BACKGROUND In type 1 diabetes (T1D), impaired insulin sensitivity may contribute to the development of diabetic kidney disease (DKD) through alterations in kidney oxidative metabolism. METHODS Young adults with T1D (n = 30) and healthy controls (HC, n = 20) underwent hyperinsulinemic-euglycemic clamp studies, MRI, 11C-acetate PET, kidney biopsies, single-cell RNA sequencing, and spatial metabolomics to assess this relationship. RESULTS Participants with T1D had significantly higher glomerular basement membrane thickness compared to HC. T1D participants exhibited lower insulin sensitivity and cortical oxidative metabolism, correlating with higher insulin sensitivity. Proximal tubular transcripts of TCA cycle and oxidative phosphorylation enzymes were lower in T1D. Spatial metabolomics showed reductions in tubular TCA cycle intermediates, indicating mitochondrial dysfunction. The Slingshot algorithm identified a lineage of proximal tubular cells progressing from stable to adaptive/maladaptive subtypes, using pseudotime trajectory analysis, which computationally orders cells along a continuum of states. This analysis revealed distinct distribution patterns between T1D and HC, with attenuated oxidative metabolism in T1D attributed to a greater proportion of adaptive/maladaptive subtypes with low expression of TCA cycle and oxidative phosphorylation transcripts. Pseudotime progression associated with higher HbA1c, BMI, GBM, and lower insulin sensitivity and cortical oxidative metabolism. CONCLUSION These early structural and metabolic changes in T1D kidneys may precede clinical DKD. TRIAL REGISTRATION CLINICALTRIALS gov NCT04074668.

中文翻译：

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减弱 1 型糖尿病年轻人的肾脏氧化代谢。


背景 在 1 型糖尿病 （T1D） 中，胰岛素敏感性受损可能通过改变肾脏氧化代谢导致糖尿病肾病 （DKD） 的发展。方法 患有 T1D （n = 30） 和健康对照 （HC，n = 20） 的年轻成人接受了高胰岛素-正常血糖钳夹研究、MRI、11C-醋酸酯 PET、肾活检、单细胞 RNA 测序和空间代谢组学，以评估这种关系。结果 与 HC 相比，T1D 参与者的肾小球基底膜厚度显著升高。T1D 参与者表现出较低的胰岛素敏感性和皮质氧化代谢，与较高的胰岛素敏感性相关。TCA 循环和氧化磷酸化酶的近端肾小管转录物在 T1D 中较低。空间代谢组学显示肾小管 TCA 循环中间体减少，表明线粒体功能障碍。Slingshot 算法使用伪时间轨迹分析确定了从稳定亚型发展到适应性/适应不良亚型的近端肾小管细胞谱系，该分析沿状态连续体对细胞进行计算排序。该分析揭示了 T1D 和 HC 之间不同的分布模式，其中 T1D 中氧化代谢减弱归因于更大比例的适应性/适应不良亚型，TCA 循环和氧化磷酸化转录物表达较低。假时间进展与较高的 HbA1c 、 BMI 、 GBM 以及较低的胰岛素敏感性和皮质氧化代谢相关。结论 T1D 肾脏的这些早期结构和代谢变化可能先于临床 DKD。试验注册 临床试验 政府 NCT04074668.