MiR-103 Regulates Pancreatic Mature ? Cells Functions By Directly Targeting Dicer1

Diabetes mellitus characterized as insufficient insulin secretion from pancreatic?cells and(or)peripheral insulin resistance,is one of the most common chronic metabolic diseases.The incidence of diabetes mellitus has increased in the past few decades.Given the critical roles of pancreatic?cells in type 1 and type 2 diabetes,more and more research focused on the pancreatic?cells.MicroRNAs(miRNAs),a class of 21-25nucleotides non-codingRNAs,act as negative regulators at post-transcriptional level by interacting with the mRNA 3'UTR of target genes,resulting in degradation of mRNA or repression of translation.Growing evidence have demonstrated that miRNAs had emerged in the regulations of pancreatic?cells morphology and functions in the development of diabetes mellitus.High fat diet(HFD)mouse,which displayed mild hyperglycemia and?cells dysfunctions,was a suitable model that was usually utilized to investigate the pancreatic?cells.Compared with normal chow diet induced mice,miR-103 was upregulated in the islets of HFD mice.We hypothesized that miR-103 probably had involved in the dysfunctions or morphology alteration of mature?cells in the development of HFD associated T2DM.In attempt to address the pathophysiological role of miR-103 in mature?cells in vivo,we generated p TRE-miR-103 transgenic mouse,which expressed the mutated miR-103 under the control of the TRE promoter(p TRE).p TRE-miR-103 mice were bred with Ins1-rtTA mice to gain the double-transgenic offsprings as miR-103 mice.In our previous work,Ins1-rtTA transgenic mouse was successfully generated that reverse tetracycline-dependent transactivator(rtTA)was driven by mouse insulin1 promoter(Ins1),which was specifically expressed in the pancreatic?cells without the leakage in other tissues.What's more,Ins1-rtTA mouse was constructed without hGH minigene,which was recently reported to affect?cells functions.Therefore,Ins1-rtTA mouse was an appropriate transgenic mouse model for the investigations of miRNAs in pancreatic?cells in vivo.miR-103 was specifically overexpressed in mature?cells of miR-103 mice after doxycycline(Dox)administration 5weeks(as miR-103^+Doxmice).miR-103^+Doxmice exhibited hyperglycemia and impaired glucose tolerance associated with reduction of insulin content and insulin secretion.Furthermore,we discovered that overexpression of miR-103 in pancreatic mature?cells in vivo or in vitro directly targeted Dicer1 thus attenuating biosynthesis of many mature miRNAs which played critical roles in the functions of mature?cells.Taken together,this is the first research to study the function of miR-103 in pancreatic mature?cells in vivo by constructing the?cell-specific transgenic mouse(miR-103^+Doxmouse).These findings indicated that miR-103 directly targeted Dicer1 to regulate insulin content and insulin secretion of mature?cells.It provided new insights into the molecular mechanisms of?cells dysfunctions in the development of diabetes mellitus,and suggested that approaches to suppress miR-103 will potentially be a novel therapeutic strategy to treat diabetes mellitus.