期刊
MOLECULAR AND CELLULAR BIOLOGY
卷 28, 期 20, 页码 6314-6328出版社
AMER SOC MICROBIOLOGY
DOI: 10.1128/MCB.00763-08
关键词
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资金
- Canadian Institutes of Health Research [MOP 74711]
- Canadian Diabetes Association
- Banting and Best Diabetes Centre
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-3 alpha and GSK-3 beta. Mice engineered to lack GSK-3 beta die in late embryogenesis from liver apoptosis, whereas mice engineered to lack GSK-3 alpha are viable and exhibit improved insulin sensitivity and hepatic glucose homeostasis. To assess the potential role of GSK-3 beta in insulin function, a conditional gene-targeting approach whereby mice in which expression of GSK-3 beta was specifically ablated within insulin-sensitive tissues were generated was undertaken. Liver-specific GSK-3 beta knockout mice are viable and glucose and insulin tolerant and display normal metabolic characteristics and insulin signaling. Mice lacking expression of GSK-3 beta 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-3 alpha and GSK-3 beta within the adult but also tissue-specific phenotypes associated with each of these isoforms.
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