Aims/hypothesis

Resistin, inducing insulin resistance, is elevated in the sera of individuals with the G-A haplotype at c.-420 C>G (rs1862513) and c.-358 G>A (rs3219175). This haplotype is associated with visceral obesity and low grip strength. To elucidate the hidden relationship between the G-A haplotype and insulin resistance, integration of specific phenotypes defined by body composition and 75 g OGTT would be a promising strategy.

Methods

The 803 Japanese participants (average age: 62 years), attending annual medical checkups, were evaluated every 5 years. Participants were categorised by skeletal muscle mass, visceral fat score and OGTT results. Hierarchical clustering was performed using body composition and glucose metabolism parameters. Whole blood cells from participants homozygous for the G-A or C-G haplotype (n=25 and 33, respectively), matched for age, sex and BMI, using propensity score matching, were used for RNA-seq, pathway analysis and RT-PCR.

Results

Multivariate analysis showed that individuals with the G-A haplotype, when accompanied by latent skeletal muscle loss and visceral obesity (latent sarcopenic obesity), presented a pronounced deterioration in insulin resistance over a 5 year period. Cluster 2, identified using hierarchical clustering, was characterised by low skeletal muscle mass, visceral obesity and insulin resistance. This cluster, with the G-A haplotype, demonstrated deterioration in insulin resistance. RNA-seq and RT-PCR revealed altered expression of mitophagy-related genes in whole blood cells of the G-A homozygotes.

Conclusions/interpretation

The G-A haplotype, accompanied by latent low skeletal muscle mass and visceral obesity, led to the deterioration of insulin resistance over a 5 year period in this cohort, possibly through the altered expression of mitophagy-related genes.

Graphical Abstract

中文翻译：

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RETN 启动子的遗传变异，伴有潜伏性肌肉减少性肥胖，导致日本队列中出现胰岛素抵抗：Toon 基因组研究

 目标/假设

抵抗素诱导胰岛素抵抗，在具有 G-A 单倍型的个体的血清中升高，达到 c.-420 C>G （rs1862513） 和 c.-358 G>A （rs3219175）。这种单倍型与内脏肥胖和握力低有关。为了阐明 G-A 单倍型与胰岛素抵抗之间的隐藏关系，整合由身体成分和 75 g OGTT 定义的特定表型将是一种很有前途的策略。

 方法

803 名日本参与者 （平均年龄： 62 岁） 每年参加一次体检，每 5 年接受一次评估。参与者按骨骼肌质量、内脏脂肪评分和 OGTT 结果进行分类。使用身体成分和葡萄糖代谢参数进行分层聚类。使用 倾向评分匹配，将 G-A 或 C-G 单倍型纯合子参与者 （分别为 n=25 和 33） 的全血细胞，年龄、性别和 BMI 匹配，用于 RNA-seq 、通路分析和 RT-PCR。

 结果

多变量分析显示，具有 G-A 单倍型的个体在伴有潜伏性骨骼肌损失和内脏肥胖 （潜伏性肌肉减少性肥胖） 时，在 5 年期间表现出胰岛素抵抗的明显恶化。使用分层聚类确定的第 2 组以骨骼肌量低、内脏肥胖和胰岛素抵抗为特征。这个具有 G-A 单倍型的簇表明胰岛素抵抗恶化。RNA-seq 和 RT-PCR 显示 G-A 纯合子全血细胞中线粒体自噬相关基因的表达发生改变。

结论/解释

G-A 单倍型伴有潜在的低骨骼肌质量和内脏肥胖，导致该队列的胰岛素抵抗在 5 年期间恶化，可能是通过线粒体自噬相关基因的表达改变。

 图形摘要