Long-term treatment with novel glycogen synthase kinase-3 inhibitor improves glucose homeostasis in ob/ob mice: molecular characterization in liver and muscle.

Abstract

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.

• Authors: Oksana Kaidanovich-Beilin, Hagit Eldar-Finkelman
• Journal: The Journal of pharmacology and experimental therapeutics (J Pharmacol Exp Ther) Vol. 316 Issue 1 Pg. 17-24 (Jan 2006) ISSN: 0022-3565 [Print] United States
• PMID: 16169938 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Cyclic AMP Response Element-Binding Protein
• Enzyme Inhibitors
• Glucose Transporter Type 4
• N-myristoyl-glycyl-lysyl-glutamyl-alanyl-prolyl-prolyl-alanyl-prolyl-prolyl-glutaminyl-phosphoseryl-proline
• Oligopeptides
• Peptides
• Tissue Extracts
• RNA
• Glycogen Synthase Kinase 3
• Glucose-6-Phosphatase
• Phosphoenolpyruvate Carboxykinase (ATP)
• Glucose

Topics

• Animals
• Blotting, Western
• Cyclic AMP Response Element-Binding Protein (metabolism)
• Enzyme Inhibitors (therapeutic use)
• Glucose (metabolism)
• Glucose Transporter Type 4 (metabolism)
• Glucose-6-Phosphatase (metabolism)
• Glycogen Synthase Kinase 3 (antagonists & inhibitors, metabolism)
• Homeostasis (drug effects)
• Liver (drug effects, enzymology)
• Male
• Mice
• Mice, Inbred C57BL
• Mice, Obese
• Muscle, Skeletal (drug effects, enzymology)
• Oligopeptides (therapeutic use)
• Peptides (metabolism)
• Phosphoenolpyruvate Carboxykinase (ATP) (metabolism)
• RNA (biosynthesis, isolation & purification)
• Reverse Transcriptase Polymerase Chain Reaction
• Tissue Extracts (chemistry)
• Up-Regulation (drug effects)