title: LKB1 and AMPK differentially regulate pancreatic β-cell identity.
abstract: Fully differentiated pancreatic β cells are essential for normal glucose homeostasis in mammals. Dedifferentiation of these cells has been suggested to occur in type 2 diabetes, impairing insulin production. Since chronic fuel excess ("glucotoxicity") is implicated in this process, we sought here to identify the potential roles in β-cell identity of the tumor suppressor liver kinase B1 (LKB1/STK11) and the downstream fuel-sensitive kinase, AMP-activated protein kinase (AMPK). Highly β-cell-restricted deletion of each kinase in mice, using an Ins1-controlled Cre, was therefore followed by physiological, morphometric, and massive parallel sequencing analysis. Loss of LKB1 strikingly (2.0-12-fold, E<0.01) increased the expression of subsets of hepatic (Alb, Iyd, Elovl2) and neuronal (Nptx2, Dlgap2, Cartpt, Pdyn) genes, enhancing glutamate signaling. These changes were partially recapitulated by the loss of AMPK, which also up-regulated β-cell "disallowed" genes (Slc16a1, Ldha, Mgst1, Pdgfra) 1.8- to 3.4-fold (E < 0.01). Correspondingly, targeted promoters were enriched for neuronal (Zfp206; P = 1.3 × 10(-33)) and hypoxia-regulated (HIF1; P = 2.5 × 10(-16)) transcription factors. In summary, LKB1 and AMPK, through only partly overlapping mechanisms, maintain β-cell identity by suppressing alternate pathways leading to neuronal, hepatic, and other characteristics. Selective targeting of these enzymes may provide a new approach to maintaining β-cell function in some forms of diabetes.
authors: Section of Cell Biology and.
authors: Marina
authors: M
authors: Kone
authors: Section of Cell Biology and.
authors: Timothy J
authors: TJ
authors: Pullen
authors: Section of Cell Biology and.
authors: Gao
authors: G
authors: Sun
authors: Swiss Institute of Bioinformatics and.
authors: Mark
authors: M
authors: Ibberson
authors: Section of Cell Biology and.
authors: Aida
authors: A
authors: Martinez-Sanchez
authors: Section of Cell Biology and.
authors: Sophie
authors: S
authors: Sayers
authors: Section of Cell Biology and.
authors: Marie-Sophie
authors: MS
authors: Nguyen-Tu
authors: Section of Cell Biology and.
authors: Chase
authors: C
authors: Kantor
authors: Department of Developmental Biology and Cancer Research, Institute for Medical Research Israel-Canada, Hebrew University-Hadassah Medical School, Jerusalem, Israel;
authors: Avital
authors: A
authors: Swisa
authors: Department of Developmental Biology and Cancer Research, Institute for Medical Research Israel-Canada, Hebrew University-Hadassah Medical School, Jerusalem, Israel;
authors: Yuval
authors: Y
authors: Dor
authors: AstraZeneca Diabetes and Obesity Drug Discovery, Alderley Edge, UK;
authors: Tracy
authors: T
authors: Gorman
authors: Section of β-Cell Development, Division of Diabetes, Endocrinology, and Metabolism, Department of Medicine, and.
authors: Jorge
authors: J
authors: Ferrer
authors: Center for Integrative Genomics, University of Lausanne, Lausanne, Switzerland;
authors: Bernard
authors: B
authors: Thorens
authors: Metabolic Research Laboratories, University of Cambridge, Cambridge, UK and.
authors: Frank
authors: F
authors: Reimann
authors: Metabolic Research Laboratories, University of Cambridge, Cambridge, UK and.
authors: Fiona
authors: F
authors: Gribble
authors: Photonics Group, Department of Physics, Imperial College London, London, UK;
authors: James A
authors: JA
authors: McGinty
authors: Photonics Group, Department of Physics, Imperial College London, London, UK;
authors: Lingling
authors: L
authors: Chen
authors: Photonics Group, Department of Physics, Imperial College London, London, UK;
authors: Paul M
authors: PM
authors: French
authors: Boehringer Ingelheim Pharma, Ingelheim, Germany.
authors: Fabian
authors: F
authors: Birzele
authors: Boehringer Ingelheim Pharma, Ingelheim, Germany.
authors: Tobias
authors: T
authors: Hildebrandt
authors: Boehringer Ingelheim Pharma, Ingelheim, Germany.
authors: Ingo
authors: I
authors: Uphues
authors: Section of Cell Biology and g.rutter@imperial.ac.uk.
authors: Guy A
authors: GA
authors: Rutter
mesh_terms: D055372:AMP-Activated Protein Kinases / Q000378:metabolism*; D000818:Animals; D003924:Diabetes Mellitus, Type 2 / Q000378:metabolism; D007328:Insulin / Q000378:metabolism*; D050417:Insulin-Secreting Cells / Q000201:enzymology*; D008810:Mice, Inbred C57BL; D017346:Protein Serine-Threonine Kinases / Q000378:metabolism*; D015398:Signal Transduction / Q000502:physiology
chemical_list: D007328:Insulin; D017346:Protein Serine-Threonine Kinases; C491654:Stk11 protein, mouse; D055372:AMP-Activated Protein Kinases
keywords: RNASeq; diabetes; insulin secretion; islet