PTG gene deletion causes impaired glycogen synthesis and developmental insulin resistance
Sean M. Crosson, … , Jeffrey E. Pessin, Alan R. Saltiel
Sean M. Crosson, … , Jeffrey E. Pessin, Alan R. Saltiel
Published May 1, 2003
Citation Information: J Clin Invest. 2003;111(9):1423-1432. https://doi.org/10.1172/JCI17975.
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Article Metabolism

PTG gene deletion causes impaired glycogen synthesis and developmental insulin resistance

Abstract

Protein targeting to glycogen (PTG) is a scaffolding protein that targets protein phosphatase 1α (PP1α) to glycogen, and links it to enzymes involved in glycogen synthesis and degradation. We generated mice that possess a heterozygous deletion of the PTG gene. These mice have reduced glycogen stores in adipose tissue, liver, heart, and skeletal muscle, corresponding with decreased glycogen synthase activity and glycogen synthesis rate. Although young PTG heterozygous mice initially demonstrate normal glucose tolerance, progressive glucose intolerance, hyperinsulinemia, and insulin resistance develop with aging. Insulin resistance in older PTG heterozygous mice correlates with a significant increase in muscle triglyceride content, with a corresponding attenuation of insulin receptor signaling. These data suggest that PTG plays a critical role in glycogen synthesis and is necessary to maintain the appropriate metabolic balance for the partitioning of fuel substrates between glycogen and lipid.

Authors

Sean M. Crosson, Ahmir Khan, John Printen, Jeffrey E. Pessin, Alan R. Saltiel

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Skeletal muscle of 18-month-old PTG+/– mice displays increased triglycer...
Skeletal muscle of 18-month-old PTG+/– mice displays increased triglyceride content and inhibition of insulin signaling pathways involved in glucose transport and glycogen synthesis. (a) Skeletal muscle triglyceride content is increased in 18-month-old PTG+/– mice. Skeletal muscle triglyceride content was estimated from organic solvent–extracted epitrochlearis muscle isolated from fasting 18-month-old animals (n = 4–12 per group). Results are reported as mean ± SEM (*P ≤ 0.05). (b) Insulin signaling is affected in the skeletal muscle of aged PTG+/– mice. Protein lysates were prepared from muscle of 9- to 10-month-old nonfasting male animals either in the basal state or after injection with 2 mU/g body weight human recombinant insulin. Western blotting was performed for total and phosphospecific Akt. Muscle homogenates were immunoprecipitated with an antibody against IRS-1 and immunoblotting was performed to determine the levels of total IRS-1 and tyrosine-phosphorylated IRS-1.