Irs1 and Irs2 signaling is essential for hepatic glucose homeostasis and systemic growth

Abstract

Insulin receptor substrates, including Irs1 and Irs2, integrate insulin and IGF receptor signals with heterologous pathways to coordinate growth and metabolism. Since Irs2 is thought to be especially important in hepatic nutrient homeostasis, we deleted Irs1 from hepatocytes of WT mice (called LKO) or genetically insulin-resistant Irs1 -/-mice (called LKO::Irs1 -/-). Viable LKO::Irs1 -/-mice were 70% smaller than WT or LKO mice, and 40% smaller than Irs1 -/-mice. Hepatic insulin receptors were functional in all the mice, but insulin signaling via the Akt-FoxO1 pathway was reduced in Irs1 -/-and LKO liver, and undetected in LKO::Irs1 -/-liver; however, Gsk3β phosphorylation (Ser9) and hepatic glycogen stores were nearly normal in all of the mice. LKO and Irs1 -/-mice developed insulin resistance and glucose intolerance that never progressed to diabetes, whereas LKO::Irs1 -/-mice developed hyperglycemia and hyperinsulinemia immediately after birth. Regardless, few hepatic genes changed expression significantly in Irs1 -/-or LKO mice, whereas hundreds of genes changed in LKO::Irs1 -/-mice -including elevated levels of Pck1, G6pc, Ppargc1, Pparg, and Igfbp1. Thus, signals delivered by Irs1 or Irs2 regulate hepatic gene expression that coordinates glucose homeostasis and systemic growth.

Normalization of Prandial Blood Glucose and Improvement of Glucose Tolerance by Liver-Specific Inhibition of SH2 Domain–Containing Inositol Phosphatase 2 (SHIP2) in Diabetic KKAy Mice

“…This is in agreement with the inhibition of PEPCK and G6Pase gene expression and decreased fasting blood glucose levels observed in db/db mice (8). Because the transcription factor forkhead box class O (FoxO)1 is a key activator of PEPCK and G6Pase gene expression (20) )-specific FoxO1 antibody (Cell Signaling Technology) detected phosphorylated FoxO1 in mouse liver lysates in another study (19). In the ␤Gal control group, a phosphorylation of FoxO1 is not expected because of the insulin resistance of the liver.…”

“…Consistently, we detected a significant increase in hepatic glycogen content. Although it has been shown recently that Akt signaling is not absolutely required for the maintenance of hepatic glycogen stores, we provide evidence that activation of Akt is sufficient to improve glycogen metabolism in the diabetic state (19).…”

Tissue-specific effects of protein malnutrition on insulin signaling pathway and lipid accumulation in growing rats

“…The increased ACC1 levels and TG content in the liver could be related to the increases in insulin signaling via IRS-2 and 4E-BP1. It is known that IRS-2 plays important roles in regulating lipid metabolism in the liver [25,[29][30][31]. We recently found that the overexpression of IRS-2 increases the intracellular TG levels in well-differentiated hepatocytes, Huh-7 cells, indicating that increased IRS-2 levels were involved in the increases of TG in cultured hepatocytes (manuscript in preparation).…”

The insulin receptor substrate (IRS) proteins

“…30 The IRS proteins have been implicated as essential signaling intermediates in insulin-regulated glucose homeostasis through the promotion of glucose uptake and the regulation of genes essential for the utilization of glucose for energy production and for the biosynthesis of macromolecules including proteins, lipids and nucleic acids that are required for cell growth and proliferation. 31 Glucose uptake is controlled by a family of facilitative glucose transporter proteins, the GLUT proteins, that transport glucose, and in some cases fructose, across the cell membrane. 32 The major insulin-stimulated glucose transporter is GLUT4.…”