LKB1 and AMPK differentially regulate pancreatic β-cell identity

Marina Kone, Timothy J. Pullen, Gao Sun, Mark Ibberson, Aida Martinez-Sanchez, Sophie Sayers, Marie Sophie Nguyen-Tu, Chase Kantor, Avital Swisa, Yuval Dor, Tracy Gorman, Jorge Ferrer, Bernard Thorens, Frank Reimann, Fiona Gribble, James A. McGinty, Lingling Chen, Paul M. French, Fabian Birzele, Tobias HildebrandtIngo Uphues, Guy A. Rutter*

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

65 Scopus citations

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.-Kone, M., Pullen, T. J., Sun, G., Ibberson, M., Martinez-Sanchez, A., Sayers, S., Nguyen-Tu, M.-S., Kantor, C., Swisa, A., Dor, Y., Gorman, T., Ferrer, J., Thorens, B., Reimann, F., Gribble, F., McGinty, J. A., Chen, L., French, P. M., Birzele, F., Hildebrandt, T., Uphues, I., Rutter, G. A. LKB1 and AMPK differentially regulate pancreatic β-cell identity.

Original languageAmerican English
Pages (from-to)4972-4985
Number of pages14
JournalFASEB Journal
Volume28
Issue number11
DOIs
StatePublished - 1 Nov 2014

Bibliographical note

Publisher Copyright:
© FASEB.

Keywords

  • Diabetes
  • Insulin secretion
  • Islet
  • RNASeq

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