APPL1 potentiates insulin secretion in pancreatic [Beta] cells by enhancing protein kinase Akt-dependent expression of SNARE proteins in mice

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 c...

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Bibliographic Details
Published in:Proceedings of the National Academy of Sciences - PNAS 2012-06, Vol.109 (23), p.8919
Main Authors: Cheng, Kenneth K Y, Lam, Karen S L, Wu, Donghai, Wang, Yu, Sweeney, Gary, Hoo, Ruby L C, Zhang, Jialiang, Xu, Aimin
Format: Article
Language:English
Subjects:
Cells
Diabetes
Glucose
Insulin resistance
Obesity
Rodents
Online Access:Get full text
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Summary: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. [PUBLICATION ABSTRACT]
ISSN:0027-8424
1091-6490