Year: 2014
Type: article
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 ( Slc 16 a1, 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. FASEB J. 28, 4972–4985 (2014). www.fasebj.org
Source: The FASEB Journal
DOI: 10.1096/fj.14-257667
Authors: 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 Hildebrandt, Ingo Uphues, Guy A. Rutter
Language: English
Subfield: Surgery
Field: Medicine
Domain: Health Sciences
Open Access status: hybrid
Estimated APC paid: $3,740
Funders: Wellcome Trust, European Federation of Pharmaceutical Industries and Associations, International Seafood Sustainability Foundation, Diabetes Research and Wellness Foundation, Imperial College London, European Commission, Directorate for Biological Sciences, Medical Research Council, Biotechnology and Biological Sciences Research Council
Awards: G1073258374, G1093531541, G119964413, Understanding pancreatic beta cell dysfunction in diabetes., Roles of GWA genes in controlling pancreatic beta cell function and mass., G2040450235, G3207356259, Role of mitochondrial calcium transport in the regulation of insulin secretion, G3555667338, Understanding regulatory variation in human diabetes., G393177772, Targeting etiologic molecular mechanisms to treat human diabetes, G5702163051, Understanding regulatory variation in human diabetes., G7571465722, G8072012048, Enteroendocrine cell function in diabetes and obesity.
OpenAlex ID: W2136938986