| Co-Investigator(Kenkyū-buntansha) |
SUZUKI Masatoshi Graduate School of Agricultural and Life Science, THE UNIVERSITY OF TOKYO, Assistant Professor, 大学院・農学生命科学研究科, 助手 (70302594)
TAKAHASHI Shin-ichi Graduate School of Agricultural and Life Science, THE UNIVERSITY OF TOKYO, Associate Professor, 大学院・農学生命科学研究科, 助教授 (00197146)
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| Budget Amount *help |
¥15,000,000 (Direct Cost: ¥15,000,000)
Fiscal Year 2001: ¥3,200,000 (Direct Cost: ¥3,200,000)
Fiscal Year 2000: ¥3,300,000 (Direct Cost: ¥3,300,000)
Fiscal Year 1999: ¥8,500,000 (Direct Cost: ¥8,500,000)
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| Research Abstract |
GH excess has been shown to lead insulin resistance; however, the molecular mechanisms remain to be elucidated. This study was undertaken to investigate the effects of GH on intracellular signals of insulin and insulin-dependent regulation of, glucose metabolism using human GH (hGH) transgenic rats (TG rats) developed in our laboratory. The TG rats were characterized by high levels of serum hGH. and IGF-I, resulting in an increase in body length and weight. In 10 weeks old TG rats, higher levels of serum insulin were detected compared with non-transgenic littermates (control rats), but serum glucose levels were normal, suggesting high levels of serum GH cause mild insulin resistance. We then isolated and cultured hepatocytes from 10 weeks old TG or control rats. Serum starved hepatocytes were treated with insulin, and tyrosine phosphorylation of insulin receptor, IRS-1 arid IRS-2, arid activities or mRNA levels of various enzymes were analyzed. In TG hepatocytes, insulin-dependent rece
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ptor autophosphorylation was reduced compared with control hepatocytes; however, IRS-1 and IRS-2 tyrosine phosphorylation increased. Glucose uptake induced by insulin was also up-regulated, which may be due to increases in insulin-dependent IRSs tyrosine phosphorylation. In contrast, glycogen synthase activity was significantly lower and the mRNA levels of PEPCK and FAS were, elevated in TG hepatocytes, suggesting that insulin resistance occurs at least on these enzymes. On the other hand, insulin-induced glucose uptake decreased in TG adipocytes, showing that high levels of serum GH impaired insulin action in adipocytes. Taken together, our results suggest that impairment of insulin-dependent glucose uptake by GH in peripheral tissues, such as adipose tissues, is compensated by up-regulation of glucose uptake in the liver in response to insulin, resulting in normalizing glucose levels. Our GH transgenic rats model shows that GH impairs insulin action at the different steps in tissue specific manners. Less
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