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糖尿病中功能失调的β细胞寿命依赖于能量守恒和正上位性。

Dysfunctional β-cell longevity in diabetes relies on energy conservation and positive epistasis.

机构信息

Hillblom Islet Research Center, David Geffen School of Medicine, University of California Los Angeles, Los Angeles, CA, USA.

Radiological Sciences, David Geffen School of Medicine, University of California Los Angeles, Los Angeles, CA, USA.

出版信息

Life Sci Alliance. 2024 Sep 23;7(12). doi: 10.26508/lsa.202402743. Print 2024 Dec.

DOI:10.26508/lsa.202402743
PMID:39313296
原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC11420665/
Abstract

Long-lived PFKFB3-expressing β-cells are dysfunctional partly because of prevailing glycolysis that compromises metabolic coupling of insulin secretion. Their accumulation in type 2 diabetes (T2D) appears to be related to the loss of apoptotic competency of cell fitness competition that maintains islet function by favoring constant selection of healthy "winner" cells. To investigate how PFKFB3 can disguise the competitive traits of dysfunctional "loser" β-cells, we analyzed the overlap between human β-cells with bona fide "loser signature" across diabetes pathologies using the HPAP scRNA-seq and spatial transcriptomics of PFKFB3-positive β-cells from nPOD T2D pancreata. The overlapping transcriptional profile of "loser" β-cells was represented by down-regulated ribosomal biosynthesis and genes encoding for mitochondrial respiration. PFKFB3-positive "loser" β-cells had the reduced expression of HLA class I and II genes. Gene-gene interaction analysis revealed that PFKFB3 can interact with the anti-apoptotic gene implicating positive epistasis as a mechanism for prolonged survival of "loser" β-cells in T2D. Inhibition of PFKFB3 resulted in the clearance of dysfunctional "loser" β-cells leading to restored glucose tolerance in the mouse model of T2D.

摘要

长寿的 PFKFB3 表达的β细胞部分功能失调，部分原因是普遍存在的糖酵解，这损害了胰岛素分泌的代谢偶联。它们在 2 型糖尿病（T2D）中的积累似乎与细胞适应性竞争的凋亡能力丧失有关，这种竞争通过偏爱健康的“胜利者”细胞的持续选择来维持胰岛功能。为了研究 PFKFB3 如何掩盖功能失调的“失败者”β细胞的竞争特征，我们使用 HPAP scRNA-seq 分析了糖尿病病理中具有真正“失败者”特征的人类β细胞之间的重叠，并对 nPOD T2D 胰腺中 PFKFB3 阳性β细胞进行了空间转录组学分析。“失败者”β细胞的重叠转录谱由核糖体生物合成和编码线粒体呼吸的基因下调表示。PFKFB3 阳性的“失败者”β细胞 HLA I 和 II 类基因的表达降低。基因-基因相互作用分析表明，PFKFB3 可以与抗凋亡基因相互作用，暗示正上位性是 T2D 中“失败者”β细胞延长存活的机制。PFKFB3 的抑制导致功能失调的“失败者”β细胞的清除，从而在 T2D 的小鼠模型中恢复了葡萄糖耐量。

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