Abstract
Insulin receptor substrate (IRS) proteins play important roles in hepatic nutrient homeostasis. Since glucokinase (GK) and glucokinase regulatory protein (GKRP) function as key glucose sensors, we have investigated the expression of GK and GKRP in liver of Irs-2 deficient mice and Irs2(−/−) mice where Irs2 was reintroduced specifically into pancreatic β-cells [RIP-Irs-2/IRS-2(−/−)]. We observed that liver GK activity was significantly lower (p<0.0001) in IRS-2(−/−) mice. However, in RIP-Irs-2/IRS-2(−/−) mice, GK activity was similar to the values observed in wild-type animals. GK activity in hypothalamus was not altered in IRS-2(−/−) mice. GK and GKRP mRNA levels in liver of IRS-2(−/−) were significantly lower, whereas in RIP-Irs-2/IRS-2(−/−) mice, both GK and GKRP mRNAs levels were comparable to wild-type animals. At the protein level, the liver content of GK was reduced in IRS-2(−/−) mice as compared with controls, although GKRP levels were similar between these experimental models. Both GK and GKRP levels were lower in RIP-Irs-2/IRS-2(−/−) mice. These results suggest that IRS-2 signalling is important for maintaining the activity of liver GK. Moreover, the differences between liver and brain GK may be explained by the fact that expression of hepatic, but not brain, GK is controlled by insulin. GK activity was restored by the β-cell compensation in the RIP-Irs-2/IRS-2 mice. Interestingly, GK and GKRP protein expression remained low in RIP-Irs-2/IRS-2(−/−) mice, perhaps reflecting different mRNA half-lives or alterations in the process of translation and post-translational regulation.
Highlights
Insulin receptor substrate-2 (IRS-2) integrates insulin and IGF-I receptor signals that are transmitted through transduction pathways to produce growth and metabolic effects
Considering that IRS-2 plays an important role in hepatic nutrient homeostasis, we have investigated the expression of GK and GK activity and glucokinase regulatory protein (GKRP) expression in the liver, using two experimental models of insulin receptor substrate-2 deficiency in mice: IRS-2 deficient mice that develop type 2 diabetes at 10– 12 weeks of age and IRS-2 deficient mice in which Irs-2 was reintroduced into pancreatic b-cells [rat insulin II promoter (RIP)-Irs-2/IRS2(2/2)] to restore pancreatic b-cell compensation
Blood plasma glucose was similar between RIP-Irs-2/IRS-2(2/2) mice and their wild type controls, but insulin circulating levels were significantly greater in RIP-Irs-2/IRS-2(2/2) (p,0.05) than their wild type controls (Table 1)
Summary
Insulin receptor substrate-2 (IRS-2) integrates insulin and IGF-I receptor signals that are transmitted through transduction pathways to produce growth and metabolic effects. IRS-2 is especially important in hepatic nutrient homeostasis as it mediates the anabolic effects of insulin through the PI3K-Akt cascade [1,2] and suppresses gluconeogenesis and apoptosis [3,4]. Mice lacking IRS-2 develop diabetes due to peripheral insulin resistance, failed hypothalamic regulation of appetite and b-cell insufficiency [5]. These mice have additional phenotypes, including a 40% reduction in brain mass [6]. The importance of IRS-2 signals in b-cell development and function is supported by several lines of research. When Irs-2 was reintroduced in pancreatic b-cells using the rat insulin II promoter (RIP), Irs-2-deficient mice did not develop diabetes, as the expression of this signalling molecule restored b-cell compensation [7]. The loss of Irs-2 expression in b-cells has been linked to type 2 diabetes in humans: microarray comparison revealed that Irs-2 is significantly reduced in islets of patients with type 2 diabetes, as compared with controls [8]
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