title: MiR-206 is expressed in pancreatic islets and regulates glucokinase activity.
abstract: Glucose homeostasis is a complex indispensable process, and its dysregulation causes hyperglycemia and type 2 diabetes mellitus. Glucokinase (GK) takes a central role in these pathways and is thus rate limiting for glucose-stimulated insulin secretion (GSIS) from pancreatic islets. Several reports have described the transcriptional regulation of Gck mRNA, whereas its posttranscriptional mechanisms of regulation, especially those involving microRNAs (miR), are poorly understood. In this study, we investigated the role of miR-206 as a posttranscriptional regulator of Gck In addition, we examined the effects of miR-206 on glucose tolerance, GSIS, and gene expression in control and germ line miR-206 knockout (KO) mice fed either with chow or high-fat diet (HFD). MiR-206 was found in Gck-expressing tissues and was differentially altered in response to HFD feeding. Pancreatic islets showed the most profound induction in the expression of miR-206 in response to HFD. Chow- and HFD-fed miR-206KO mice have improved glucose tolerance and GSIS but unaltered insulin sensitivity. In silico analysis of Gck mRNA revealed a conserved 8-mer miR-206 binding site. Hence, the predicted regulation of Gck by miR-206 was confirmed in reporter and GK activity assays. Concomitant with increased GK activity, miR-206KO mice had elevated liver glycogen content and plasma lactate concentrations. Our findings revealed a novel mechanism of posttranscriptional regulation of Gck by miR-206 and underline the crucial role of pancreatic islet miR-206 in the regulation of whole body glucose homeostasis in a murine model that mimics the metabolic syndrome.
authors.affiliation: Institute of Molecular Biology and Biochemistry, Medical University of Graz, Graz, Austria.
authors.forename: Manjula
authors.initials: M
authors.lastname: Vinod
authors.affiliation: Institute of Molecular Biology and Biochemistry, Medical University of Graz, Graz, Austria.
authors.forename: Jay V
authors.initials: JV
authors.lastname: Patankar
authors.affiliation: Institute of Molecular Biology and Biochemistry, Medical University of Graz, Graz, Austria.
authors.forename: Vinay
authors.initials: V
authors.lastname: Sachdev
authors.affiliation: Institute of Molecular Biology and Biochemistry, Medical University of Graz, Graz, Austria.
authors.forename: Saša
authors.initials: S
authors.lastname: Frank
authors.affiliation: Institute of Molecular Biology and Biochemistry, Medical University of Graz, Graz, Austria.
authors.forename: Wolfgang F
authors.initials: WF
authors.lastname: Graier
authors.affiliation: Institute of Molecular Biology and Biochemistry, Medical University of Graz, Graz, Austria.
authors.forename: Dagmar
authors.initials: D
authors.lastname: Kratky
authors.affiliation: Institute of Molecular Biology and Biochemistry, Medical University of Graz, Graz, Austria.
authors.forename: Gerhard M
authors.initials: GM
authors.lastname: Kostner
mesh_terms: D000818:Animals; D003198:Computer Simulation; D059305:Diet, High-Fat; D005941:Glucokinase / Q000235:genetics* / Q000378:metabolism; D005947:Glucose / Q000378:metabolism; D005951:Glucose Tolerance Test; D006003:Glycogen / Q000378:metabolism; D007328:Insulin / Q000378:metabolism; D000078790:Insulin Secretion; D007515:Islets of Langerhans / Q000378:metabolism*; D019344:Lactic Acid / Q000378:metabolism; D008099:Liver / Q000378:metabolism; D008297:Male; D024821:Metabolic Syndrome; D051379:Mice; D018345:Mice, Knockout; D035683:MicroRNAs / Q000235:genetics*; D012323:RNA Processing, Post-Transcriptional; D012333:RNA, Messenger / Q000378:metabolism*; D060888:Real-Time Polymerase Chain Reaction; D059467:Transcriptome
chemical_list: D007328:Insulin; D035683:MicroRNAs; C540669:Mirn206 microRNA, mouse; D012333:RNA, Messenger; D019344:Lactic Acid; D006003:Glycogen; D005941:Glucokinase; D005947:Glucose
keywords: glucose sensing; glucose tolerance; insulin sensitivity; miR-206; pancreatic islets