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 adenovirusmediated 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.

Dual functions of adaptor protein, phosphotyrosine interaction, PH domain and leucine zipper containing 1 (APPL1) in insulin signaling and insulin secretion

“…It has been proposed that the first phase of insulin secretion is supported by docked granules. Consistent with this model, the work by Cheng et al (5) finds that the number of docked granules is reduced in APPL1 KO β-cells.…”

“…As expected from significant studies, although the work by Cheng et al (5) shows the importance of a key regulator of insulin signaling in insulin secretion, it also raises a number of important unanswered questions (5). First, how does APPL1 regulate SNARE protein transcription and translation?…”

“…Indeed, insulin-stimulated Akt phosphorylation is impaired in APPL1 KO β-cells, whereas a parallel insulin-dependent ERK phosphorylation is not affected. The work by Cheng et al (5) then reasons that, if the effect of APPL1 is because of reduced Akt phosphorylation, then increasing Akt action should restore the defect in APPL1 KO mice. Therefore, the work by Cheng et al (5) expresses a constitutively active Akt in APPL1 KO islets and examines whether SNARE protein levels and GSIS could be restored.…”

“…In this study, Cheng et al (5) investigate the function of APPL1 in insulin secretion. Besides regulating Akt activation and determining substrate specificity (13), APPL1 interacts with adiponectin receptors and mediates the insulin-sensitizing effects of adiponectin in muscle and endothelial cells (14,15).…”

“…However, the molecular crosstalk between insulin signaling and insulin secretion remains poorly understood. In PNAS, the work by Cheng et al (5) describes that adaptor protein, phosphotyrosine interaction, PH domain and leucine zipper containing 1 (APPL1), a binding partner of Akt2 and a key regulator of insulin signaling, is involved in the regulation of insulin secretion.…”