title: RNA-binding protein CUGBP1 regulates insulin secretion via activation of phosphodiesterase 3B in mice.
abstract: CUG-binding protein 1 (CUGBP1) is a multifunctional RNA-binding protein that regulates RNA processing at several stages including translation, deadenylation and alternative splicing, as well as RNA stability. Recent studies indicate that CUGBP1 may play a role in metabolic disorders. Our objective was to examine its role in endocrine pancreas function through gain- and loss-of-function experiments and to further decipher the underlying molecular mechanisms.
  
  
  
  A mouse model in which type 2 diabetes was induced by a high-fat diet (HFD; 60% energy from fat) and mice on a standard chow diet (10% energy from fat) were compared. Pancreas-specific CUGBP1 overexpression and knockdown mice were generated. Different lengths of the phosphodiesterase subtype 3B (PDE3B) 3' untranslated region (UTR) were cloned for luciferase reporter analysis. Purified CUGBP1 protein was used for gel shift experiments.
  
  
  
  CUGBP1 is present in rodent islets and in beta cell lines; it is overexpressed in the islets of diabetic mice. Compared with control mice, the plasma insulin level after a glucose load was significantly lower and glucose clearance was greatly delayed in mice with pancreas-specific CUGBP1 overexpression; the opposite results were obtained upon pancreas-specific CUGBP1 knockdown. Glucose- and glucagon-like peptide1 (GLP-1)-stimulated insulin secretion was significantly attenuated in mouse islets upon CUGBP1 overexpression. This was associated with a strong decrease in intracellular cAMP levels, pointing to a potential role for cAMP PDEs. CUGBP1 overexpression had no effect on the mRNA levels of PDE1A, 1C, 2A, 3A, 4A, 4B, 4D, 7A and 8B subtypes, but resulted in increased PDE3B expression. CUGBP1 was found to directly bind to a specific ATTTGTT sequence residing in the 3' UTR of PDE3B and stabilised PDE3B mRNA. In the presence of the PDE3 inhibitor cilostamide, glucose- and GLP-1-stimulated insulin secretion was no longer reduced by CUGBP1 overexpression. Similar to CUGBP1, PDE3B was overexpressed in the islets of diabetic mice.
  
  
  
  We conclude that CUGBP1 is a critical regulator of insulin secretion via activating PDE3B. Repressing this protein might provide a potential strategy for treating type 2 diabetes.
authors.affiliation: National Laboratory of Biomacromolecules, Institute of Biophysics, Chinese Academy of Sciences, Beijing, 100101, People's Republic of China.
authors.forename: Kui
authors.initials: K
authors.lastname: Zhai
authors.affiliation: National Laboratory of Biomacromolecules, Institute of Biophysics, Chinese Academy of Sciences, Beijing, 100101, People's Republic of China.
authors.forename: Lei
authors.initials: L
authors.lastname: Gu
authors.affiliation: National Laboratory of Biomacromolecules, Institute of Biophysics, Chinese Academy of Sciences, Beijing, 100101, People's Republic of China.
authors.forename: Zhiguang
authors.initials: Z
authors.lastname: Yang
authors.affiliation: National Laboratory of Biomacromolecules, Institute of Biophysics, Chinese Academy of Sciences, Beijing, 100101, People's Republic of China.
authors.forename: Yang
authors.initials: Y
authors.lastname: Mao
authors.affiliation: National Laboratory of Biomacromolecules, Institute of Biophysics, Chinese Academy of Sciences, Beijing, 100101, People's Republic of China.
authors.forename: Meng
authors.initials: M
authors.lastname: Jin
authors.affiliation: National Laboratory of Biomacromolecules, Institute of Biophysics, Chinese Academy of Sciences, Beijing, 100101, People's Republic of China.
authors.forename: Yan
authors.initials: Y
authors.lastname: Chang
authors.affiliation: National Laboratory of Biomacromolecules, Institute of Biophysics, Chinese Academy of Sciences, Beijing, 100101, People's Republic of China.
authors.forename: Qi
authors.initials: Q
authors.lastname: Yuan
authors.affiliation: Inserm, UMR-S 1180, Faculté de Pharmacie, Université Paris-Sud, 5 rue J.-B. Clément, 92296, Châtenay-Malabry, France.
authors.forename: Veronique
authors.initials: V
authors.lastname: Leblais
authors.affiliation: National Laboratory of Biomacromolecules, Institute of Biophysics, Chinese Academy of Sciences, Beijing, 100101, People's Republic of China.|State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai, People's Republic of China.
authors.forename: Huiwen
authors.initials: H
authors.lastname: Wang
authors.affiliation: Inserm, UMR-S 1180, Faculté de Pharmacie, Université Paris-Sud, 5 rue J.-B. Clément, 92296, Châtenay-Malabry, France. rodolphe.fischmeister@inserm.fr.
authors.forename: Rodolphe
authors.initials: R
authors.lastname: Fischmeister
authors.affiliation: National Laboratory of Biomacromolecules, Institute of Biophysics, Chinese Academy of Sciences, Beijing, 100101, People's Republic of China. gj28@ibp.ac.cn.
authors.forename: Guangju
authors.initials: G
authors.lastname: Ji
mesh_terms: D000818:Animals; D015153:Blotting, Western; D000067879:CELF1 Protein / Q000235:genetics / Q000378:metabolism*; D000242:Cyclic AMP / Q000378:metabolism; D054684:Cyclic Nucleotide Phosphodiesterases, Type 3 / Q000235:genetics / Q000378:metabolism*; D047468:Immunoprecipitation; D007328:Insulin / Q000378:metabolism*; D000078790:Insulin Secretion; D008297:Male; D051379:Mice; D016133:Polymerase Chain Reaction; D020871:RNA Stability / Q000235:genetics / Q000502:physiology; D012333:RNA, Messenger / Q000235:genetics
chemical_list: D000067879:CELF1 Protein; C502743:CELF1 protein, mouse; D007328:Insulin; D012333:RNA, Messenger; D000242:Cyclic AMP; D054684:Cyclic Nucleotide Phosphodiesterases, Type 3; C517293:Pde3b protein, mouse
keywords: CUGBP1; Insulin secretion; PDE3B; RNA-binding protein; Type 2 diabetes; cAMP