Pancreatic glucokinase is activated by insulin-like growth factor-I.
Glucokinase (GK) plays a key role in the regulation of glucose use and glucose-stimulated insulin secretion in pancreatic islet cells. Gene targeting of the IGF-I receptor down-regulated pancreatic islet GK activity. That finding prompted us to examine the potential mechanism that may control GK gene activity using an islet cell line, INS-1, known to express IGF-I receptor. Exposure of these cells to IGF-I induced GK protein expression and activity of the enzyme in a dose-dependent manner. In addition, IGF-I induced activity of a reporter construct containing the GK promoter in parallel with the effect on endogenous GK mRNA levels. The stimulatory effect of IGF-I on GK promoter activity was abrogated by wortmannin and LY294002, specific inhibitors of phosphatidylinositol 3-kinase. Exposure of cells to IGF-I elicited a rapid phosphorylation of Akt and FoxO1, a known target of Akt signaling. Constitutively active Akt stimulates the activity of the GK promoter, and a dominant-negative mutant of Akt or mutagenesis of a FoxO1 response element in the GK promoter abolished the ability of IGF-I to stimulate the promoter activity. Furthermore, cell knockdown of FoxO1 with small interfering RNA disrupted the effect of IGF-I on GK expression. These results demonstrate that the phosphatidylinositol 3-kinase/Akt/FoxO1 pathway contributes to the regulation of GK gene expression in response to IGF-I stimulation.
Yoshida
Kazuya
K
Division of Endocrinology and Metabolism, Department of Internal Medicine, Faculty of Medicine, Kagawa University, 1750-1 Miki-cho, Kita-gun, Kagawa 761-0793, Japan.
Murao
Koji
K
Imachi
Hitomi
H
Cao
Wen M
WM
Yu
Xiao
X
Li
Junhua
J
Ahmed
Rania A M
RA
Kitanaka
Noriko
N
Wong
Norman C W
NC
Unterman
Terry G
TG
Magnuson
Mark A
MA
Ishida
Toshihiko
T
D000818:Animals; D004268:DNA-Binding Proteins / Q000378:metabolism; D004789:Enzyme Activation / Q000187:drug effects* / Q000235:genetics; D051858:Forkhead Transcription Factors / Q000378:metabolism; D005941:Glucokinase / Q000235:genetics / Q000378:metabolism*; D007334:Insulin-Like Growth Factor I / Q000494:pharmacology*; D009419:Nerve Tissue Proteins / Q000378:metabolism; D010179:Pancreas / Q000187:drug effects / Q000201:enzymology* / Q000378:metabolism; D019869:Phosphatidylinositol 3-Kinases / Q000502:physiology; D010766:Phosphorylation; D011401:Promoter Regions, Genetic / Q000187:drug effects; D051057:Proto-Oncogene Proteins c-akt / Q000502:physiology; D051381:Rats; D017526:Receptor, IGF Type 1 / Q000378:metabolism / Q000502:physiology; D014407:Tumor Cells, Cultured; D000071161:Forkhead Box Protein O1
D004268:DNA-Binding Proteins; D051858:Forkhead Transcription Factors; D005941:Glucokinase; D007334:Insulin-Like Growth Factor I; D009419:Nerve Tissue Proteins; D019869:Phosphatidylinositol 3-Kinases; D051057:Proto-Oncogene Proteins c-akt; D017526:Receptor, IGF Type 1; C074639:Foxo1 protein, rat; D000071161:Forkhead Box Protein O1