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

KELLERER M;SESTI G

Secondo

Investigation

;SEFFER E;OBERMAIERKUSSER B;PONGRATZ DE;MOSTHAF L;HARING HU

1993

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Abstract

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 generated by alternative splicing of a small exon and display distinct patterns of tissue-specific expression. Using the polymerase chain reaction we have recently shown that skeletal muscle of non-diabetic individuals contains predominantly mRNA encoding HIR-A while in skeletal muscle derived from subjects with Type 2 (non-insulin-dependent) diabetes mellitus similar amounts of each mRNA are expressed. We used a polyclonal antibody which discriminates between HIR-A and HIR-B to assess the isoform expression at the protein level. The antibody showed clearly distinct displacement of insulin binding in skeletal muscle membranes of non-diabetic subjects compared to Type 2 diabetic subjects (displacement of specific I-125-insulin binding: 13 non-diabetic subjects 70.0 % +/- 14.34, 12 Type 2 diabetic subjects 32.6 % +/- 17.45). A control antibody which does not discriminate between both isoforms showed similar displacement of I-125-insulin in membranes of non-diabetic and Type 2 diabetic subjects. These data suggest that the altered expression of receptor isotype mRNA in the skeletal muscle of Type 2 diabetic subjects leads to an altered receptor isoform pattern in the plasma membrane. While skeletal muscle membranes of non-diabetic subjects contain predominantly HIR-A, membranes of Type 2 diabetic subjects show an increased level of HIR-B in addition to HIR-A.