Tissue-specific impairment of insulin signaling in vasculature and skeletal muscle of fructose-fed rats.
The relation between insulin resistance/hyperinsulinemia and cardiovascular diseases has attracted much attention. Insulin affects not only glucose metabolism, but also protein synthesis and cell growth. Insulin stimulates both the phosphatidylinositol 3-kinase (PI3-K) and mitogen-activated protein kinase (MAPK) pathways, but the relationship between cardiovascular disease and selective insulin signal pathways is unclear. We investigated the tissue specificity and intracellular signal transduction selectivity of insulin resistance in the vasculature and skeletal muscle of fructose-fed rats (FFR). Sprague-Dawley rats were fed either normal rat chow (control rats) or fructose-rich chow. Normal saline with or without 1,000 (microg/kg) insulin was injected, and then the thoracic aorta or soleus muscle was removed under anesthetization. Insulin-induced tyrosine phosphorylation of insulin receptor beta subunit (IRbeta) and insulin receptor substrate-1 (IRS-1) and tyrosine/threonine phosphorylation of p44/42 MAPK (ERK-1/2) were evaluated. There were no significant differences in the degree of phosphorylation of IRbeta or ERK-1/2 in the thoracic aorta or in the soleus muscle between FFR and controls. However, tyrosine phosphorylation of IRS-1 in the soleus muscle of FFR was significantly reduced to 80% (p<0.001) of that in controls. The results suggest that PI3-K pathway in skeletal muscle is selectively impaired in FFR, and this impairment may induce hyperinsulinemia, which in turn may stimulate the MAPK pathway and lead to atherosclerosis. Thus PI3-K pathway may be one of the factors underlying the onset of cardiovascular disease in patients with insulin resistance.
Hyakukoku
Masaya
M
Second Department of Internal Medicine, Sapporo Medical University School of Medicine, Sapporo, Japan. hyakoku-masaya@nshp-muroran.or.jp
Higashiura
Katsuhiro
K
Ura
Nobuyuki
N
Murakami
Hideyuki
H
Yamaguchi
Koichi
K
Wang
Ling
L
Furuhashi
Masato
M
Togashi
Nobuhiko
N
Shimamoto
Kazuaki
K
D000818:Animals; D001013:Aorta, Thoracic / Q000378:metabolism*; D019422:Dietary Sucrose / Q000494:pharmacology; D005632:Fructose / Q000494:pharmacology*; D007004:Hypoglycemic Agents / Q000378:metabolism / Q000494:pharmacology*; D007328:Insulin / Q000378:metabolism / Q000494:pharmacology*; D055504:Insulin Receptor Substrate Proteins; D007333:Insulin Resistance / Q000502:physiology; D020935:MAP Kinase Signaling System / Q000187:drug effects / Q000502:physiology*; D008297:Male; D019950:Mitogen-Activated Protein Kinase 1 / Q000378:metabolism; D048052:Mitogen-Activated Protein Kinase 3; D020928:Mitogen-Activated Protein Kinases / Q000378:metabolism; D018482:Muscle, Skeletal / Q000378:metabolism*; D010750:Phosphoproteins / Q000378:metabolism; D010767:Phosphorylcholine; D051381:Rats; D017207:Rats, Sprague-Dawley; D011972:Receptor, Insulin / Q000378:metabolism; D013912:Threonine / Q000378:metabolism; D014443:Tyrosine / Q000378:metabolism
D019422:Dietary Sucrose; D007004:Hypoglycemic Agents; D007328:Insulin; D055504:Insulin Receptor Substrate Proteins; C526296:Irs1 protein, rat; D010750:Phosphoproteins; D010767:Phosphorylcholine; D013912:Threonine; D005632:Fructose; D014443:Tyrosine; D011972:Receptor, Insulin; D019950:Mitogen-Activated Protein Kinase 1; D048052:Mitogen-Activated Protein Kinase 3; D020928:Mitogen-Activated Protein Kinases