Department of Endocrinology and Metabolism, Peking University People's Hospital, Peking University Diabetes Center, Beijing, China.
Department of Endocrinology, Pinggu Teaching Hospital, Capital Medical University, Beijing, China.
Front Endocrinol (Lausanne). 2022 Oct 12;13:953631. doi: 10.3389/fendo.2022.953631. eCollection 2022.
Mitochondrial DNA (mtDNA) plays an important role in the pathogenesis of diabetes. Variants in mtDNA have been reported in diabetes, but studies on the whole mtDNA variants were limited. Our study aims to explore the association of whole mtDNA variants with diabetes and diabetic kidney disease (DKD).
The whole mitochondrial genome was screened by next-generation sequencing in cohort 1 consisting of 50 early-onset diabetes (EOD) patients with a maternally inherited diabetes (MID) family history. A total of 42 variants possibly associated with mitochondrial diseases were identified according to the filtering strategy. These variants were sequenced in cohort 2 consisting of 90 EOD patients with MID. The association between the clinical phenotype and these variants was analyzed. Then, these variants were genotyped in cohort 3 consisting of 1,571 type 2 diabetes mellitus patients and 496 subjects with normal glucose tolerance (NGT) to analyze the association between variants with diabetes and DKD.
Patients with variants in the non-coding region had a higher percentage of obesity and levels of fasting insulin (62.1% vs. 24.6%, P = 0.001; 80.0% vs. 26.5% P < 0.001). The patients with the variants in rRNA had a higher prevalence of obesity (71.4% vs. 30.3%, P = 0.007), and the patients with the variants in mitochondrial complex I had a higher percentage of the upper tertile of FINS (64.3% vs. 34.3%, P = 0.049). Among 20 homogeneous variants successfully captured, two known variants (m.A3943G, m.A10005G) associated with other mitochondrial diseases were only in the diabetic group, but not in the NGT group, which perhaps indicated its possible association with diabetes. The prevalence of DKD was significantly higher in the group with the 20 variants than those without these variants (18.7% vs. 14.6%, P = 0.049) in the participants with diabetes of cohort 3.
MtDNA variants are associated with MID and DKD, and our findings advance our understanding of mtDNA in diabetes and DKD. It will have important implications for the individual therapy of mitochondrial diabetes.
线粒体 DNA（mtDNA）在糖尿病的发病机制中起着重要作用。已有研究报道 mtDNA 变异与糖尿病相关，但全 mtDNA 变异的研究有限。本研究旨在探讨全 mtDNA 变异与糖尿病及糖尿病肾病（DKD）的关系。
采用下一代测序技术对 50 例有母系遗传糖尿病（MID）家族史的早发糖尿病（EOD）患者（队列 1）进行全线粒体基因组筛查。根据筛选策略，共鉴定出 42 种可能与线粒体疾病相关的变异。对 90 例 MID 的 EOD 患者（队列 2）进行这些变异的测序。分析这些变异与临床表型的关系。然后，对 1571 例 2 型糖尿病患者和 496 例糖耐量正常（NGT）受试者（队列 3）进行这些变异的基因分型，分析变异与糖尿病和 DKD 的关系。
非编码区变异患者肥胖和空腹胰岛素水平较高（62.1%比 24.6%，P = 0.001；80.0%比 26.5%，P < 0.001）。rRNA 变异患者肥胖发生率较高（71.4%比 30.3%，P = 0.007），线粒体复合物 I 变异患者空腹胰岛素上三分之一比例较高（64.3%比 34.3%，P = 0.049）。在成功捕获的 20 个同质变异中，两个与其他线粒体疾病相关的已知变异（m.A3943G、m.A10005G）仅在糖尿病组中，而在 NGT 组中没有，这可能表明其与糖尿病有关。在队列 3 的糖尿病患者中，携带 20 个变异的患者 DKD 患病率显著高于不携带这些变异的患者（18.7%比 14.6%，P = 0.049）。
mtDNA 变异与 MID 和 DKD 相关，本研究结果加深了我们对糖尿病和 DKD 中线粒体 DNA 的认识。这将对线粒体糖尿病的个体化治疗具有重要意义。
