Regulation of human insulin receptor RNA splicing invivo.

Alternative splicing involving the inclusion orexclusion of exon 11 in insulin receptor mRNA results in two isoforms of thealpha subunit. The two subunits display tissue-specific variation in relativeabundance at both RNA and protein levels and discrete differences in biologicalproperties. We have previously reported a small decrease in the relative levelof RNA molecules lacking exon 11 (Ex 11-) in skeletal muscle ofnon-insulin-dependent diabetes mellitus (NIDDM) patients. In the present study,we describe a drastically altered ratio in favor of Ex 11- RNA in a NIDDMpatient with markedly impaired insulin-mediated glucose utilization. The ratiobetween the splice variants changed from 74% to 48% Ex 11- RNA after initiationof insulin treatment, which considerably improved his blood glucoseconcentrations and insulin-stimulated glucose utilization rate. This shows thatsplicing can be regulated by metabolic and/or hormonal factors in response tochanges in the in vivo milieu. No genomic deletion or base substitution ineither the coding regions or exon-intron borders was found that explains thealtered splicing. Heterozygous mutations were excluded in sequences of putativeimportance for splicing outside the analyzed regions as both alleles wereexpressed and spliced in an identical fashion. Furthermore, these resultssuggest that this patient fails to regulate alternative splicing of exon 11 inthe manner observed in most NIDDM patients and that this defect is associatedwith the extreme impairment in insulin action.