title: Development of glucose intolerance in male transgenic mice overexpressing human glycogen synthase kinase-3beta on a muscle-specific promoter.
abstract: 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.
authors.affiliation: Department of Vascular Biology, GlaxoSmithKline, Harlow, UK.
authors.forename: Nigel J
authors.initials: NJ
authors.lastname: Pearce
authors.forename: Jonathan R S
authors.initials: JR
authors.lastname: Arch
authors.forename: John C
authors.initials: JC
authors.lastname: Clapham
authors.forename: Matthew P
authors.initials: MP
authors.lastname: Coghlan
authors.forename: Stacey L
authors.initials: SL
authors.lastname: Corcoran
authors.forename: Carolyn A
authors.initials: CA
authors.lastname: Lister
authors.forename: Andrea
authors.initials: A
authors.lastname: Llano
authors.forename: Gary B
authors.initials: GB
authors.lastname: Moore
authors.forename: Gregory J
authors.initials: GJ
authors.lastname: Murphy
authors.forename: Stephen A
authors.initials: SA
authors.lastname: Smith
authors.forename: Colleen M
authors.initials: CM
authors.lastname: Taylor
authors.forename: John W
authors.initials: JW
authors.lastname: Yates
authors.forename: Alastair D
authors.initials: AD
authors.lastname: Morrison
authors.forename: Alexander J
authors.initials: AJ
authors.lastname: Harper
authors.forename: Lynne
authors.initials: L
authors.lastname: Roxbee-Cox
authors.forename: Alejandro
authors.initials: A
authors.lastname: Abuin
authors.forename: Ed
authors.initials: E
authors.lastname: Wargent
authors.forename: Julie C
authors.initials: JC
authors.lastname: Holder
mesh_terms: D000818:Animals; D015153:Blotting, Western; D001823:Body Composition / Q000502:physiology; D001835:Body Weight / Q000502:physiology; D017931:DNA Primers; D018076:DNA, Complementary / Q000096:biosynthesis / Q000235:genetics; D005260:Female; D018149:Glucose Intolerance / Q000235:genetics*; D005951:Glucose Tolerance Test; D006003:Glycogen / Q000378:metabolism; D038362:Glycogen Synthase Kinase 3 / Q000096:biosynthesis* / Q000235:genetics*; D000071679:Glycogen Synthase Kinase 3 beta; D006801:Humans; D055504:Insulin Receptor Substrate Proteins; D007333:Insulin Resistance / Q000235:genetics / Q000502:physiology; D008055:Lipids / Q000097:blood; D008099:Liver / Q000378:metabolism; D008297:Male; D051379:Mice; D008822:Mice, Transgenic; D018482:Muscle, Skeletal / Q000378:metabolism / Q000502:physiology*; D010641:Phenotype; D010750:Phosphoproteins / Q000096:biosynthesis / Q000235:genetics; D011401:Promoter Regions, Genetic / Q000502:physiology*; D012333:RNA, Messenger / Q000096:biosynthesis / Q000235:genetics; D020133:Reverse Transcriptase Polymerase Chain Reaction
chemical_list: D017931:DNA Primers; D018076:DNA, Complementary; C526292:IRS1 protein, human; D055504:Insulin Receptor Substrate Proteins; C526295:Irs1 protein, mouse; D008055:Lipids; D010750:Phosphoproteins; D012333:RNA, Messenger; D006003:Glycogen; C000605506:GSK3B protein, human; D000071679:Glycogen Synthase Kinase 3 beta; C000605507:Gsk3b protein, mouse; D038362:Glycogen Synthase Kinase 3