title: SAD-A potentiates glucose-stimulated insulin secretion as a mediator of glucagon-like peptide 1 response in pancreatic β cells.
abstract: 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.
authors: Key Laboratory of Human Functional Genomics of Jiangsu Province, Nanjing Medical University, Nanjing, China.
authors: Jia
authors: J
authors: Nie
authors: Brendan N
authors: BN
authors: Lilley
authors: Y Albert
authors: YA
authors: Pan
authors: Omar
authors: O
authors: Faruque
authors: Xiaolei
authors: X
authors: Liu
authors: Weiping
authors: W
authors: Zhang
authors: Joshua R
authors: JR
authors: Sanes
authors: Xiao
authors: X
authors: Han
authors: Yuguang
authors: Y
authors: Shi
mesh_terms: D000818:Animals; D002118:Calcium / Q000378:metabolism; D002460:Cell Line; D000242:Cyclic AMP / Q000378:metabolism / Q000494:pharmacology; D052216:Glucagon-Like Peptide 1 / Q000378:metabolism*; D005947:Glucose / Q000378:metabolism* / Q000494:pharmacology; D018149:Glucose Intolerance / Q000235:genetics; D054795:Incretins / Q000378:metabolism; D007328:Insulin / Q000378:metabolism*; D000078790:Insulin Secretion; D007515:Islets of Langerhans / Q000187:drug effects / Q000378:metabolism*; D051379:Mice; D008810:Mice, Inbred C57BL; D008817:Mice, Mutant Strains; D008822:Mice, Transgenic; D010179:Pancreas / Q000378:metabolism / Q000503:physiopathology; D010766:Phosphorylation; D017346:Protein Serine-Threonine Kinases / Q000235:genetics / Q000378:metabolism*; D013912:Threonine / Q000378:metabolism
chemical_list: D054795:Incretins; D007328:Insulin; D013912:Threonine; D052216:Glucagon-Like Peptide 1; D000242:Cyclic AMP; C496825:Brsk2 protein, mouse; D017346:Protein Serine-Threonine Kinases; D005947:Glucose; D002118:Calcium
references: Proc Natl Acad Sci U S A. 2007 Mar 27;104(13):5680-5
references: 17372192
references: J Clin Endocrinol Metab. 2005 Nov;90(11):5991-7
references: 16144950
references: Diabetes. 2010 Jan;59(1):287-92
references: 19808892
references: Am J Physiol Endocrinol Metab. 2011 Nov;301(5):E797-806
references: 21750265
references: Annu Rev Pharmacol Toxicol. 2012;52:381-400
references: 22017684
references: J Cell Sci. 2010 Jan 15;123(Pt 2):286-94
references: 20026642
references: Proc Natl Acad Sci U S A. 2007 Feb 20;104(8):2979-84
references: 17301223
references: Am J Physiol Endocrinol Metab. 2010 Jun;298(6):E1261-73
references: 20354156
references: Diabetes. 2002 Dec;51 Suppl 3:S389-93
references: 12475781
references: Nature. 1998 Sep 10;395(6698):194-8
references: 9744280
references: J Biol Chem. 2007 Apr 6;282(14):10341-51
references: 17287212
references: Biochemistry. 2008 Apr 1;47(13):4151-9
references: 18324781
references: Diabetes. 2002 Feb;51 Suppl 1:S68-73
references: 11815461
references: Science. 2005 Feb 11;307(5711):929-32
references: 15705853
references: J Endocrinol. 2007 Mar;192(3):605-14
references: 17332528
references: J Clin Invest. 2011 Jun;121(6):2118-25
references: 21633180
references: Nat Rev Endocrinol. 2010 Feb;6(2):102-9
references: 20098450
references: J Clin Invest. 2007 Oct;117(10):2860-8
references: 17909627
references: Cell Metab. 2009 Oct;10(4):285-95
references: 19808021
references: Biochem Biophys Res Commun. 2006 Sep 8;347(4):867-71
references: 16870137
references: Cell Metab. 2008 Jul;8(1):26-37
references: 18590690
references: Cell Metab. 2006 Mar;3(3):153-65
references: 16517403
references: Nat Cell Biol. 2009 Sep;11(9):1081-92
references: 19648910
references: Nat Cell Biol. 2000 Nov;2(11):805-11
references: 11056535
references: Cell Metab. 2009 Oct;10(4):296-308
references: 19808022
references: Diabetes. 2002 Dec;51 Suppl 3:S434-42
references: 12475787
references: J Biol Chem. 2012 Jul 27;287(31):26435-44
references: 22669945
references: Annu Rev Biochem. 2006;75:137-63
references: 16756488
references: Diabetes. 1966 Aug;15(8):555-9
references: 5912065
references: Diabetes. 2009 Mar;58(3):663-72
references: 19073772
references: Proc Natl Acad Sci U S A. 2011 Oct 11;108(41):16876-82
references: 21949366
references: J Biol Chem. 1999 Nov 12;274(46):32565-73
references: 10551809
references: Diabetes. 2010 Dec;59(12):3090-8
references: 20802254
references: Neuron. 2006 Apr 20;50(2):261-75
references: 16630837
references: Mol Cell Biol. 2010 Nov;30(21):5043-56
references: 20733003
references: J Clin Invest. 2006 Jul;116(7):1802-12
references: 16823478
references: Proc Natl Acad Sci U S A. 2007 Dec 4;104(49):19333-8
references: 18040047
references: J Biol Chem. 2012 Nov 2;287(45):38305-15
references: 22992738
references: Diabetologia. 1996 May;39(5):594-9
references: 8739920
references: Cell. 2007 May 4;129(3):549-63
references: 17482548