Stress-Induced MicroRNA-708 Impairs β-Cell Function and Growth

Abstract

The pancreatic β-cell transcriptome is highly sensitive to external signals such as glucose oscillations and stress cues. MicroRNAs (miRNAs) have emerged as key factors in gene expression regulation. Here, we aimed to identify miRNAs that are modulated by glucose in mouse pancreatic islets. We identified miR-708 as the most upregulated miRNA in islets cultured at low glucose concentrations, a setting that triggers a strong stress response. miR-708 was also potently upregulated by triggering endoplasmic reticulum (ER) stress with thapsigargin and in islets of / mice. Low-glucose induction of miR-708 was blocked by treatment with the chemical chaperone 4-phenylbutyrate, uncovering the involvement of ER stress in this response. An integrative analysis identified neuronatin () as a potential glucose-regulated target of miR-708. Indeed, expression was inversely correlated with miR-708 in islets cultured at different glucose concentrations and in/ mouse islets and was reduced after miR-708 overexpression. Consistent with the role of Nnat in the secretory function of β-cells, miR-708 overexpression impaired glucose-stimulated insulin secretion (GSIS), which was recovered by overexpression. Moreover, miR-708 inhibition recovered GSIS in islets cultured at low glucose. Finally, miR-708 overexpression suppressed β-cell proliferation and induced β-cell apoptosis. Collectively, our results provide a novel mechanism of glucose regulation of β-cell function and growth by repressing stress-induced miR-708.

Targeting microRNAs as a Therapeutic Strategy to Reduce Oxidative Stress in Diabetes

“…Of note, overexpression of Neuronatin restored the Glucose-Stimulated Insulin Secretion (GSIS) in murine and human islets cultured at low glucose levels. These results demonstrated that miR-708 could be used as potential target to restore β cell function under stress conditions [52,53].…”

Identification of Neuroendocrine Stress Response-Related Circulating MicroRNAs as Biomarkers for Type 2 Diabetes Mellitus and Insulin Resistance

“…By targets Argonaute2, miR-184 plays adaptive role of the miRNA pathway based on metabolic state ( 27 ). Stress-induced overexpression of miR-708 suppressed β-cell proliferation and induced β-cell apoptosis, which provide a novel mechanism of glucose regulation of β-cell function and growth ( 28 ). Comparing to tissue biomarkers, circulating miRNAs are preferred due to easier sampling and testing.…”

Endoplasmic reticulum stress epigenetics is related to adiposity, dyslipidemia, and insulin resistance

“…Also, upregulation of NFE2L2 by increasing miR-200a protected against diabetic nephropathy in mice treated with an analogue of curcumin [42]. Similarly, miR-708 was potently upregulated by triggering ER stress in pancreatic islets of ob/ob mice, whose overexpression suppressed b-cell proliferation and induced b-cell apoptosis [43]. Additionally, it was demonstrated that a modest increase in maternal dietary fat in mice programmed triglyceride storage in the liver of their offspring at the adult stage that was controlled by the eIF2a kinase Gcn2 (Eif2ak4), which stimulated epigenetic modification (trimethylation of lysine 4 of histone 3) at the Pparg2 gene in the neonatal liver [44].…”