptin receptor, mouse
  • Oleic Acid
  • Acetyltransferases
  • Fatty Acid Elongases