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Lancet. 1996 Jun 8;347(9015):1586-90.

Functional activation of mutant human insulin receptor by monoclonal antibody.

Author information

1
Department of Medicine, University of Cambridge, Addenbrooke's Hospital, UK.

Abstract

BACKGROUND:

A mutant insulin receptor, Ser323Leu, has been reported in two severely insulin-resistant patients with Rabson-Mendenhall syndrome. In both cases, extreme hyperglycaemia could not be controlled by conventional antidiabetic therapy. The SER323Leu mutant insulin receptor is inserted normally in the plasma membrane but has very low binding affinity for insulin. A monoclonal antibody directed against the extracellular domain of the insulin receptor (83.14) can mimic the natural ligand as far as the first step after ligand binding--autophosphorylation of the intracellular domain of the receptor. We have investigated whether antibody binding can imitate autophosphorylation of the Ser323Leu mutant receptor and lead to metabolic events within the cell.

METHODS:

The effects of insulin and the insulin-receptor monoclonal antibody on receptor autophosphorylation and glycogen synthesis were compared in Chinese hamster ovary cells expressing the wild-type human insulin receptor, mock-transfected cells, cells expressing an insulin-receptor mutant without autophosphorylation capacity, and cells expressing the Ser323Leu mutant receptor.

FINDINGS:

Cells expressing the SER323Leu mutant receptor had very low specific insulin binding and, unlike cells expressing wild-type insulin receptors, did not show autophosphorylation or stimulation of glycogen synthesis in response to insulin. However, exposure of cells expressing the Ser323Leu mutant receptor to monoclonal antibody 83.14 resulted in autophosphorylation and stimulation of glycogen synthesis similar to that seen in cells expressing wild-type insulin receptors.

INTERPRETATION:

Although insulin does not bind to cells expressing the Ser323Leu mutation, insulin signalling can be mimicked by exposure of the cells to an antibody to the extracellular domain of the insulin receptor. Activation by monoclonal antibodies of mutant transmembrane receptors that show normal cell-surface expression but defective ligand binding may provide an approach to the therapy of some subtypes of inherited hormone resistance for which little effective treatment is available.

PMID:
8667867
[Indexed for MEDLINE]

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