title: GGPPS-mediated Rab27A geranylgeranylation regulates β cell dysfunction during type 2 diabetes development by affecting insulin granule docked pool formation.
abstract: Loss of first-phase insulin secretion associated with β cell dysfunction is an independent predictor of type 2 diabetes mellitus (T2DM) onset. Here we found that a critical enzyme involved in protein prenylation, geranylgeranyl pyrophosphate synthase (GGPPS), is required to maintain first-phase insulin secretion. GGPPS shows a biphasic expression pattern in islets of db/db mice during the progression of T2DM: GGPPS is increased during the insulin compensatory period, followed by a decrease during β cell dysfunction. Ggpps deletion in β cells results in typical T2DM β cell dysfunction, with blunted glucose-stimulated insulin secretion and consequent insulin secretion insufficiency. However, the number and size of islets and insulin biosynthesis are unaltered. Transmission electron microscopy shows a reduced number of insulin granules adjacent to the cellular membrane, suggesting a defect in docked granule pool formation, while the reserve pool is unaffected. Ggpps ablation depletes GGPP and impairs Rab27A geranylgeranylation, which is responsible for the docked pool deficiency in Ggpps-null mice. Moreover, GGPPS re-expression or GGPP administration restore glucose-stimulated insulin secretion in Ggpps-null islets. These results suggest that GGPPS-controlled protein geranylgeranylation, which regulates formation of the insulin granule docked pool, is critical for β cell function and insulin release during the development of T2DM.
authors.affiliation: State Key Laboratory of Pharmaceutical Biotechnology and MOE Key Laboratory of Model Animal for Disease Study, Model Animal Research Centre and School of Medicine, Nanjing University, People's Republic of China.
authors.forename: Shan
authors.initials: S
authors.lastname: Jiang
authors.affiliation: State Key Laboratory of Pharmaceutical Biotechnology and MOE Key Laboratory of Model Animal for Disease Study, Model Animal Research Centre and School of Medicine, Nanjing University, People's Republic of China.
authors.forename: Di
authors.initials: D
authors.lastname: Shen
authors.affiliation: State Key Laboratory of Pharmaceutical Biotechnology and MOE Key Laboratory of Model Animal for Disease Study, Model Animal Research Centre and School of Medicine, Nanjing University, People's Republic of China.
authors.forename: Wen-Jun
authors.initials: WJ
authors.lastname: Jia
authors.affiliation: Key Laboratory of Human Functional Genomics of Jiangsu Province, Nanjing Medical University, People's Republic of China.
authors.forename: Xiao
authors.initials: X
authors.lastname: Han
authors.affiliation: State Key Laboratory of Pharmaceutical Biotechnology and MOE Key Laboratory of Model Animal for Disease Study, Model Animal Research Centre and School of Medicine, Nanjing University, People's Republic of China.
authors.forename: Ning
authors.initials: N
authors.lastname: Shen
authors.affiliation: State Key Laboratory of Pharmaceutical Biotechnology and MOE Key Laboratory of Model Animal for Disease Study, Model Animal Research Centre and School of Medicine, Nanjing University, People's Republic of China.
authors.forename: Weiwei
authors.initials: W
authors.lastname: Tao
authors.affiliation: State Key Laboratory of Pharmaceutical Biotechnology and MOE Key Laboratory of Model Animal for Disease Study, Model Animal Research Centre and School of Medicine, Nanjing University, People's Republic of China.
authors.forename: Xiang
authors.initials: X
authors.lastname: Gao
authors.affiliation: State Key Laboratory of Pharmaceutical Biotechnology and MOE Key Laboratory of Model Animal for Disease Study, Model Animal Research Centre and School of Medicine, Nanjing University, People's Republic of China.
authors.forename: Bin
authors.initials: B
authors.lastname: Xue
authors.affiliation: State Key Laboratory of Pharmaceutical Biotechnology and MOE Key Laboratory of Model Animal for Disease Study, Model Animal Research Centre and School of Medicine, Nanjing University, People's Republic of China.
authors.forename: Chao-Jun
authors.initials: CJ
authors.lastname: Li
mesh_terms: D000818:Animals; D001402:B-Lymphocytes / Q000378:metabolism*; D015153:Blotting, Western; D003924:Diabetes Mellitus, Type 2 / Q000378:metabolism*; D051231:Farnesyltranstransferase / Q000378:metabolism*; D047468:Immunoprecipitation; D007328:Insulin / Q000378:metabolism*; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D046529:Microscopy, Electron, Transmission; D009097:Multienzyme Complexes / Q000378:metabolism*; D017368:Protein Prenylation / Q000502:physiology; D034741:RNA, Small Interfering; D060888:Real-Time Polymerase Chain Reaction; D022142:Secretory Vesicles / Q000378:metabolism / Q000648:ultrastructure; D014162:Transfection; D020691:rab GTP-Binding Proteins / Q000378:metabolism*; D000075745:rab27 GTP-Binding Proteins
chemical_list: C495428:Ggps1 protein, mouse; D007328:Insulin; D009097:Multienzyme Complexes; D034741:RNA, Small Interfering; D000075745:rab27 GTP-Binding Proteins; D051231:Farnesyltranstransferase; C512962:Rab27a protein, mouse; D020691:rab GTP-Binding Proteins
keywords: GGPPS; Rab27A; docked pool; insulin secretion; protein geranylgeranylation