Received for publication June 20, 2005.
Revised September 14, 2005.
Accepted for publication September 14, 2005.

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 PEPCK (50%) and increased hepatic glycogen content by 50%. On the other hand, L803-mts did not affect G-6-phosphatase mRNA levels or its enzymatic activity in the liver. Investigation for possible mechanisms responsible for PEPCK suppression indicated that phosphorylation of CREB at serine¹³³ was reduced remarkably by L803-mts, which was also associated with reduced phosphorylation at serine¹²⁹ and no change in total CREB. This suggested that PEPCK was suppressed by GSK-3-inhibtion-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.

Key words: CREB, GSK-3, diabetes, insulin resistance, insulin signaling, protein kinase inhibiotor

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