Long-term treatment with novel glycogen synthase kinase-3 inhibitor improves glucose homeostasis in ob/ob mice: molecular characterization in liver and muscle.
Glycogen synthase kinase-3 (GSK-3) is critically involved in insulin signaling, and its selective inhibition may present a new therapy for treatment of insulin resistance and type 2 diabetes. The current studies were designed to examine the impact of long-term in vivo inhibition of GSK-3 and its effects in the specific tissues. ob/ob mice were treated daily with one dose (400 nmol, i.p.) of a selective GSK-3 peptide inhibitor, L803-mts, for 3 weeks. Treatment with L803-mts reduced blood glucose levels, improved glucose tolerance, and prevented elevation of hyperglycemia with age. However, L803-mts did not affect either body weight or food consumption and was not toxic, as judged by histopathology and blood chemistry analyses. Consistent with these results, L803-mts suppressed mRNA levels of hepatic phosphoenolpyruvate carboxykinase (PEPCK) (50%) and increased hepatic glycogen content by 50%. On the other hand, L803-mts did not affect glucose 6-phosphate (G-6-P) phosphatase (G-6-Pase) mRNA levels or its enzymatic activity in the liver. Investigation for possible mechanisms responsible for PEPCK suppression indicated that phosphorylation of cAMP-responsive element transcription factor (CREB) at Ser(133) was reduced remarkably by L803-mts, which was also associated with reduced phosphorylation at Ser(129) and no change in total CREB. This suggested that PEPCK was suppressed by GSK-3 inhibition-mediated inactivation of CREB. In skeletal muscle, treatment with L803-mts led both to up-regulation in GLUT4 expression and to a 20% increase in glycogen content. Our studies show that long-term treatment with GSK-3 inhibitor improves glucose homeostasis in ob/ob mice and demonstrates a novel role of GSK-3 in regulating hepatic CREB activity and expression of muscle GLUT4.
Kaidanovich-Beilin
Oksana
O
Department of Human Genetics and Molecular Medicine, Sackler School of Medicine, Tel-Aviv University, Tel-Aviv 69978, Israel.
Eldar-Finkelman
Hagit
H
D000818:Animals; D015153:Blotting, Western; D017362:Cyclic AMP Response Element-Binding Protein / Q000378:metabolism; D004791:Enzyme Inhibitors / Q000627:therapeutic use*; D005947:Glucose / Q000378:metabolism*; D051275:Glucose Transporter Type 4 / Q000378:metabolism; D005952:Glucose-6-Phosphatase / Q000378:metabolism; D038362:Glycogen Synthase Kinase 3 / Q000037:antagonists & inhibitors* / Q000378:metabolism; D006706:Homeostasis / Q000187:drug effects*; D008099:Liver / Q000187:drug effects / Q000201:enzymology*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008820:Mice, Obese; D018482:Muscle, Skeletal / Q000187:drug effects / Q000201:enzymology*; D009842:Oligopeptides / Q000627:therapeutic use*; D010455:Peptides / Q000378:metabolism; D019764:Phosphoenolpyruvate Carboxykinase (ATP) / Q000378:metabolism; D012313:RNA / Q000096:biosynthesis / Q000302:isolation & purification; D020133:Reverse Transcriptase Polymerase Chain Reaction; D014020:Tissue Extracts / Q000737:chemistry; D015854:Up-Regulation / Q000187:drug effects
D017362:Cyclic AMP Response Element-Binding Protein; D004791:Enzyme Inhibitors; D051275:Glucose Transporter Type 4; C509073:N-myristoyl-glycyl-lysyl-glutamyl-alanyl-prolyl-prolyl-alanyl-prolyl-prolyl-glutaminyl-phosphoseryl-proline; D009842:Oligopeptides; D010455:Peptides; D014020:Tissue Extracts; D012313:RNA; D038362:Glycogen Synthase Kinase 3; D005952:Glucose-6-Phosphatase; D019764:Phosphoenolpyruvate Carboxykinase (ATP); D005947:Glucose