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Irs1 and Irs2 signaling is essential for hepatic glucose homeostasis and systemic growth
Xiaocheng Dong, … , Xianjin Yi, Morris F. White
Xiaocheng Dong, … , Xianjin Yi, Morris F. White
Published January 4, 2006
Citation Information: J Clin Invest. 2006;116(1):101-114. https://doi.org/10.1172/JCI25735.
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Research Article Metabolism

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

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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.

Authors

Xiaocheng Dong, Sunmin Park, Xueying Lin, Kyle Copps, Xianjin Yi, Morris F. White

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Figure 4

Glucose homeostasis.

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Glucose homeostasis.
(A and B) Nonfasting (A) and fasting (B) blood gluc...
(A and B) Nonfasting (A) and fasting (B) blood glucose (average ± SEM) was measured in at least 8 male mice (6 weeks old) per group. (C) Glucose tolerance tests were performed at 5 weeks of age in male mice fasted for 16 hours (at least 8 mice per genotype). The average ± SEM blood glucose was plotted at the indicated time intervals after i.p. injection of 2 g d-glucose/kg body weight. *P < 0.05, LKO vs. control. (D) Fasting blood glucose levels (average ± SEM, n = 8) were measured in 16-week-old male mice in each group. (E and F) Blood glucose levels (average ± SEM, n = 8) were measured in fasted and nonfasted male mice of each group at 8 weeks of age. (G) Glucose tolerance tests were conducted on at least 6 male mice in each group (6 weeks old) after a 16-hour overnight fast. Blood glucose levels (average ± SEM) were determined at the indicated time points after i.p. injection of 2 g d-glucose/kg body weight. (H) Insulin tolerance tests were performed in nonfasted 8-week-old male mice in each group. Blood glucose (average ± SEM, n = 6) was plotted against the time after the i.p. insulin injection.

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