Modulation of insulin signalling by insulin sensitizers.
Insulin resistance is a hallmark of Type II diabetes. It is well documented that insulin sensitizers such as peroxisome-proliferator-activated receptor gamma agonists and aspirin improve insulin action in vivo. The detailed mechanisms by which the insulin sensitizers promote insulin signalling, however, are not completely understood and remain somewhat controversial. In the present review, we summarize our studies attempting to explore the molecular mechanisms underlying the effects of insulin sensitizers in cells and in animal models of insulin resistance. In 3T3-L1 adipocytes and/or in HEK-293 cells stably expressing recombinant IRS1 protein (insulin receptor substrate protein 1), the peroxisome-proliferator-activated receptor gamma agonist rosiglitazone and aspirin promote insulin signalling by decreasing inhibitory IRS1 serine phosphorylation. Increased IRS1 Ser-307 phosphorylation and concomitant decreased insulin signalling as measured by insulin-stimulated IRS1 tyrosine phosphorylation and Akt threonine phosphorylation were observed in adipose tissues of Zucker obese rats compared with lean control rats. Treatment with rosiglitazone for 24 and 48 h increased insulin signalling and decreased IRS1 Ser-307 phosphorylation concomitantly. Treatment of the Zucker obese rats with rosiglitazone for 24 h also reversed the high circulating levels of free fatty acids, which have been shown to correlate with increased IRS1 serine phosphorylation. Taken together, the results suggest that IRS1 inhibitory serine phosphorylation is a key component of insulin resistance and its reversal may be physiologically relevant to insulin sensitization in vivo.
Jiang
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Metabolic Disorders - Diabetes, Merck Research Laboratories, PO Box 2000, Rahway, NJ 07065, USA.
Zhang
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D000818:Animals; D006801:Humans; D007328:Insulin / Q000378:metabolism*; D055504:Insulin Receptor Substrate Proteins; D007333:Insulin Resistance; D047493:PPAR alpha / Q000819:agonists / Q000378:metabolism; D010750:Phosphoproteins / Q000378:metabolism; D010768:Phosphoserine / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects*
C526292:IRS1 protein, human; D007328:Insulin; D055504:Insulin Receptor Substrate Proteins; C526296:Irs1 protein, rat; D047493:PPAR alpha; D010750:Phosphoproteins; D010768:Phosphoserine