Development of glucose intolerance in male transgenic mice overexpressing human glycogen synthase kinase-3beta on a muscle-specific promoter.
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.
Pearce
Nigel J
NJ
Department of Vascular Biology, GlaxoSmithKline, Harlow, UK.
Arch
Jonathan R S
JR
Clapham
John C
JC
Coghlan
Matthew P
MP
Corcoran
Stacey L
SL
Lister
Carolyn A
CA
Llano
Andrea
A
Moore
Gary B
GB
Murphy
Gregory J
GJ
Smith
Stephen A
SA
Taylor
Colleen M
CM
Yates
John W
JW
Morrison
Alastair D
AD
Harper
Alexander J
AJ
Roxbee-Cox
Lynne
L
Abuin
Alejandro
A
Wargent
Ed
E
Holder
Julie C
JC
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
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