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

• Published in: Metabolism, clinical and experimental clinical and experimental, 2004-10, Vol.53 (10), p.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: Article
• Language: English
• Subjects: Animals; Blotting, Western; Body Composition - physiology; Body Weight - physiology; DNA Primers; DNA, Complementary - biosynthesis; DNA, Complementary - genetics; Female; Glucose Intolerance - genetics; Glucose Tolerance Test; Glycogen - metabolism; Glycogen Synthase Kinase 3 - biosynthesis; Glycogen Synthase Kinase 3 - genetics; Glycogen Synthase Kinase 3 beta; Humans; Insulin Receptor Substrate Proteins; Insulin Resistance - genetics; Insulin Resistance - physiology; Lipids - blood; Liver - metabolism; Male; Mice; Mice, Transgenic; Muscle, Skeletal - metabolism; Muscle, Skeletal - physiology; Phenotype; Phosphoproteins - biosynthesis; Phosphoproteins - genetics; Promoter Regions, Genetic - physiology; Reverse Transcriptase Polymerase Chain Reaction; RNA, Messenger - biosynthesis; RNA, Messenger - genetics
• ISSN: 0026-0495

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-3beta in skeletal muscle. GSK-3beta 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-3beta 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-3beta 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-3beta transgenic mice did not develop glucose intolerance despite 7-fold overexpression of GSK-3beta 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-3beta 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.