Development of glucose intolerance in male transgenic mice overexpressing human glycogen synthase kinase-3β on a muscle-specific promoter
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- 作者：Nigel J. Pearce ; Jonathan R. S. Arch ; John C. Clapham ; Matthew P. Coghlan ; Stacey L. Corcoran ; Carolyn A. Lister ; Andrea Llano ; Gary B. Moore ; Gregory J. Murphy ; Stephen A. Smith ; Colleen M. Taylor ; John W. Yates ; Alastair D. Morrison ; Alex ; er J. Harper ; Lynne Roxbee-Cox ; Alej ; ro Abuin ; Ed Wargent
- 刊名：Metabolism
- 出版年：2004
- 出版时间：October 2004
- 年：2004
- 卷：53
- 期：10
- 页码：1322-1330
- 全文大小：386 K
文摘
Glycogen synthase kinase-3 (GSK-3) protein levels and activity are elevated in skeletal muscle in type 2 diabetes, and inversely correlated with both glycogen synthase activity and insulin-stimulated glucose disposal. To explore this relationship, we have produced transgenic mice that overexpress human GSK-3β in skeletal muscle. GSK-3β transgenic mice were heavier, by up to 20 % (P < .001), than their age-matched controls due to an increase in fat mass. The male GSK-3β transgenic mice had significantly raised plasma insulin levels and by 24 weeks of age became glucose-intolerant as determined by a 50 % increase in the area under their oral glucose tolerance curve (P < .001). They were also hyperlipidemic with significantly raised serum cholesterol (+90 % ), nonesterified fatty acids (NEFAs) (+55 % ), and triglycerides (+170 % ). At 29 weeks of age, GSK-3β protein levels were 5-fold higher, and glycogen synthase activation (−27 % ), glycogen levels (−58 % ) and insulin receptor substrate-1 (IRS-1) protein levels (−67 % ) were significantly reduced in skeletal muscle. Hepatic glycogen levels were significantly increased 4-fold. Female GSK-3β transgenic mice did not develop glucose intolerance despite 7-fold overexpression of GSK-3β protein and a 20 % reduction in glycogen synthase activation in skeletal muscle. However, plasma NEFAs and muscle IRS-1 protein levels were unchanged in females. We conclude that overexpression of human GSK-3β in skeletal muscle of male mice resulted in impaired glucose tolerance despite raised insulin levels, consistent with the possibility that elevated levels of GSK-3 in type 2 diabetes are partly responsible for insulin resistance.