Heterogenous impairment of α cell function in type 2 diabetes is linked to cell maturation state.
Heterogenous impairment of α cell function in type 2 diabetes is linked to cell maturation state.
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DOI：
10.1016/j.cmet.2021.12.021
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发表时间：
2022-02-01
期刊：
影响因子：
29
通讯作者：
MacDonald PE
中科院分区：
文献类型：
--
作者：
Dai XQ;Camunas-Soler J;Briant LJB;Dos Santos T;Spigelman AF;Walker EM;Arrojo E Drigo R;Bautista A;Jones RC;Avrahami D;Lyon J;Nie A;Smith N;Zhang Y;Johnson J;Manning Fox JE;Michelakis ED;Light PE;Kaestner KH;Kim SK;Rorsman P;Stein RW;Quake SR;MacDonald PE
糖尿病患者胰腺α-细胞分泌胰高血糖素失调。潜在的机制，以及功能障碍是否在细胞中均匀发生，仍不清楚。我们使用电生理学、转录组学和计算方法检测了来自人类供体和小鼠的α-细胞。升高的葡萄糖通过降低P/ q型Ca2+通道活性来抑制α-细胞的胞吐，这在2型糖尿病（T2D）中被破坏。在高脂肪喂养小鼠后，α-细胞向“β-细胞样”的电生理特征转变，这与身份受损的迹象相一致。在人类α-细胞中，我们确定了细胞膜特性与细胞表面信号受体、线粒体呼吸复合体组装和细胞成熟之间的联系。利用电生理数据的机器学习进行细胞类型分类表明，来自T2D供体的α-细胞存在“电生理同一性”的异质性丧失。事实上，α-细胞胞吐功能受损的一个亚群是通过祖细胞和谱系标记的富集以及未成熟转录组表型的上调来定义的，这表明α-细胞成熟状态和功能障碍之间存在重要联系。糖尿病患者胰腺α-细胞分泌胰高血糖素失调。Dai等研究了电学和转录组学α-细胞表型，发现2型糖尿病的功能障碍与细胞成熟状态和α-细胞身份受损有关。值得注意的是，富含谱系标记的α-细胞亚群似乎特别容易出现功能障碍。
In diabetes, glucagon secretion from pancreatic α-cells is dysregulated. The underlying mechanisms, and whether dysfunction occurs uniformly amongst cells, remain unclear. We examined α-cells from human donors and mice using electrophysiological, transcriptomic, and computational approaches. Rising glucose suppresses α-cell exocytosis by reducing P/Q-type Ca2+ channel activity, and this is disrupted in type 2 diabetes (T2D). Upon high-fat-feeding of mice, α-cells shift towards a ‘β-cell-like’ electrophysiologic profile in concert with indications of impaired identity. In human α-cells we identify links between cell membrane properties and cell surface signalling receptors, mitochondrial respiratory complex assembly, and cell maturation. Cell type classification using machine learning of electrophysiology data demonstrates a heterogenous loss of ‘electrophysiologic identity’ in α-cells from donors with T2D. Indeed, a sub-set of α-cells with impaired exocytosis is defined by an enrichment in progenitor and lineage markers, and up-regulation of an immature transcriptomic phenotype, suggesting important links between α-cell maturation state and dysfunction. In diabetes, glucagon secretion from pancreatic α-cells is dysregulated. Dai et al. examined electrical and transcriptomic α-cell phenotypes and find that dysfunction in type 2 diabetes is linked to cell maturation state and impaired α-cell identity. Notably, a sub-set of α-cells enriched for lineage markers appears uniquely susceptible to dysfunction.
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影响因子：
4.6
作者：
Bankhead P;Loughrey MB;Fernández JA;Dombrowski Y;McArt DG;Dunne PD;McQuaid S;Gray RT;Murray LJ;Coleman HG;James JA;Salto-Tellez M;Hamilton PW
通讯作者：
Hamilton PW
DOI：
10.1093/bioinformatics/btu638
发表时间：
2015-01-15
期刊：
Bioinformatics (Oxford, England)
影响因子：
--
作者：
Anders S;Pyl PT;Huber W
通讯作者：
Huber W
影响因子：
7.7
作者：
Collins SC;Hoppa MB;Walker JN;Amisten S;Abdulkader F;Bengtsson M;Fearnside J;Ramracheya R;Toye AA;Zhang Q;Clark A;Gauguier D;Rorsman P
通讯作者：
Rorsman P
影响因子：
29
作者：
Chakravarthy H;Gu X;Enge M;Dai X;Wang Y;Damond N;Downie C;Liu K;Wang J;Xing Y;Chera S;Thorel F;Quake S;Oberholzer J;MacDonald PE;Herrera PL;Kim SK
通讯作者：
Kim SK
单细胞染色质可及性识别胰岛细胞类型和特定州糖尿病风险的调节计划。
影响因子：
30.8
作者：
Chiou, Joshua;Zeng, Chun;Cheng, Zhang;Han, Jee Yun;Schlichting, Michael;Miller, Michael;Mendez, Robert;Huang, Serina;Wang, Jinzhao;Sui, Yinghui;Deogaygay, Allison;Okino, Mei-Lin;Qiu, Yunjiang;Sun, Ying;Kudtarkar, Parul;Fang, Rongxin;Preissl, Sebastian;Sander, Maike;Gorkin, David U.;Gaulton, Kyle J.
通讯作者：
Gaulton, Kyle J.