Nanoscale Spatial Regulation of Insulin Receptor Signalling Clusters using DNA Nanostructures

Type 2 diabetes is a major public health problem globally. However, the signalling pathways underlying the disease are still incompletely understood. Improper signalling via the insulin receptor (IR) is a key factor in the development of insulin resistance and many have focussed on the IR as a target for potential diabetes treatments. Recent work has provided evidence for the formation of IR clusters at the cell membrane yet it is not known how this cluster formation affects IR-mediated signalling downstream. To investigate if and how the nanoscale spatial organization of the IR changes its response, we have designed and constructed DNA nanostructures on which we can precisely position insulin molecules in various stoichiometries, densities, and geometries. We have confirmed via surface plasmon resonance (SPR) that these insulin-DNA nanostructures can bind the insulin receptor, and have shown that they can activate insulin receptors in the cell membrane of cultured adipocytes. These nanostructures constitute an exciting new tool for the interrogation and manipulation of IR spatial organization at the cell membrane and have the potential to provide crucial insights which would contribute to the development of next-generation insulin drugs and improved diabetes treatments.