**2.2.2 Insulin**

Insulin is involved in the upregulation of megalin, which in turn may be associated with increased endocytosis and metabolism of glomerular-filtered proteins, leading to intracellular metabolic overload. Cross-talk between insulin-insulin receptor substrate/phosphoinositide 3-kinase and angiotensin II-ERK1/2 signaling pathways was previously observed in cultured PTCs (Hosojima et al. 2009), and the balance between the actions and interactions of angiotensin II and insulin may also be important in regulating the expression of megalin *in vivo*. Hyperinsulinemia associated with metabolic syndrome is thought to stimulate insulin signaling in PTCs, while impaired insulin signaling (so-called insulin resistance) is suggested to occur in kidney cells in type 2 diabetic models; moreover, the intrarenal activation of angiotensin II appears to be associated with the development of insulin resistance (Tiwari et al. 2007). Recently, megalin was shown to be downregulated by the lipopolysaccharide-tumor necrosis factorα-ERK1/2 signaling pathway that may also impair insulin signaling in diabetes (Takeyama et al. 2011). In addition, positive control of megalin expression has been demonstrated by peroxisome proliferator-activated receptor isoforms peroxisome proliferator-activated receptor (PPAR)α and PPARγ and their insulin-sensitizing agonists (Cabezas et al. 2011).
