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LKB1 deletion with the RIP2.Cre transgene modifies pancreatic β-cell morphology and enhances insulin secretion in vivo
- Source :
- American Journal of Physiology-Endocrinology and Metabolism
- Publication Year :
- 2010
- Publisher :
- American Physiological Society, 2010.
-
Abstract
- 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 β-cell and hypothalamic neurons using the rat insulin promoter (RIP2). Cre transgene (βAMPKdKO) diminishes insulin secretion in vivo, deletion of LKB1 in the β-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 β-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 βAMPKdKO mice, βLKB1KO 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 β-cell mass and the size of individual islets and β-cells were increased and islet architecture was markedly altered in βLKB1KO 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 Ca2+ were sharply reduced in βLKB1KO 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 β-cell function.
- Subjects :
- insulin secretion
food intake
Physiology
Endocrinology, Diabetes and Metabolism
AMP-Activated Protein Kinases
Cell morphology
Eating
Mice
0302 clinical medicine
AMP-activated protein kinase
Insulin-Secreting Cells
Insulin
Transgenes
pancreas
Mice, Knockout
0303 health sciences
biology
Reverse Transcriptase Polymerase Chain Reaction
Kinase
Articles
β-cell
Specific Pathogen-Free Organisms
Receptor-Interacting Protein Serine-Threonine Kinases
Signal transduction
Signal Transduction
medicine.medical_specialty
Blotting, Western
STK11
Mice, Transgenic
030209 endocrinology & metabolism
Protein Serine-Threonine Kinases
03 medical and health sciences
Receptor-Interacting Protein Serine-Threonine Kinase 2
Physiology (medical)
Internal medicine
medicine
Animals
Protein kinase A
030304 developmental biology
Body Weight
AMPK
Glucose Tolerance Test
liver kinase B1
Mice, Inbred C57BL
Insulin receptor
Endocrinology
Diabetes Mellitus, Type 2
Microscopy, Fluorescence
biology.protein
RNA
Subjects
Details
- ISSN :
- 15221555 and 01931849
- Volume :
- 298
- Database :
- OpenAIRE
- Journal :
- American Journal of Physiology-Endocrinology and Metabolism
- Accession number :
- edsair.doi.dedup.....0236b3d848bae0d883630b75e9bffb44
- Full Text :
- https://doi.org/10.1152/ajpendo.00100.2010