| First Author | Cheng KK | Year | 2012 |
| Journal | Proc Natl Acad Sci U S A | Volume | 109 |
| Issue | 23 | Pages | 8919-24 |
| PubMed ID | 22566644 | Mgi Jnum | J:184770 |
| Mgi Id | MGI:5426301 | Doi | 10.1073/pnas.1202435109 |
| Citation | Cheng KK, et al. (2012) APPL1 potentiates insulin secretion in pancreatic beta cells by enhancing protein kinase Akt-dependent expression of SNARE proteins in mice. Proc Natl Acad Sci U S A 109(23):8919-24 |
| abstractText | 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 beta 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 beta 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 beta 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 beta-cell dysfunction in type 2 diabetes. |
