一般人口正在老龄化,涉及慢性疾病如2型糖尿病的发病率增加。随着老龄化,FHL2的DNA甲基化增加,以及在人胰岛中四个半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。
分析来自人胰岛的公开可用的微阵列数据集的FHL2表达。在FHL2缺陷小鼠中,我们研究了葡萄糖清除和胰岛素分泌。在分离的鼠FHL2缺陷的胰岛中确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的敲减和过表达,以描述FHL2功能的潜在机制。
人胰岛的转录组学显示,HbA1c水平升高的个体显示FHL2表达增加,与胰岛素分泌途径呈负相关。根据这一观察,FHL2缺陷小鼠通过增加血浆胰岛素水平比野生型同窝动物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,尽管胰岛素含量和胰岛大小相似,但在GSIS分析中,从FHL2缺陷小鼠中分离的胰岛比野生型小鼠分泌更多的胰岛素。为了支持这一观察,我们证明了在胰岛素分泌中至关重要的转录因子的表达增加,MAFBZIP转录因子A(MafA),在FHL2缺陷胰岛中GLUT2的高表达和不良因子c-Jun的低表达。在MIN6细胞中进一步描绘了FHL2的潜在机制。FHL2敲低导致叉头盒蛋白O1(FOXO1)及其下游基因如Mafa和Pdx1(编码胰腺和十二指肠同源盒1)的激活增强,以及葡萄糖摄取增加。另一方面,MIN6细胞中FHL2过表达阻断GSIS,增加了活性氧的形成并增加了c-Jun活性。
我们的数据表明,FHL2缺乏改善了β细胞的胰岛素分泌,并改善了小鼠的葡萄糖耐量。鉴于FHL2在人类中的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,我们认为,老年人体内FHL2表达增强有助于葡萄糖耐受不良和2型糖尿病的发展.
使用的人类胰岛微阵列数据集是公开可用的,可以在https://www上找到。ncbi.nlm.nih.gov/geo/.
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.
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.
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.
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.
The human islet microarray datasets used are publicly available and can be found on https://www.ncbi.nlm.nih.gov/geo/ .