Elovl6 Deficiency Improves Glycemic Control in Diabetic db/db Mice by Expanding β-Cell Mass and Increasing Insulin Secretory Capacity.
Hui ZhaoTakashi MatsuzakaYuta NakanoKaori MotomuraNie TangTomotaka YokooYuka OkajimaSong-Iee HanYoshinori TakeuchiYuichi AitaHitoshi IwasakiShigeru YatohHiroaki SuzukiMotohiro SekiyaNaoya YahagiYoshimi NakagawaHirohito SoneNobuhiro YamadaHitoshi ShimanoPublished in: Diabetes (2017)
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.
Keyphrases
- type diabetes
- glycemic control
- single cell
- insulin resistance
- oxidative stress
- endoplasmic reticulum stress
- high fat diet induced
- cell therapy
- blood glucose
- magnetic resonance imaging
- weight loss
- stem cells
- body mass index
- fatty acid
- magnetic resonance
- gene expression
- induced apoptosis
- cell proliferation
- diabetic rats
- genome wide
- cell death
- binding protein
- copy number
- cell cycle arrest
- replacement therapy
- wound healing