Tissue-Specific Role of Glycogen Synthase Kinase 3β in Glucose Homeostasis and Insulin Action

Abstract

Dysregulation of the protein kinase glycogen synthase kinase 3 (GSK-3) has been implicated in the development of type 2 diabetes mellitus. GSK-3 protein expression and kinase activity are elevated in diabetes, while selective GSK-3 inhibitors have shown promise as modulators of glucose metabolism and insulin sensitivity. There are two GSK-3 isoforms in mammals, GSK-3α and GSK-3β. Mice engineered to lack GSK-3β die in late embryogenesis from liver apoptosis, whereas mice engineered to lack GSK-3α are viable and exhibit improved insulin sensitivity and hepatic glucose homeostasis. To assess the potential role of GSK-3β in insulin function, a conditional gene-targeting approach whereby mice in which expression of GSK-3β was specifically ablated within insulin-sensitive tissues were generated was undertaken. Liver-specific GSK-3β knockout mice are viable and glucose and insulin tolerant and display “normal” metabolic characteristics and insulin signaling. Mice lacking expression of GSK-3β in skeletal muscle are also viable but, in contrast to the liver-deleted animals, display improved glucose tolerance that is coupled with enhanced insulin-stimulated glycogen synthase regulation and glycogen deposition. These data indicate that there are not only distinct roles for GSK-3α and GSK-3β within the adult but also tissue-specific phenotypes associated with each of these isoforms.

SUPPLEMENTAL MATERIAL

Supplemental material for this article may be found at http://mcb.asm.org/ .

ACKNOWLEDGMENTS

We thank T. Hansotia (SLRI) and G. Wiggin (SLRI) for critical review of the manuscript and discussion and M. Woo, A. Klip, A. Tung, and K. Sakamoto for valuable technical advice and assistance. We thank J. Guinovart (University of Barcelona), P. T. Cohen (University of Dundee), and S. Burden (Skirball Institute, NY) for reagents.

Funding for this work was provided by the Canadian Institutes of Health Research (J.R.W. [MOP 74711], S.P., and B.W.D.), the Canadian Diabetes Association (J.R.W.), and the Banting and Best Diabetes Centre (J.R.W., S.P., and K.M.).