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.

Potential role of branched‐chain amino acids in glucose metabolism through the accelerated induction of the glucose‐sensing apparatus in the liver

“…However, we could hypothesize for this action including the participation of PKB/Akt signaling to regulate the genes, especially for glucokinase. The upregulation of glucokinase is induced by Insulin/IGF-1 signaling through the rapid phosphorylation of PKB/Akt and FoxO1, a known target of Akt signaling [Yoshida et al, 2007]. High concentration of glucose is reported to induce the activation of ERK1/2 and PKB/Akt [Kim et al, 2006].…”

Pancreatic transcription factors and their role in the birth, life and survival of the pancreatic β cell

“…The rat glucokinase promoter binds β2/E47 at an E box (Moates et al 2003) but the equivalent human sites have lost the consensus sequences and their deletion has no significant effect on expression (Watada et al 1996). The rat glucokinase promoter contains a Foxo1 response element (FRS) at position -550 which binds the forkhead transcription factor Foxo1 (Yoshida et al 2007)and represents the final step in the signalling pathway of Insulin-like growth factor-1 (IGF1) stimulation of glucokinase expression. In contrast to the rat promoter, the human glucokinase promoter lacks this regulatory element and computational analysis of 1 Kbp of promoter sequence failed to detect an alternative site or other Foxo consensus sequence.…”

IGF-1 Protects Against Dexamethasone-Induced Cell Death in Insulin Secreting INS-1 Cells Independent of AKT/PKB Phosphorylation

“…One pathway involves tyrosine phosphorylation of specific insulin receptor substrates (IRS-1 to IRS-4) and subsequent activation of phosphatidylinositol-3 kinase (PI3K), PDK-1 and protein kinase B (PKB/Akt), that regulates gene expression, glucose transport, glycogen synthesis and has anti-apoptotic effects [11][12][13][14][15]. Another pathway leads to the stimulation of the mitogen-activated protein kinase (MAPK) cascade through Grb/SOS and ras inducing gene expression and cell proliferation [16].…”