title: LKB1 and AMPKα1 are required in pancreatic alpha cells for the normal regulation of glucagon secretion and responses to hypoglycemia.
abstract: OBJECTIVE
  Glucagon release from pancreatic alpha cells is required for normal glucose homoeostasis and is dysregulated in both Type 1 and Type 2 diabetes. The tumour suppressor LKB1 (STK11) and the downstream kinase AMP-activated protein kinase (AMPK), modulate cellular metabolism and growth, and AMPK is an important target of the anti-hyperglycaemic agent metformin. While LKB1 and AMPK have emerged recently as regulators of beta cell mass and insulin secretion, the role of these enzymes in the control of glucagon production in vivo is unclear.
  
  
  METHODS
  Here, we ablated LKB1 (αLKB1KO), or the catalytic alpha subunits of AMPK (αAMPKdKO, -α1KO, -α2KO), selectively in ∼45% of alpha cells in mice by deleting the corresponding flox'd alleles with a preproglucagon promoter (PPG) Cre.
  
  
  RESULTS
  Blood glucose levels in male αLKB1KO mice were lower during intraperitoneal glucose, aminoimidazole carboxamide ribonucleotide (AICAR) or arginine tolerance tests, and glucose infusion rates were increased in hypoglycemic clamps (p < 0.01). αLKB1KO mice also displayed impaired hypoglycemia-induced glucagon release. Glucose infusion rates were also elevated (p < 0.001) in αAMPKα1 null mice, and hypoglycemia-induced plasma glucagon increases tended to be lower (p = 0.06). Glucagon secretion from isolated islets was sensitized to the inhibitory action of glucose in αLKB1KO, αAMPKdKO, and -α1KO, but not -α2KO islets.
  
  
  CONCLUSIONS
  An LKB1-dependent signalling cassette, involving but not restricted to AMPKα1, is required in pancreatic alpha cells for the control of glucagon release by glucose.
authors.affiliation: Section of Cell Biology and Functional Genomics, Division of Diabetes, Endocrinology and Metabolism, Department of Medicine, Imperial College London, London, UK.
authors.forename: Gao
authors.initials: G
authors.lastname: Sun
authors.affiliation: Section of Cell Biology and Functional Genomics, Division of Diabetes, Endocrinology and Metabolism, Department of Medicine, Imperial College London, London, UK.
authors.forename: Gabriela
authors.initials: G
authors.lastname: da Silva Xavier
authors.affiliation: AstraZeneca, Alderley Edge, Cheshire, UK.
authors.forename: Tracy
authors.initials: T
authors.lastname: Gorman
authors.affiliation: AstraZeneca, Alderley Edge, Cheshire, UK.
authors.forename: Claire
authors.initials: C
authors.lastname: Priest
authors.affiliation: Section of Cell Biology and Functional Genomics, Division of Diabetes, Endocrinology and Metabolism, Department of Medicine, Imperial College London, London, UK.
authors.forename: Antonia
authors.initials: A
authors.lastname: Solomou
authors.affiliation: Section of Cell Biology and Functional Genomics, Division of Diabetes, Endocrinology and Metabolism, Department of Medicine, Imperial College London, London, UK.
authors.forename: David J
authors.initials: DJ
authors.lastname: Hodson
authors.affiliation: Inserm, U1016, Institut Cochin, Paris, France ; CNRS, UMR8104, Paris, France ; Université Paris Descartes, Sorbonne Paris cité, Paris, France.
authors.forename: Marc
authors.initials: M
authors.lastname: Foretz
authors.affiliation: Inserm, U1016, Institut Cochin, Paris, France ; CNRS, UMR8104, Paris, France ; Université Paris Descartes, Sorbonne Paris cité, Paris, France.
authors.forename: Benoit
authors.initials: B
authors.lastname: Viollet
authors.affiliation: Department of Genetic Medicine & Development, Faculty of Medicine, University of Geneva, Geneva, Switzerland.
authors.forename: Pedro-Luis
authors.initials: PL
authors.lastname: Herrera
authors.affiliation: Cambridge Institute for Medical Research, Addenbrooke's Hospital, Cambridge, UK.
authors.forename: Helen
authors.initials: H
authors.lastname: Parker
authors.affiliation: Cambridge Institute for Medical Research, Addenbrooke's Hospital, Cambridge, UK.
authors.forename: Frank
authors.initials: F
authors.lastname: Reimann
authors.affiliation: Cambridge Institute for Medical Research, Addenbrooke's Hospital, Cambridge, UK.
authors.forename: Fiona M
authors.initials: FM
authors.lastname: Gribble
authors.affiliation: University Paris Diderot-Paris 7-Unit of Functional and Adaptive Biology (BFA) EAC 7059C NRS, France.
authors.forename: Stephanie
authors.initials: S
authors.lastname: Migrenne
authors.affiliation: University Paris Diderot-Paris 7-Unit of Functional and Adaptive Biology (BFA) EAC 7059C NRS, France.
authors.forename: Christophe
authors.initials: C
authors.lastname: Magnan
authors.affiliation: AstraZeneca, Alderley Edge, Cheshire, UK.
authors.forename: Anna
authors.initials: A
authors.lastname: Marley
authors.affiliation: Section of Cell Biology and Functional Genomics, Division of Diabetes, Endocrinology and Metabolism, Department of Medicine, Imperial College London, London, UK.
authors.forename: Guy A
authors.initials: GA
authors.lastname: Rutter
keywords: AICAR, aminoimidazole carboxamide ribonucleotide; AMPK; AMPK, AMP-activated protein kinase; Alpha cell; Glucagon secretion; Knockout; LKB1; LKB1, liver kinase B1; PPG; PPG, preproglucagon promoter; T2D, Type 2 diabetes
references.citation: Diabetes. 2011 Feb;60(2):391-7
references.pmid: 21270251
references.citation: Diabetes. 2006 Feb;55(2):390-7
references.pmid: 16443772
references.citation: Biochem J. 2003 May 1;371(Pt 3):761-74
references.pmid: 12589707
references.citation: Biochem Pharmacol. 2004 Aug 1;68(3):409-16
references.pmid: 15242807
references.citation: Diabetologia. 2007 Feb;50(2):370-9
references.pmid: 17136393
references.citation: Nat Cell Biol. 2014 Mar;16(3):234-44
references.pmid: 24561619
references.citation: Diabetes. 2005 Jun;54(6):1789-97
references.pmid: 15919801
references.citation: J Physiol. 2000 Nov 1;528(Pt 3):509-20
references.pmid: 11060128
references.citation: Diabetologia. 2012 Sep;55(9):2445-55
references.pmid: 22638549
references.citation: Annu Rev Physiol. 1992;54:847-60
references.pmid: 1562194
references.citation: Diabetes. 2010 Dec;59(12):3090-8
references.pmid: 20802254
references.citation: Am J Physiol Endocrinol Metab. 2010 Jun;298(6):E1261-73
references.pmid: 20354156
references.citation: Cell Metab. 2005 Jul;2(1):21-33
references.pmid: 16054096
references.citation: EMBO J. 2004 Feb 25;23(4):833-43
references.pmid: 14976552
references.citation: Cell Metab. 2009 Oct;10(4):285-95
references.pmid: 19808021
references.citation: Nature. 2002 Sep 12;419(6903):162-7
references.pmid: 12226664
references.citation: Development. 2000 Jun;127(11):2317-22
references.pmid: 10804174
references.citation: Diabetes. 2007 Feb;56(2):320-7
references.pmid: 17259375
references.citation: J Clin Invest. 2006 Jul;116(7):1776-83
references.pmid: 16823475
references.citation: Diabetologia. 2007 Jan;50(1):142-50
references.pmid: 17131145
references.citation: Diabetes. 2010 Sep;59(9):2198-208
references.pmid: 20547976
references.citation: Am J Physiol. 1999 Aug;277(2):E283-90
references.pmid: 10444424
references.citation: J Biol Chem. 2006 Sep 1;281(35):25336-43
references.pmid: 16835226
references.citation: Cell Metab. 2009 Oct;10(4):296-308
references.pmid: 19808022
references.citation: Proc Natl Acad Sci U S A. 2000 Apr 11;97(8):4023-8
references.pmid: 10760274
references.citation: Endocr Rev. 2007 Feb;28(1):84-116
references.pmid: 17261637
references.citation: Nat Cell Biol. 2003 Apr;5(4):330-5
references.pmid: 12640462
references.citation: Nutr Rev. 1997 Feb;55(2):31-43
references.pmid: 9155216
references.citation: Nature. 1998 Jan 8;391(6663):184-7
references.pmid: 9428765
references.citation: Endocrinology. 1974 Oct;95(4):1005-10
references.pmid: 4413179
references.citation: J Clin Invest. 1970 Apr;49(4):837-48
references.pmid: 4986215
references.citation: Diabetes. 2011 Nov;60(11):2872-82
references.pmid: 21926270
references.citation: Diabetologia. 2011 Jan;54(1):125-34
references.pmid: 20938634
references.citation: Mol Biol Cell. 2005 Jun;16(6):2670-80
references.pmid: 15788565
references.citation: FEBS Lett. 2007 Sep 4;581(22):4235-40
references.pmid: 17706201
references.citation: Endocrinology. 1991 Nov;129(5):2521-9
references.pmid: 1682137
references.citation: Endocrinology. 1987 Jul;121(1):323-31
references.pmid: 3297643
references.citation: Diabetes. 2005 Jun;54(6):1808-15
references.pmid: 15919803
references.citation: Biochem J. 2010 Jul 15;429(2):323-33
references.pmid: 20465544
references.citation: Diabetes. 2005 May;54(5):1331-9
references.pmid: 15855317
references.citation: Diabetes Nutr Metab. 2002 Oct;15(5):330-3; discussion 362
references.pmid: 12625480
references.citation: Cell Calcium. 2004 Apr;35(4):357-65
references.pmid: 15036952
references.citation: Dis Model Mech. 2014 Nov;7(11):1275-86
references.pmid: 25190708
references.citation: Nat Rev Mol Cell Biol. 2007 Oct;8(10):774-85
references.pmid: 17712357
references.citation: Diabetes. 1998 Jul;47(7):995-1005
references.pmid: 9648820
references.citation: Cell Metab. 2005 Jul;2(1):9-19
references.pmid: 16054095
references.citation: Nature. 2011 Apr 14;472(7342):230-3
references.pmid: 21399626
references.citation: Cell Metab. 2009 Apr;9(4):350-61
references.pmid: 19356716
references.citation: Am J Physiol Endocrinol Metab. 2003 Apr;284(4):E671-8
references.pmid: 12626323
references.citation: Diabetes. 2009 Feb;58(2):299-301
references.pmid: 19171745
references.citation: FASEB J. 2010 Dec;24(12):5080-91
references.pmid: 20724523
references.citation: Cell Mol Life Sci. 2015 Feb;72(3):453-467
references.pmid: 25323131
references.citation: J Clin Invest. 2003 Jan;111(1):91-8
references.pmid: 12511592
references.citation: Diabetologia. 2010 May;53(5):924-36
references.pmid: 20221584
references.citation: Trends Mol Med. 2007 Jun;13(6):252-9
references.pmid: 17452018