Regulation of insulin receptor mRNA splicing in rat tissues. Effect of fasting, aging, and diabetes.

Recent findings suggested that alterations in insulin receptor isoform expression might be involved in the molecular mechanism of insulin resistance. Using reverse transcription reaction followed by competitive polymerase chain reaction, we measured the level of the receptor mRNA variants in rat insulin-sensitive tissues, under conditions of decreased insulin effectiveness (fasting, aging, and diabetes). The liver expressed the mRNA variant with exon 11 predominantly, and the hind limb skeletal muscles expressed the mRNA without exon 11. The heart and epididymal adipose tissue expressed both variants. Fasting and streptozocin-induced diabetes increased the level of receptor mRNAs in the liver but did not modify the repartition between the two variants. The modification of the expression ratio, in favor of the form with exon 11, found by some authors in the skeletal muscle of insulin-resistant patients was not observed in rat muscles that expressed > 99% of the form without exon 11 under all the conditions tested. In adipose tissue, the proportion of both mRNA variants was never altered (45% of exon 11-positive [Ex11+]), while the total receptor mRNA concentration changed markedly during fasting or aging. The only modification observed in the isoform distribution was a significant decrease in Ex11+ mRNA concentration in the liver, muscle, and heart of old rats. We conclude that alternative splicing of insulin receptor mRNA is not involved in the impairment of insulin action during fasting or diabetes. Its potential role in the insulin resistance of old animals remains to be defined.