Glucose-Dependent miR-125b Is a Negative Regulator of β-Cell Function

Abstract

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.

Circulating microRNAs associated with gestational diabetes mellitus: useful biomarkers?

“…However, a smaller study was unable to detect any difference in circulating miR-16-5p (Hocaoglu et al 2019), but this could be due to the low number of included subjects. Moreover, miR-16-5p was also found to be significantly increased in the first trimester (Cao et al 2017, Sorensen et al 2021, 2022, which suggests that miR-16-5p could potentially be used as a diagnostic as well as a prognostic biomarker of GDM. This is emphasized by the finding that miR-16-5p in combination with miR-29a-3p and the also GDM-associated miR-134-5p forms a superior diagnostic measure compared with 2 h plasma glucose following an OGTT (Sorensen et al 2021), which is one of the recommended diagnostic measures of the IADPSG (International Association of Diabetes and Pregnancy Study Groups 2010).…”

“…2). Only 33 different miRNA species were investigated in more than 1 original study, with miR-29a-3p and miR-16-5p being the most studied miRNAs, investigated in 6 (Zhao et al 2011, Wander et al 2017, Tagoma et al 2018, Gillet et al 2019, Martinez-Ibarra et al 2019, Sorensen et al 2021, 2022 and 6 (Zhu et al 2015, Cao et al 2017, Tagoma et al 2018, Hocaoglu et al 2019, Martinez-Ibarra et al 2019, Sorensen et al 2021, 2022 original studies, respectively. miR-223-3p (Wander et al 2017, Tagoma et al 2018, Yoffe et al 2019, Sorensen et al 2021), miR-330-3p (Martinez-Ibarra et al 2019, Pfeiffer et al 2020, Xiao et al 2020, Sorensen et al 2021) and miR-132-3p (Zhao et al 2011, Tagoma et al 2018, Gillet et al 2019 were each investigated in four studies, while miR-155-5p (Wander et al 2017, Tagoma et al 2018, Hocaoglu et al 2019), miR-210-3p (Wander et al 2017, Tagoma et al 2018, Gillet et al 2019), miR-19a/b-3p (Cao et al 2017, Stirm et al 2018, Tagoma et al 2018), miR-17-5p (Cao et al 2017, Lamadrid-Romero et al 2018, Tagoma et al 2018) and miR-125a/b-5p…”

“…These findings suggest that miR-125a and miR-125b play an important role in the regulation of insulin resistance and lipogenesis. Moreover, miR-125b is a negative regulator of insulin secretion, possibly via control intracellular lysosomes (Cheung et al 2022), altogether suggesting that upregulation of miR-125 species may contribute to the development of T2D. Lamadrid-Romero et al (2018) investigated the expression of miR-125b-5p during all three trimesters of pregnancy (T1, T2 and T3) and showed increased circulating levels of miR-125b-5p in T2 and T3 in women with NGT during pregnancy, while levels in GDM complicated pregnant women were regulated differently showing increased levels of miR-125b-5p during T1, but decreased levels in during T2 and T3.…”

Signaling pathways and intervention for therapy of type 2 diabetes mellitus

“…Additionally, the promoting effect of AMPK on GSIS has been recently reported. It has shown that β cell‐specific deletion of AMPK increases the levels of miR‐125b‐5p, which could subsequently impair GSIS in both MIN6 cells and human islets 136 . As well, silencing of the metal‐dependent protein phosphatase 1E (PPM1E), the most markedly downregulated protein phosphatase in T2DM patients’ islets, can promote GSIS through increasing the phosphorylation of CaMKII, AMPK, and ACC 137 .…”

“…It has shown that β cell‐specific deletion of AMPK increases the levels of miR‐125b‐5p, which could subsequently impair GSIS in both MIN6 cells and human islets. 136 As well, silencing of the metal‐dependent protein phosphatase 1E (PPM1E), the most markedly downregulated protein phosphatase in T2DM patients’ islets, can promote GSIS through increasing the phosphorylation of CaMKII, AMPK, and ACC. 137 Altogether, these conflicting results warrant further investigations to provide more reliable information on the role of AMPK in T2DM and its clinical application.…”