HUMAN DIABETES-ASSOCIATED WITH DEFECTS IN NUCLEAR REGULATORY PROTEINSFOR THE INSULIN-RECEPTOR GENE

The control of gene transcription is mediated bq sequence-specific DNA -binding proteins (trans-acting factors) that bind to upstream regulat ory elements (cis elements), We have previously identified two DNA-bin ding proteins that specifically interact with two unique AT-rich seque nces of the 5' regulatory region of the insulin receptor gene which ha ve in vivo promoter activity, Herein we have investigated the expressi on of these DNA-binding proteins in cells from two unrelated patients with insulin resistance and non-insulin-dependent diabetes mellitus. I n these patients, the insulin receptor gene was normal. In EBV-transfo rmed lymphoblasts from both patients, insulin receptor mRNA levels and insulin receptor expression were decreased. The expression of nuclear -binding proteins for the 5' regulatory region of the insulin receptor gene was markedly reduced, and this defect paralleled the decrease in insulin receptor protein expression. These studies indicate that DNA- binding proteins to the regulatory region of the insulin receptor gene are important for expression of the insulin receptor. Further, they s uggest that in affected individuals, defects in the expression of thes e proteins may cause decreased insulin receptor expression and insulin resistance.