Analysis of hepatic gene transcription in mice expressing insulin-insensitive GSK3.
GSK3 (glycogen synthase kinase-3) regulation is proposed to play a key role in the hormonal control of many cellular processes. Inhibition of GSK3 in animal models of diabetes leads to normalization of blood glucose levels, while high GSK3 activity has been reported in Type II diabetes. Insulin inhibits GSK3 by promoting phosphorylation of a serine residue (Ser-21 in GSK3alpha, Ser-9 in GSK3beta), thereby relieving GSK3 inhibition of glycogen synthesis in muscle. GSK3 inhibition in liver reduces expression of the gluconeogenic genes PEPCK (phosphoenolpyruvate carboxykinase), G6Pase (glucose-6-phosphatase), as well as IGFBP1 (insulin-like growth factor binding protein-1). Overexpression of GSK3 in cells antagonizes insulin regulation of these genes. In the present study we demonstrate that regulation of these three genes by feeding is normal in mice that express insulin-insensitive GSK3. Therefore inactivation of GSK3 is not a prerequisite for insulin repression of these genes, despite the previous finding that GSK3 activity is absolutely required for maintaining their expression. Interestingly, insulin injection of wild-type mice, which activates PKB (protein kinase B) and inhibits GSK3 to a greater degree than feeding (50% versus 25%), does not repress these genes. We suggest for the first time that although pharmacological inhibition of GSK3 reduces hepatic glucose production even in insulin-resistant states, feeding can repress the gluconeogenic genes without inhibiting GSK3.
Lipina
Christopher
C
Division of Pathology and Neurosciences, University of Dundee, Ninewells Hospital, Dundee DD1 9SY, Scotland, UK.
Huang
Xu
X
Finlay
David
D
McManus
Edward J
EJ
Alessi
Dario R
DR
Sutherland
Calum
C
D000818:Animals; D002262:Carboxy-Lyases / Q000235:genetics / Q000378:metabolism; D004435:Eating / Q000502:physiology; D005502:Food; D005786:Gene Expression Regulation / Q000187:drug effects; D005943:Gluconeogenesis; D005947:Glucose / Q000096:biosynthesis / Q000378:metabolism; D005952:Glucose-6-Phosphatase / Q000235:genetics / Q000378:metabolism; D038362:Glycogen Synthase Kinase 3 / Q000037:antagonists & inhibitors / Q000235:genetics* / Q000378:metabolism*; D006801:Humans; D007328:Insulin / Q000378:metabolism / Q000494:pharmacology*; D018970:Insulin-Like Growth Factor Binding Protein 1 / Q000235:genetics / Q000378:metabolism; D008099:Liver / Q000187:drug effects / Q000378:metabolism*; D051379:Mice; D009154:Mutation; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D020218:Response Elements; D015398:Signal Transduction; D051780:Sterol Regulatory Element Binding Protein 1 / Q000235:genetics / Q000378:metabolism; D014158:Transcription, Genetic
D007328:Insulin; D018970:Insulin-Like Growth Factor Binding Protein 1; D051780:Sterol Regulatory Element Binding Protein 1; D051057:Proto-Oncogene Proteins c-akt; D038362:Glycogen Synthase Kinase 3; D005952:Glucose-6-Phosphatase; D002262:Carboxy-Lyases; D005947:Glucose