title: Pancreatic glucokinase is activated by insulin-like growth factor-I.
abstract: 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.
authors.affiliation: Division of Endocrinology and Metabolism, Department of Internal Medicine, Faculty of Medicine, Kagawa University, 1750-1 Miki-cho, Kita-gun, Kagawa 761-0793, Japan.
authors.forename: Kazuya
authors.initials: K
authors.lastname: Yoshida
authors.forename: Koji
authors.initials: K
authors.lastname: Murao
authors.forename: Hitomi
authors.initials: H
authors.lastname: Imachi
authors.forename: Wen M
authors.initials: WM
authors.lastname: Cao
authors.forename: Xiao
authors.initials: X
authors.lastname: Yu
authors.forename: Junhua
authors.initials: J
authors.lastname: Li
authors.forename: Rania A M
authors.initials: RA
authors.lastname: Ahmed
authors.forename: Noriko
authors.initials: N
authors.lastname: Kitanaka
authors.forename: Norman C W
authors.initials: NC
authors.lastname: Wong
authors.forename: Terry G
authors.initials: TG
authors.lastname: Unterman
authors.forename: Mark A
authors.initials: MA
authors.lastname: Magnuson
authors.forename: Toshihiko
authors.initials: T
authors.lastname: Ishida
mesh_terms: 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
chemical_list: 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