SAD-A potentiates glucose-stimulated insulin secretion as a mediator of glucagon-like peptide 1 response in pancreatic β cells

Mol Cell Biol. 2013 Jul;33(13):2527-34. doi: 10.1128/MCB.00285-13. Epub 2013 Apr 29.


Type 2 diabetes is characterized by defective glucose-stimulated insulin secretion (GSIS) from pancreatic β 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 pancreas and 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)/Ca(2+)-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.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Calcium / metabolism
  • Cell Line
  • Cyclic AMP / metabolism
  • Cyclic AMP / pharmacology
  • Glucagon-Like Peptide 1 / metabolism*
  • Glucose / metabolism*
  • Glucose / pharmacology
  • Glucose Intolerance / genetics
  • Incretins / metabolism
  • Insulin / metabolism*
  • Insulin Secretion
  • Islets of Langerhans / drug effects
  • Islets of Langerhans / metabolism*
  • Mice
  • Mice, Inbred C57BL
  • Mice, Mutant Strains
  • Mice, Transgenic
  • Pancreas / metabolism
  • Pancreas / physiopathology
  • Phosphorylation
  • Protein Serine-Threonine Kinases / genetics
  • Protein Serine-Threonine Kinases / metabolism*
  • Threonine / metabolism


  • Incretins
  • Insulin
  • Threonine
  • Glucagon-Like Peptide 1
  • Cyclic AMP
  • Brsk2 protein, mouse
  • Protein Serine-Threonine Kinases
  • Glucose
  • Calcium