Fig. 10.

Proposed mechanism of podocyte IR degradation and its consequences. Normal insulin signalling to podocytes leads to phosphorylation of IRS proteins, predominantly IRS-2 [54], and activation of downstream signalling events, including the phosphorylation of Akt and mTOR. Nephrin is also required for insulin-stimulated glucose uptake (in part via interaction of nephrin with VAMP2 [39, 40] and insulin-stimulated actin remodelling). Hyperinsulinaemia, occurring in diabetes and insulin resistance, causes an increase in proteasomal and lysosomal degradation of the podocyte IR, attenuating downstream signal transduction. Ultimately, loss of podocyte IRs may exacerbate albuminuria and features of diabetic nephropathy, dysregulating the ER stress response [17], VEGF-A secretion [56], ROS production [57], autophagy [57], cell viability [20] and actin remodelling, and reducing glucose uptake. ER, endoplasmic reticulum; GSV, GLUT storage vesicle; UPR, unfolded protein response; VAMP2, vesicle-associated membrane protein 2