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

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

Author information

1
Department of Internal Medicine (Endocrinology and Metabolism), Faculty of Medicine, University of Tsukuba, Tsukuba, Ibaraki, Japan.
2
Department of Internal Medicine (Endocrinology and Metabolism), Faculty of Medicine, University of Tsukuba, Tsukuba, Ibaraki, Japan t-matsuz@md.tsukuba.ac.jp hshimano@md.tsukuba.ac.jp.
3
Experimental Animal Laboratory, Research Center for Genomic Medicine, Saitama Medical University, Hidaka City, Saitama, Japan.
4
International Institute for Integrative Sleep Medicine (WPI-IIIS), University of Tsukuba, Tsukuba, Ibaraki, Japan.
5
Department of Internal Medicine, Faculty of Medicine, Niigata University, Niigata, Japan.
6
Life Science Center of Tsukuba Advanced Research Alliance (TARA), University of Tsukuba, Tsukuba, Ibaraki, Japan.
7
Japan Agency for Medical Research and Development-Core Research for Evolutional Science and Technology (AMED-CREST), Chiyoda-ku, Tokyo, Japan.

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 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.

PMID:
28461456
DOI:
10.2337/db16-1277
[Indexed for MEDLINE]
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