Insulin Receptor (IR) Moves from Surface to Inside Nucleus After Binding Insulin; IR Then Binds to RNA Polymerase on Chromatin at ~4,000 Different Sites Across the Genome, Primarily in Promoter Regions, Where It Can Regulate Gene Expression

The discovery of insulin in the 1920s marked the breakthrough in the almost 3,500-year-long mystery of diabetes, a disease first described in ancient Egyptian papyruses. Until its discovery, physicians struggled to explain how symptoms such as sugary urine, constant thirst, and frequent urination could lead to ailments ranging from blindness and nerve damage to coma and death. Over the past century, scientists have detailed the hormone’s central role as a regulator of blood sugar, mapped its cell-signaling pathways, and established its involvement in diabetes and a staggering array of other chronic conditions, including neurodegeneration, cardiovascular disease, and cancer. Still, many aspects of insulin signaling remain unclear, particularly its long-term effects on cells, and there are currently no effective cures for the hundreds of millions of people around the world living with diabetes. Now, researchers from Harvard Medical School (HMS) have made key new insights into the molecular behavior of insulin. In article, published online on April 4, 2019 in Cell, the Harvard scientists describe an unexpected mechanism by which insulin triggers changes to the expression of thousands of genes throughout the genome. Their analyses show that the insulin receptor—a protein complex at the cell surface—physically relocates to the cell nucleus after it detects and binds insulin. Once in the nucleus, the insulin receptor helps initiate the expression of genes involved in insulin-related functions and diseases. This process was impaired in mice with insulin resistance.
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