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Glucose-mediated insulin secretion is improved in FHL2-deficient mice and elevated FHL2 expression in humans is associated with type 2 diabetes
Diabetologia ( IF 8.2 ) Pub Date : 2022-07-08 , DOI: 10.1007/s00125-022-05750-1
Jayron J Habibe 1, 2, 3, 4 , Maria P Clemente-Olivo 1, 2, 3 , Torsten P M Scheithauer 5 , Elena Rampanelli 5 , Hilde Herrema 5 , Mariska Vos 1, 2, 3 , Arnout Mieremet 1, 2, 3 , Max Nieuwdorp 5 , Daniel H van Raalte 6 , Etto C Eringa 4, 7 , Carlie J M de Vries 1, 2, 3
Affiliation  

Aims/hypothesis

The general population is ageing, involving an enhanced incidence of chronic diseases such as type 2 diabetes. With ageing, DNA methylation of FHL2 increases, as well as expression of the four and a half LIM domains 2 (FHL2) protein in human pancreatic islets. We hypothesised that FHL2 is actively involved in glucose metabolism.

Methods

Publicly available microarray datasets from human pancreatic islets were analysed for FHL2 expression. In FHL2-deficient mice, we studied glucose clearance and insulin secretion. Gene expression analysis and glucose-stimulated insulin secretion (GSIS) were determined in isolated murine FHL2-deficient islets to evaluate insulin-secretory capacity. Moreover, knockdown and overexpression of FHL2 were accomplished in MIN6 cells to delineate the underlying mechanism of FHL2 function.

Results

Transcriptomics of human pancreatic islets revealed that individuals with elevated levels of HbA1c displayed increased FHL2 expression, which correlated negatively with insulin secretion pathways. In line with this observation, FHL2-deficient mice cleared glucose more efficiently than wild-type littermates through increased plasma insulin levels. Insulin sensitivity was comparable between these genotypes. Interestingly, pancreatic islets isolated from FHL2-deficient mice secreted more insulin in GSIS assays than wild-type mouse islets even though insulin content and islet size was similar. To support this observation, we demonstrated increased expression of the transcription factor crucial in insulin secretion, MAF BZIP transcription factor A (MafA), higher expression of GLUT2 and reduced expression of the adverse factor c-Jun in FHL2-deficient islets. The underlying mechanism of FHL2 was further delineated in MIN6 cells. FHL2-knockdown led to enhanced activation of forkhead box protein O1 (FOXO1) and its downstream genes such as Mafa and Pdx1 (encoding pancreatic and duodenal homeobox 1), as well as increased glucose uptake. On the other hand, FHL2 overexpression in MIN6 cells blocked GSIS, increased the formation of reactive oxygen species and increased c-Jun activity.

Conclusions/interpretation

Our data demonstrate that FHL2 deficiency improves insulin secretion from beta cells and improves glucose tolerance in mice. Given that FHL2 expression in humans increases with age and that high expression levels of FHL2 are associated with beta cell dysfunction, we propose that enhanced FHL2 expression in elderly individuals contributes to glucose intolerance and the development of type 2 diabetes.

Data availability

The human islet microarray datasets used are publicly available and can be found on https://www.ncbi.nlm.nih.gov/geo/.

Graphical abstract



中文翻译:

葡萄糖介导的胰岛素分泌在 FHL2 缺陷小鼠中得到改善,人类 FHL2 表达升高与 2 型糖尿病有关

目标/假设

总人口正在老龄化,这导致 2 型糖尿病等慢性病的发病率增加。随着衰老,FHL2的 DNA 甲基化增加,以及人类胰岛中四个半 LIM 结构域 2 (FHL2) 蛋白的表达。我们假设 FHL2 积极参与葡萄糖代谢。

方法

分析了来自人类胰岛的公开可用微阵列数据集的 FHL2 表达。在 FHL2 缺陷小鼠中,我们研究了葡萄糖清除率和胰岛素分泌。在分离的小鼠 FHL2 缺陷胰岛中测定基因表达分析和葡萄糖刺激的胰岛素分泌 (GSIS),以评估胰岛素分泌能力。此外,在 MIN6 细胞中完成了 FHL2 的敲低和过表达,以描述 FHL2 功能的潜在机制。

结果

人类胰岛的转录组学显示 HbA 1c水平升高的个体FHL2 表达增加,与胰岛素分泌途径呈负相关。根据这一观察结果,FHL2 缺陷小鼠通过增加血浆胰岛素水平比野生型同窝小鼠更有效地清除葡萄糖。这些基因型之间的胰岛素敏感性相当。有趣的是,从 FHL2 缺陷小鼠中分离出的胰岛在 GSIS 检测中比野生型小鼠胰岛分泌更多的胰岛素,尽管胰岛素含量和胰岛大小相似。为了支持这一观察结果,我们证明了在胰岛素分泌中至关重要的转录因子、MAF BZIP 转录因子 A (MafA) 的表达增加、GLUT2 的更高表达和 FHL2 缺陷胰岛中不利因子 c-Jun 的表达减少。FHL2 的潜在机制在 MIN6 细胞中得到进一步描述。MafaPdx1(编码胰腺和十二指肠同源框 1),以及葡萄糖摄取增加。另一方面,MIN6 细胞中的 FHL2 过表达可阻断 GSIS,增加活性氧的形成并增加 c-Jun 活性。

结论/解释

我们的数据表明,FHL2 缺陷可改善 β 细胞的胰岛素分泌并改善小鼠的葡萄糖耐量。鉴于人类的 FHL2 表达随着年龄的增长而增加,并且 FHL2 的高表达水平与 β 细胞功能障碍有关,我们提出老年人 FHL2 表达增强会导致葡萄糖耐受不良和 2 型糖尿病的发展。

数据可用性

使用的人类胰岛微阵列数据集是公开可用的,可以在 https://www.ncbi.nlm.nih.gov/geo/ 上找到。

图形概要

更新日期:2022-07-08
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