EXPRESSION OF INSULIN-RECEPTOR SPLICED VARIANTS AND THEIR FUNCTIONAL CORRELATES IN MUSCLE FROM PATIENTS WITH NON-INSULIN-DEPENDENT DIABETES-MELLITUS

Due to alternative splicing of exon 11 of the receptor gene, the human insulin receptor exists in two forms, that have distinct tissue-speci fic expression and are functionally different. Needle biopsies obtaine d from vastus lateralis muscle from 20 patients with noninsulin-depend ent diabetes mellitus (NIDDM) and 20 normal control subjects were anal yzed for the relative expression of insulin receptor mRNA variants in a novel assay using fluorescence-labeled primers and subsequent analys is on an automated DNA sequencer. In subgroups of patients and control subjects, insulin binding and tyrosine kinase activity were examined in wheat germ agglutinin-purified insulin receptors isolated from musc le biopsies. Moreover, insulin-stimulated glucose disposal was studied by means of the euglycemic hyperinsulinemic clamp technique. No diffe rence in the relative expression of spliced variants of the insulin re ceptor mRNA was observed (control subjects, 71.4 +/- 1.3% insulin rece ptor mRNA with exon 11; NIDDM patients, 71.5 +/- 1.3% insulin receptor mRNA with exon 11). No significant interrelationships were demonstrat ed among the relative expression of insulin receptor mRNA variants, in sulin binding, and tyrosine kinase activity toward the exogenous subst rate poly(Glu-Tyr(4:1)). Furthermore, no significant relationship was demonstrated between the glucose disposal rate and the relative expres sion of insulin receptor splice variants. In conclusion, in skeletal m uscle from both normal control subjects and NIDDM patients, the propor tion of insulin receptor mRNA with exon 11 is about 70%. In addition, no significant correlations exist among insulin binding, insulin recep tor tyrosine kinase activity, glucose disposal rate, and expression of alternative spliced insulin receptors in human skeletal muscle.