Regulation of SMC Proliferation in Insulin Resistance. The sine qua non of insulin resistance in adipose tissue, liver, and muscle is compensatory hyperinsulin-emia. In the insulin resistant state, tyrosine phosphorylation of the insulin receptor and signaling via the insulin receptor substrate (IRS)-1/2/PI-3 kinase/Akt pathway is impaired resulting in diminished metabolic effects. In contrast, tyrosine phosphorylation of ERK1/2 MAPK by insulin is maintained and perpetuated by other growth factors resulting in SMC proliferation and migration. As demonstrated by Walcher et al¹⁸ C-peptide, secreted in equimolar amounts to insulin, activates both the PI-3 kinase/Akt and ERK1/2 MAPK pathways via upstream activation of the Src kinase. Activation of these pathways results in SMC proliferation through phosphorylation of the retinoblastoma protein and cell cycle progression.