Pancreatic glucokinase is activated by insulin-like growth factor-I.

Yoshida K, Murao K, Imachi H, Cao WM, Yu X, Li J, Ahmed RA, Kitanaka N, Wong NC, Unterman TG, Magnuson MA, Ishida T
Endocrinology. 2007 148 (6): 2904-13

PMID: 17317782 · DOI:10.1210/en.2006-1149

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.

MeSH Terms (15)

Animals DNA-Binding Proteins Enzyme Activation Forkhead Transcription Factors Glucokinase Insulin-Like Growth Factor I Nerve Tissue Proteins Pancreas Phosphatidylinositol 3-Kinases Phosphorylation Promoter Regions, Genetic Proto-Oncogene Proteins c-akt Rats Receptor, IGF Type 1 Tumor Cells, Cultured

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