SFEBES2018 Poster Presentations Diabetes & cardiovascular (27 abstracts)
Introduction: Pancreatic β-cells control glucose homeostasis by secreting insulin in response to high glucose. MiRNAs regulate β-cell function and contribute to β-cell failure in type 2 diabetes. MiR-184 regulates β-cell compensatory expansion during pregnancy and obesity and its expression is reduced by glucose through unknown mechanisms. AMPK is a suggested target of antidiabetic drugs and an important energy sensor. Its β-cell-selective inactivation (βAMPKdKO) impairs β-cell identity, insulin secretion and dysregulates several miRNAs, including miR-184. We hypothesize that AMPK mediates glucose-dependent regulation of miR-184 and aim to identify the underlying mechanisms.
Methods: Control and transgenic animals were fed a chow or a ketogenic (low sugar) diet for 28 days. MiR-184 was measured by RT-qPCR in mouse and human islets. ATAC-seq and ChIP-qPCR with an anti-CTCF antibody were performed in isolated mouse islets.
Results: MiR-184 expression is decreased in mouse and male human islets cultured for 48h at high glucose concentration and its expression increases in human islets treated with AMPK activators. Islets isolated from mice fed a ketogenic diet present higher levels of miR-184. This effect is not observed when AMPK or its main upstream kinase LKB1 (βLKB1KO) is deleted. MiR-184 primary transcript is reduced in βAMPKdKO islets suggesting that AMPK regulates miR-184 transcription. ATAC-seq data identifies increased chromatin accessibility in two regions upstream MIR184 in βLKB1KO islets. According to ChIP-qPCR data CTCF bind the most proximal region.
Conclusion: AMPK mediates glucose-dependent down-regulation of miR-184 in vitro and in vivo possibly contributing to the deleterious effect of hyperglycaemia during diabetes. Our data suggest that AMPK might regulate miR-184 transcription by limiting CTCF binding to MIR184. We aim to validate our hypothesis and understand the role of AMPK in the regulation of CTCF activity and its implications in energy homeostasis and diabetes.
19 Nov 2018 - 21 Nov 2018