SAD-A Potentiates Glucose-Stimulated Insulin Secretion as a Mediator of Glucagon-Like Peptide 1 Response in Pancreatic β Cells

Jia Nie, Brendan N. Lilley, Y. Albert Pan, Omar Faruque, Xiaolei Liu, Weiping Zhang, Joshua R. Sanes, Xiao Han

Research output: Contribution to journalArticle

19 Scopus citations

Abstract

Type 2 diabetes is characterized by defective glucose-stimulated insulin secretion (GSIS) from pancreatic cells, which can be restored by glucagon-like peptide 1 (GLP-1), an incretin hormone commonly used for the treatment of type 2 diabetes. However, molecular mechanisms by which GLP-1 affects glucose responsiveness in islet β cells remain poorly understood. Here we investigated a role of SAD-A, an AMP-activated protein kinase (AMPK)-related kinase, in regulating GSIS in mice with conditional SAD-A deletion. We show that selective deletion of SAD-A in pancreas impaired incretin's effect on GSIS, leading to glucose intolerance. Conversely, overexpression of SAD-A significantly enhanced GSIS and further potentiated GLP-1's effect on GSIS from isolated mouse islets. In support of SAD-A as a mediator of incretin response, SAD-A is expressed exclusively in pancreasand brain, the primary targeting tissues of GLP-1 action. Additionally, SAD-A kinase is activated in response to stimulation by GLP-1 through cyclic AMP (cAMP)/Ca2+dependent signaling pathways in islet β cells. Furthermore, we identified Thr443 as a key autoinhibitory phosphorylation site which mediates SAD-A's effect on incretin response in islet β cells. Consequently, ablation of Thr443 significantly enhanced GLP-1's effect on GSIS from isolated mouse islets. Together, these findings identified SAD-A kinase as a pancreas-specific mediator of incretin response in islet β cells.

Original languageEnglish (US)
Pages (from-to)2527-2534
Number of pages8
JournalMolecular and Cellular Biology
Volume33
Issue number13
DOIs
StatePublished - Jul 1 2013

ASJC Scopus subject areas

  • Molecular Biology
  • Cell Biology

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