In some patients with genetic forms of extreme
insulin resistance, there is a marked decrease in the number of
insulin receptors on the cell surface. We studied an
insulin-resistant patient (RM-1) with the
Rabson-Mendenhall syndrome. As judged by
insulin-binding studies, Epstein-Barr virus-transformed lymphocytes from patient RM-1 exhibit a 90% decrease in the number of
insulin receptors. Similarly, with either
lactoperoxidase-catalyzed radioiodination of
cell surface receptors or biosynthetic labeling of receptors with [3H]
glucosamine, we demonstrated an 80-90% decrease in the number of
insulin receptors in cells from patient RM-1. Previous studies have shown that the marked decrease in
insulin receptors of the Rabson-Mendenhall patient is not due to accelerated receptor degradation. Therefore, we investigated the possibility that a slow rate of receptor biosynthesis might account for the 90% reduction of
insulin receptors in cells from this patient.
Insulin-receptor biosynthesis proceeds through a
glycoprotein precursor with an apparent Mr of 190,000. It undergoes
endopeptidase cleavage and further posttranslational processing to yield the mature 135,000- and 95,000-Mr
glycoprotein subunits. We studied the biosynthesis of the 190,000-Mr precursor and mature receptor subunits by a pulse-chase labeling technique with [2-3H]
mannose. The time course of
insulin-receptor biosynthesis appeared normal in cells from patient RM-1, despite a 10-fold reduction in the number of receptors on the cell surface. Parallel pulse-chase experiments with either [2-3H]
mannose or [35S]
methionine yielded the same results regardless of which label was employed. Thus, the receptor precursor in the Rabson-Mendenhall patient seems to be synthesized at a normal rat.(ABSTRACT TRUNCATED AT 250 WORDS)