Abstract

Objective Systemic levels of up-regulated IL-1β and IL-1 receptors promote the pathogenesis of inflammation-associated diabetes. IL-1 receptor antagonist (IL-Ra) has shown slightly elevated beta cell function in patients with type 2 diabetes without significant improvement of hyperglycaemia . We investigated whether miR-153 , an IL-1β responsive miRNA , could mimic IL-1β effects and whether its interruption would improve blood glucose control then offer an assistant curative approach to inflammation-associated diabetes. Materials/methods Antago- miR-153 and Ago- miR-153 were injected into the abdominal aorta of leptin receptor-mutant db / db mice and C57BL/6 J mice, respectively. Blood glucose levels, glucose tolerance tests , insulin tolerance tests and insulin levels were regularly checked. Proteomic profiling combined with unbiased bioinformatics analysis, as well as experimental techniques, were utilized to identify target genes of miR-153 . Anti- miR-153 and plasmid-based recovery assays were also performed using primary mouse islets and beta cell lines. Results The miR-153 expression level was increased in IL-1β–treated beta cells and primary islets from the diabetic rodents. Pancreas overexpression of miR-153 caused glucose intolerance in C57BL/6 J mice but no alterations in body weight or insulin sensitivity . The inhibition of miR-153 temporarily reduced hyperglycaemia of db / db mice due to enhanced insulin secretion . Antago- miR-153 treatment ameliorated glucose intolerance in db / db mice during our observation period but did not improve insulin sensitivity. Mechanistically, miR-153 targeted three members of SNAREs to disturb insulin granule docking, thereby decreasing basal insulin secretion. Overexpression of anti- miR-153 or SNARE rescued the IL-1β–induced basal insulin secretion defect. Furthermore, miR-153 targeted beta cell–specific transcriptional factors and survival molecules to inhibit insulin bi