Section of Cell Biology and Functional Genomics, Department of Metabolism, Digestion and Reproduction, Imperial College London, London, U.K.
Beta Cell Genome Regulation Laboratory, Department of Metabolism, Digestion and Reproduction, Imperial College London, London, U.K.
Diabetes. 2022 Jul 1;71(7):1525-1545. doi: 10.2337/db21-0803.
Impaired pancreatic β-cell function and insulin secretion are hallmarks of type 2 diabetes. miRNAs are short, noncoding RNAs that silence gene expression vital for the development and function of β cells. We have previously shown that β cell-specific deletion of the important energy sensor AMP-activated protein kinase (AMPK) results in increased miR-125b-5p levels. Nevertheless, the function of this miRNA in β cells is unclear. We hypothesized that miR-125b-5p expression is regulated by glucose and that this miRNA mediates some of the deleterious effects of hyperglycemia in β cells. Here, we show that islet miR-125b-5p expression is upregulated by glucose in an AMPK-dependent manner and that short-term miR-125b-5p overexpression impairs glucose-stimulated insulin secretion (GSIS) in the mouse insulinoma MIN6 cells and in human islets. An unbiased, high-throughput screen in MIN6 cells identified multiple miR-125b-5p targets, including the transporter of lysosomal hydrolases M6pr and the mitochondrial fission regulator Mtfp1. Inactivation of miR-125b-5p in the human β-cell line EndoCβ-H1 shortened mitochondria and enhanced GSIS, whereas mice overexpressing miR-125b-5p selectively in β cells (MIR125B-Tg) were hyperglycemic and glucose intolerant. MIR125B-Tg β cells contained enlarged lysosomal structures and had reduced insulin content and secretion. Collectively, we identify miR-125b as a glucose-controlled regulator of organelle dynamics that modulates insulin secretion.
β 细胞功能障碍和胰岛素分泌受损是 2 型糖尿病的特征。miRNAs 是短的非编码 RNA，可沉默对 β 细胞发育和功能至关重要的基因表达。我们之前曾表明，β 细胞特异性缺失重要的能量传感器 AMP 激活的蛋白激酶 (AMPK) 会导致 miR-125b-5p 水平升高。然而，这种 miRNA 在 β 细胞中的功能尚不清楚。我们假设 miR-125b-5p 的表达受葡萄糖调控，并且该 miRNA 介导高血糖对 β 细胞的一些有害影响。在这里，我们表明，胰岛 miR-125b-5p 的表达受葡萄糖调控，且 AMPK 依赖性上调，短期 miR-125b-5p 过表达可损害小鼠胰岛素瘤 MIN6 细胞和人胰岛中的葡萄糖刺激胰岛素分泌 (GSIS)。MIN6 细胞中的一种无偏见的高通量筛选鉴定了多个 miR-125b-5p 靶标，包括溶酶体水解酶的转运蛋白 M6pr 和线粒体分裂调节剂 Mtfp1。人 β 细胞系 EndoCβ-H1 中 miR-125b-5p 的失活缩短了线粒体并增强了 GSIS，而在 β 细胞中过表达 miR-125b-5p 的小鼠（MIR125B-Tg）表现为高血糖和葡萄糖不耐受。MIR125B-Tg 胰岛β 细胞含有增大的溶酶体结构，胰岛素含量和分泌减少。总的来说，我们将 miR-125b 鉴定为一种受葡萄糖调控的细胞器动态调节剂，可调节胰岛素分泌。
