Development of glucose intolerance in male transgenic mice overexpressing human glycogen synthase kinase-3β on a muscle-specific promoter

• Published in: Metabolism, clinical and experimental Vol. 53; no. 10; pp. 1322 - 1330
• Main Authors: Pearce, Nigel J., Arch, Jonathan R.S., Clapham, John C., Coghlan, Matthew P., Corcoran, Stacey L., Lister, Carolyn A., Llano, Andrea, Moore, Gary B., Murphy, Gregory J., Smith, Stephen A., Taylor, Colleen M., Yates, John W., Morrison, Alastair D., Harper, Alexander J., Roxbee-Cox, Lynne, Abuin, Alejandro, Wargent, Ed, Holder, Julie C.
• Format: Journal Article
• Language: English
• Published: New York, NY Elsevier Inc 01-10-2004; Elsevier
• Subjects: Biological and medical sciences; Diabetes. Impaired glucose tolerance; Endocrine pancreas. Apud cells (diseases); Endocrinopathies; Etiopathogenesis. Screening. Investigations. Target tissue resistance; Medical sciences; Endocrinopathy; Type 2 diabetes; Pancreatic hormone; Transgenic animal; Lipids; Activity; Male; Glucose; Synthase; Fat mass; Blood plasma; Promoter; Serum; Impaired glucose tolerance; Human; Digestive system; Enzyme; Glycogen; Transferases; Rodentia; Oral administration; Tolerance; Striated muscle; Insulin; Cholesterol; Vertebrata; Mammalia; Mouse; Kinase; Protein kinase
• ISSN: 0026-0495; 1532-8600
• DOI: 10.1016/j.metabol.2004.05.008

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.