1. Irs1 and Irs2 signaling is essential for hepatic glucose homeostasis and systemic growth
- Author
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Morris F. White, Sunmin Park, Kyle D. Copps, Xianjin Yi, Xiaocheng Dong, and Xueying Lin
- Subjects
medicine.medical_specialty ,endocrine system ,medicine.medical_treatment ,Apoptosis ,Carbohydrate metabolism ,Mice ,Insulin resistance ,Bone Density ,Internal medicine ,medicine ,Hyperinsulinemia ,Glucose homeostasis ,Animals ,Homeostasis ,Pancreas ,Mice, Knockout ,biology ,Insulin ,Body Weight ,Intracellular Signaling Peptides and Proteins ,Organ Size ,General Medicine ,medicine.disease ,Phosphoproteins ,IRS2 ,Receptor, Insulin ,IRS1 ,Insulin receptor ,Endocrinology ,Glucose ,Liver ,biology.protein ,Insulin Receptor Substrate Proteins ,Erratum ,Signal Transduction ,Research Article - 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 Irs2 [corrected] 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, Gsk3beta 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.
- Published
- 2006