Altered expression levels and impaired steps in the pathway to phosphatidylinositol 3-kinase activation via insulin receptor substrates 1 and 2 in Zucker fatty rats.
To elucidate the mechanism of obesity-related insulin resistance, we investigated the impaired steps in the processes of phosphatidylinositol (PI) 3-kinase activation through binding with insulin receptor substrates 1 and 2 (IRS-1 and IRS-2) in liver and muscle of Zucker fatty rats. The expressions of IRS-1 and IRS-2 were shown to be downregulated in both liver and muscle in fatty rats (hepatic IRS-1, 83%; hepatic IRS-2, 45%; muscle IRS-1, 60%; muscle IRS-2, 78%), resulting in decreased tyrosine phosphorylation in response to insulin stimulation. Despite the decrease in the tyrosine phosphorylation levels of hepatic IRS-1 and IRS-2 being mild to moderate, associated PI 3-kinase activities were dramatically decreased in fatty rats (IRS-1, 14%; IRS-2, 10%), which may suggest alteration in the sites of phosphorylated tyrosine residues of hepatic IRS-1 and IRS-2. In addition, we demonstrated that the expressions of p85alpha and p55alpha regulatory subunits of PI 3-kinase were reduced (p85alpha, 67%; p55alpha, 54%), and that the p50alpha regulatory subunit was markedly upregulated (176%) in the livers of fatty rats without apparent alterations in expressions of the catalytic subunits p110alpha and p110beta. These alterations may reflect the obesity-related insulin resistance commonly observed in human NIDDM.
Anai
M
M
Institute for Adult Diseases, Asahi Life Foundation, Tokyo, Japan.
Funaki
M
M
Ogihara
T
T
Terasaki
J
J
Inukai
K
K
Katagiri
H
H
Fukushima
Y
Y
Yazaki
Y
Y
Kikuchi
M
M
Oka
Y
Y
Asano
T
T
D000418:Albumins / Q000032:analysis / Q000235:genetics; D000595:Amino Acid Sequence; D000818:Animals; D001483:Base Sequence; D001786:Blood Glucose / Q000032:analysis / Q000378:metabolism; D015536:Down-Regulation; D004789:Enzyme Activation / Q000502:physiology; D005260:Female; D015971:Gene Expression Regulation, Enzymologic; D007328:Insulin / Q000097:blood; D055504:Insulin Receptor Substrate Proteins; D007333:Insulin Resistance / Q000502:physiology; D047908:Intracellular Signaling Peptides and Proteins; D008099:Liver / Q000737:chemistry / Q000201:enzymology* / Q000502:physiology; D008969:Molecular Sequence Data; D018482:Muscle, Skeletal / Q000737:chemistry / Q000201:enzymology* / Q000502:physiology; D009218:Myosins / Q000032:analysis / Q000235:genetics; D019869:Phosphatidylinositol 3-Kinases / Q000032:analysis / Q000235:genetics / Q000378:metabolism*; D010750:Phosphoproteins / Q000032:analysis / Q000235:genetics / Q000502:physiology*; D010766:Phosphorylation; D012333:RNA, Messenger / Q000032:analysis / Q000737:chemistry / Q000235:genetics; D051381:Rats; D011924:Rats, Zucker; D015398:Signal Transduction / Q000502:physiology; D014443:Tyrosine / Q000378:metabolism
D000418:Albumins; D001786:Blood Glucose; C526292:IRS1 protein, human; C526297:IRS2 protein, human; D007328:Insulin; D055504:Insulin Receptor Substrate Proteins; D047908:Intracellular Signaling Peptides and Proteins; C526296:Irs1 protein, rat; C526299:Irs2 protein, rat; D010750:Phosphoproteins; D012333:RNA, Messenger; D014443:Tyrosine; D019869:Phosphatidylinositol 3-Kinases; D009218:Myosins