Abstract：
OBJECTIVE: Bariatric surgery is highly effective for the treatment of obesity in individuals without (OB1) and in those with type 2 diabetes (T2D2). However, whether bariatric surgery triggers similar or distinct molecular changes in OB and T2D remains unknown. Given that individuals with type 2 diabetes often exhibit more severe metabolic deterioration, we hypothesized that bariatric surgery induces distinct molecular adaptations in skeletal muscle, the major site of glucose uptake, of OB and T2D after surgery-induced weight loss.
METHODS: All participants (OB, n = 13; T2D, n = 13) underwent detailed anthropometry before and one year after the surgery. Skeletal muscle biopsies were isolated at both time points and subjected to transcriptome and methylome analyses using a comprehensive bioinformatic pipeline.
RESULTS: Before surgery, T2D had higher fasting glucose and insulin levels but lower whole-body insulin sensitivity, only glycemia remained higher in T2D than in OB after surgery. Surgery-mediated weight loss affected different subsets of genes with 2,013 differentially expressed in OB and 959 in T2D. In OB differentially expressed genes were involved in insulin, PPAR signaling and oxidative phosphorylation pathways, whereas ribosome and splicesome in T2D. LASSO regression analysis revealed distinct candidate genes correlated with improvement of phenotypic traits in OB and T2D. Compared to OB, DNA methylation was less affected in T2D in response to bariatric surgery. This may be due to increased global hydroxymethylation accompanied by decreased expression of one of the type 2 diabetes risk gene, TET2, encoding a demethylation enzyme in T2D.
CONCLUSIONS: OB and T2D exhibit differential skeletal muscle transcriptome responses to bariatric surgery, presumably resulting from perturbed epigenetic flexibility.
METHODS: All participants (OB, n = 13; T2D, n = 13) underwent detailed anthropometry before and one year after the surgery. Skeletal muscle biopsies were isolated at both time points and subjected to transcriptome and methylome analyses using a comprehensive bioinformatic pipeline.
RESULTS: Before surgery, T2D had higher fasting glucose and insulin levels but lower whole-body insulin sensitivity, only glycemia remained higher in T2D than in OB after surgery. Surgery-mediated weight loss affected different subsets of genes with 2,013 differentially expressed in OB and 959 in T2D. In OB differentially expressed genes were involved in insulin, PPAR signaling and oxidative phosphorylation pathways, whereas ribosome and splicesome in T2D. LASSO regression analysis revealed distinct candidate genes correlated with improvement of phenotypic traits in OB and T2D. Compared to OB, DNA methylation was less affected in T2D in response to bariatric surgery. This may be due to increased global hydroxymethylation accompanied by decreased expression of one of the type 2 diabetes risk gene, TET2, encoding a demethylation enzyme in T2D.
CONCLUSIONS: OB and T2D exhibit differential skeletal muscle transcriptome responses to bariatric surgery, presumably resulting from perturbed epigenetic flexibility.
摘要：
目的：减肥手术对于治疗无肥胖（OB1）和2型糖尿病（T2D2）患者的肥胖非常有效。然而,减肥手术是否会引发OB和T2D相似或明显的分子变化尚不清楚.鉴于2型糖尿病患者通常表现出更严重的代谢恶化，我们假设减肥手术诱导骨骼肌不同的分子适应，葡萄糖摄取的主要部位，手术后导致体重减轻的OB和T2D。
方法：所有参与者（OB，n=13；T2D，n=13）在手术前和手术后一年进行了详细的人体测量。在两个时间点分离骨骼肌活检，并使用全面的生物信息学管道进行转录组和甲基化组分析。
结果：手术前，T2D的空腹血糖和胰岛素水平较高，但全身胰岛素敏感性较低，手术后T2D患者仅血糖高于OB患者.手术介导的体重减轻影响了不同的基因亚群，在OB中差异表达2,013，在T2D中差异表达959。在OB中差异表达的基因与胰岛素有关，PPAR信号和氧化磷酸化通路,而核糖体和剪接体在T2D中。LASSO回归分析显示，不同的候选基因与OB和T2D的表型性状改善相关。与OB相比，在减重手术后的T2D中，DNA甲基化受到的影响较小。这可能是由于全球羟甲基化增加，伴随着2型糖尿病风险基因之一的表达降低。TET2，在T2D中编码一种去甲基化酶。
结论：OB和T2D对减肥手术表现出不同的骨骼肌转录组反应，推测是由扰动的表观遗传灵活性造成的。
方法：所有参与者（OB，n=13；T2D，n=13）在手术前和手术后一年进行了详细的人体测量。在两个时间点分离骨骼肌活检，并使用全面的生物信息学管道进行转录组和甲基化组分析。
结果：手术前，T2D的空腹血糖和胰岛素水平较高，但全身胰岛素敏感性较低，手术后T2D患者仅血糖高于OB患者.手术介导的体重减轻影响了不同的基因亚群，在OB中差异表达2,013，在T2D中差异表达959。在OB中差异表达的基因与胰岛素有关，PPAR信号和氧化磷酸化通路,而核糖体和剪接体在T2D中。LASSO回归分析显示，不同的候选基因与OB和T2D的表型性状改善相关。与OB相比，在减重手术后的T2D中，DNA甲基化受到的影响较小。这可能是由于全球羟甲基化增加，伴随着2型糖尿病风险基因之一的表达降低。TET2，在T2D中编码一种去甲基化酶。
结论：OB和T2D对减肥手术表现出不同的骨骼肌转录组反应，推测是由扰动的表观遗传灵活性造成的。
