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2 型糖尿病中共调节因子 TLE1 的表达降低与胰岛 α 细胞数量增加有关。

Reduced Expression of the Co-regulator TLE1 in Type 2 Diabetes Is Associated with Increased Islet α-Cell Number.

机构信息

Institute of Cellular Medicine, Diabetes Research Group, Newcastle University Medical School, Framlington Place, UK.

Institute of Biomedical and Clinical Sciences, University of Exeter Medical School, Exeter, UK.

出版信息

Endocrinology. 2020 Apr 1;161(4). doi: 10.1210/endocr/bqaa011.

DOI:10.1210/endocr/bqaa011
PMID:32065829
Abstract

β-Cell dysfunction in type 2 diabetes (T2D) is associated with loss of cellular identity and mis-expression of alternative islet hormones, including glucagon. The molecular basis for these cellular changes has been attributed to dysregulation of core β-cell transcription factors, which regulate β-cell identity through activating and repressive mechanisms. The TLE1 gene lies near a T2D susceptibility locus and, recently, the glucagon repressive actions of this transcriptional coregulator have been demonstrated in vitro. We investigated whether TLE1 expression is disrupted in human T2D, and whether this is associated with increased islet glucagon-expressing cells. Automated image analysis following immunofluorescence in donors with (n = 7) and without (n = 7) T2D revealed that T2D was associated with higher islet α/β cell ratio (Control: 0.7 ± 0.1 vs T2D: 1.6 ± 0.4; P < .05) and an increased frequency of bihormonal (insulin+/glucagon+) cells (Control: 0.8 ± 0.2% vs T2D: 2.0 ± 0.4%, P < .05). In nondiabetic donors, the majority of TLE1-positive cells were mono-hormonal β-cells (insulin+/glucagon-: 98.2 ± 0.5%; insulin+/glucagon+: 0.7 ± 0.2%; insulin-/glucagon+: 1.1 ± 0.4%; P < .001). TLE1 expression was reduced in T2D (Control: 36 ± 2.9% vs T2D: 24 ± 2.6%; P < .05). Reduced islet TLE1 expression was inversely correlated with α/β cell ratio (r = -0.55; P < .05). TLE1 knockdown in EndoC-βH1 cells was associated with a 2.5-fold increase in glucagon gene mRNA and mis-expression of glucagon in insulin-positive cells. These data support TLE1 as a putative regulator of human β-cell identity, with dysregulated expression in T2D associated with increased glucagon expression potentially reflecting β- to α-cell conversion.

摘要

2 型糖尿病(T2D)中的β细胞功能障碍与细胞身份丧失和胰岛激素的替代表达有关,包括胰高血糖素。这些细胞变化的分子基础归因于核心β细胞转录因子的失调,这些转录因子通过激活和抑制机制调节β细胞身份。TLE1 基因位于 T2D 易感位点附近,最近,体外研究表明该转录核心调节剂对胰高血糖素具有抑制作用。我们研究了 TLE1 表达是否在人类 T2D 中受到破坏,以及这是否与胰岛胰高血糖素表达细胞增加有关。对有(n=7)和无(n=7)T2D 的供体进行免疫荧光后自动图像分析显示,T2D 与更高的胰岛α/β细胞比例相关(对照:0.7±0.1 比 T2D:1.6±0.4;P<.05)和双激素(胰岛素+/胰高血糖素+)细胞的频率增加(对照:0.8±0.2%比 T2D:2.0±0.4%,P<.05)。在非糖尿病供体中,大多数 TLE1 阳性细胞是单激素β细胞(胰岛素+/胰高血糖素-:98.2±0.5%;胰岛素+/胰高血糖素+:0.7±0.2%;胰岛素-/胰高血糖素+:1.1±0.4%;P<.001)。T2D 中 TLE1 表达减少(对照:36±2.9%比 T2D:24±2.6%;P<.05)。胰岛 TLE1 表达减少与α/β 细胞比例呈负相关(r=-0.55;P<.05)。EndoC-βH1 细胞中的 TLE1 敲低与胰高血糖素基因 mRNA 增加 2.5 倍和胰岛素阳性细胞中胰高血糖素的错误表达有关。这些数据支持 TLE1 作为人类β细胞身份的潜在调节剂,在 T2D 中表达失调与胰高血糖素表达增加相关,可能反映β-到α-细胞转化。

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