The human insulin receptor exists in two isoforms, HIR-A and HIR-B, which are generated by alternative splicing of a primary gene transcript and differ by a 12-amino acid insertion sequence in the alpha-subunit. The two receptor isoforms bind insulin with different affinities and are differentially expressed in human tissues. We report here a tissue-specific alteration of the insulin receptor RNA splice pattern in non-insulin-dependent diabetes mellitus (NIDDM) patients. Whereas skeletal muscle of healthy individuals contains exclusively high-affinity HIR-A-encoding RNA, we consistently find low-affinity HIR-B RNA expression in NIDDM muscle tissue at levels similar to HIR-A.