ALTERED PATTERN OF INSULIN-RECEPTOR ISOTYPES IN SKELETAL-MUSCLE MEMBRANES OF TYPE-2 (NON-INSULIN-DEPENDENT) DIABETIC SUBJECTS

The human insulin receptor exists in two isoforms (HIR-A alpha-subunit 719 amino acids and HIR-B alpha-subunit 731 amino acids) which are ge nerated by alternative splicing of a small exon and display distinct p atterns of tissue-specific expression. Using the polymerase chain reac tion we have recently shown that skeletal muscle of non-diabetic indiv iduals contains predominantly mRNA encoding HIR-A while in skeletal mu scle derived from subjects with Type 2 (non-insulin-dependent) diabete s mellitus similar amounts of each mRNA are expressed. We used a polyc lonal antibody which discriminates between HIR-A and HIR-B to assess t he isoform expression at the protein level. The antibody showed clearl y distinct displacement of insulin binding in skeletal muscle membrane s of non-diabetic subjects compared to Type 2 diabetic subjects (displ acement of specific I-125-insulin binding: 13 non-diabetic subjects 70 .0 % +/- 14.34, 12 Type 2 diabetic subjects 32.6 % +/- 17.45). A contr ol antibody which does not discriminate between both isoforms showed s imilar displacement of I-125-insulin in membranes of non-diabetic and Type 2 diabetic subjects. These data suggest that the altered expressi on of receptor isotype mRNA in the skeletal muscle of Type 2 diabetic subjects leads to an altered receptor isoform pattern in the plasma me mbrane. While skeletal muscle membranes of non-diabetic subjects conta in predominantly HIR-A, membranes of Type 2 diabetic subjects show an increased level of HIR-B in addition to HIR-A.