fig4

Figure 4. Hierarchical network model of peripheral insulin sensitivity and failure modes. The diagram summarizes four principles: a hierarchical threshold of tissue sensitivity to insulin, in which adipose tissue responds first, followed by liver and then muscle; inter-organ communication centered on the liver as a metabolic hub; a constitutive portal-pulsatile insulin architecture with higher portal than peripheral insulin concentrations; and three major failure modes of the network - adipose, hepatic, and muscular - that converge on hyperglycemia and glucose intolerance. This framework links physiological organization to the rationale for combination therapies that target multiple nodes of the network. FFAs: Free fatty acids; VLDL: very-low-density lipoprotein.