Network medicine-travelling with the insulin receptor: Encounter of the second type

Important progress has been made in understanding many aspects of insulin action in the last 10 years. Attention will be focused here on the physical protein interaction network of the internalized insulin receptor (IR) and its relationships with the genetic architecture of type 2 diabetes mellitus (T2D). The IR recognizes signals from the outside (circulating insulin) and engages the insulin signaling response. Within seconds, the IR is also involved in insulin internalization and its subsequent degradation in endosomes (physiological clearance of insulin). A T2D disease module sharing functional similarities with insulin secretion in pancreatic islets was recently identified in the close neighborhood of the internalized IR in liver. This module brought a new light on the apparent functional heterogeneity of numerous genes at risk to T2D by linking them to a few noncanonical layers of signaling feedback loops. These findings should be translated into a better understanding of the primary mechanisms of the disease and consequently a more precise sub-classification of T2D, ultimately leading to precision medicine and the development of new therapeutical drugs.