LKB1 deletion with the RIP2.Cre transgene modifies pancreatic beta-cell morphology and enhances insulin secretion in vivo.
The tumor suppressor liver kinase B1 (LKB1), also called STK11, is a protein kinase mutated in Peutz-Jeghers syndrome. LKB1 phosphorylates AMP-activated protein kinase (AMPK) and several related protein kinases. Whereas deletion of both catalytic isoforms of AMPK from the pancreatic beta-cell and hypothalamic neurons using the rat insulin promoter (RIP2).Cre transgene (betaAMPKdKO) diminishes insulin secretion in vivo, deletion of LKB1 in the beta-cell with an inducible Pdx-1.CreER transgene enhances insulin secretion in mice. To determine whether the differences between these models reflect genuinely distinct roles for the two kinases in the beta-cell or simply differences in the timing and site(s) of deletion, we have therefore created mice deleted for LKB1 with the RIP2.Cre transgene. In marked contrast to betaAMPKdKO mice, betaLKB1KO mice showed diminished food intake and weight gain, enhanced insulin secretion, unchanged insulin sensitivity, and improved glucose tolerance. In line with the phenotype of Pdx1-CreER mice, total beta-cell mass and the size of individual islets and beta-cells were increased and islet architecture was markedly altered in betaLKB1KO islets. Signaling by mammalian target of rapamycin (mTOR) to eIF4-binding protein-1 and ribosomal S6 kinase was also enhanced. In contrast to Pdx1-CreER-mediated deletion, the expression of Glut2, glucose-induced changes in membrane potential and intracellular Ca(2+) were sharply reduced in betaLKB1KO mouse islets and the stimulation of insulin secretion was modestly inhibited. We conclude that LKB1 and AMPK play distinct roles in the control of insulin secretion and that the timing of LKB1 deletion, and/or its loss from extrapancreatic sites, influences the final impact on beta-cell function.
Sun
Gao
G
Division of Diabetes, Endocrinology and Metabolism, Department of Medicine, Imperial College London, London, UK.
Tarasov
Andrei I
AI
McGinty
James A
JA
French
Paul M
PM
McDonald
Angela
A
Leclerc
Isabelle
I
Rutter
Guy A
GA
D055372:AMP-Activated Protein Kinases / Q000378:metabolism; D000818:Animals; D015153:Blotting, Western; D001835:Body Weight / Q000502:physiology; D003924:Diabetes Mellitus, Type 2 / Q000201:enzymology / Q000235:genetics / Q000378:metabolism*; D004435:Eating / Q000502:physiology; D005951:Glucose Tolerance Test; D007328:Insulin / Q000097:blood / Q000378:metabolism*; D000078790:Insulin Secretion; D050417:Insulin-Secreting Cells / Q000201:enzymology / Q000378:metabolism* / Q000648:ultrastructure; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008822:Mice, Transgenic; D008856:Microscopy, Fluorescence; D017346:Protein Serine-Threonine Kinases / Q000172:deficiency* / Q000235:genetics / Q000378:metabolism; D012313:RNA; D053475:Receptor-Interacting Protein Serine-Threonine Kinase 2; D053422:Receptor-Interacting Protein Serine-Threonine Kinases / Q000235:genetics; D020133:Reverse Transcriptase Polymerase Chain Reaction; D015398:Signal Transduction; D013047:Specific Pathogen-Free Organisms; D019076:Transgenes
D007328:Insulin; D012313:RNA; D017346:Protein Serine-Threonine Kinases; D053475:Receptor-Interacting Protein Serine-Threonine Kinase 2; D053422:Receptor-Interacting Protein Serine-Threonine Kinases; C506255:Ripk2 protein, mouse; C491654:Stk11 protein, mouse; D055372:AMP-Activated Protein Kinases