title: APPL1 potentiates insulin secretion in pancreatic β cells by enhancing protein kinase Akt-dependent expression of SNARE proteins in mice.
abstract: Insulin resistance and defective insulin secretion are the two major features of type 2 diabetes. The adapter protein APPL1 is an obligatory molecule in regulating peripheral insulin sensitivity, but its role in insulin secretion remains elusive. Here, we show that APPL1 expression in pancreatic β cells is markedly decreased in several mouse models of obesity and diabetes. APPL1 knockout mice exhibit glucose intolerance and impaired glucose-stimulated insulin secretion (GSIS), whereas transgenic expression of APPL1 prevents high-fat diet (HFD)-induced glucose intolerance partly by enhancing GSIS. In both pancreatic islets and rat β cells, APPL1 deficiency causes a marked reduction in expression of the exocytotic machinery SNARE proteins (syntaxin-1, synaptosomal-associated protein 25, and vesicle-associated membrane protein 2) and an obvious decrease in the number of exocytotic events. Such changes are accompanied by diminished insulin-stimulated Akt activation. Furthermore, the defective GSIS and reduced expression of SNARE proteins in APPL1-deficient β cells can be rescued by adenovirus-mediated expression of APPL1 or constitutively active Akt. These findings demonstrate that APPL1 couples insulin-stimulated Akt activation to GSIS by promoting the expression of the core exocytotic machinery involved in exocytosis and also suggest that reduced APPL1 expression in pancreatic islets may serve as a pathological link that couples insulin resistance to β-cell dysfunction in type 2 diabetes.
authors.affiliation: Department of Medicine, The University of Hong Kong, Hong Kong, China.
authors.forename: Kenneth K Y
authors.initials: KK
authors.lastname: Cheng
authors.forename: Karen S L
authors.initials: KS
authors.lastname: Lam
authors.forename: Donghai
authors.initials: D
authors.lastname: Wu
authors.forename: Yu
authors.initials: Y
authors.lastname: Wang
authors.forename: Gary
authors.initials: G
authors.lastname: Sweeney
authors.forename: Ruby L C
authors.initials: RL
authors.lastname: Hoo
authors.forename: Jialiang
authors.initials: J
authors.lastname: Zhang
authors.forename: Aimin
authors.initials: A
authors.lastname: Xu
mesh_terms: D048868:Adaptor Proteins, Signal Transducing / Q000235:genetics / Q000378:metabolism*; D000818:Animals; D003924:Diabetes Mellitus, Type 2 / Q000378:metabolism*; D059305:Diet, High-Fat; D005786:Gene Expression Regulation / Q000235:genetics*; D007150:Immunohistochemistry; D047468:Immunoprecipitation; D007328:Insulin / Q000378:metabolism*; D000078790:Insulin Secretion; D050417:Insulin-Secreting Cells / Q000378:metabolism* / Q000648:ultrastructure; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008822:Mice, Transgenic; D008854:Microscopy, Electron; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism*; D051381:Rats; D060888:Real-Time Polymerase Chain Reaction; D050600:SNARE Proteins / Q000378:metabolism*
chemical_list: D048868:Adaptor Proteins, Signal Transducing; C510733:Appl1 protein, mouse; D007328:Insulin; D050600:SNARE Proteins; D051057:Proto-Oncogene Proteins c-akt