Abstract
Diabetic kidney disease (DKD) is a major microvascular complication of diabetes and a common cause of end-stage renal disease worldwide. DKD manifests as an increased urinary protein excretion (albuminuria). Multiple studies have shown that insulin resistance correlates with the development of albuminuria in non-diabetic and diabetic patients. There is also accumulating evidence that glomerular epithelial cells or podocytes are insulin sensitive and that insulin signaling in podocytes is essential for maintaining normal kidney function. At the cellular level, the mechanisms leading to the development of insulin resistance include mutations in the insulin receptor gene, impairments in the phosphoinositide 3-kinase (PI3K)/AKT signaling pathway, or perturbations in the trafficking of glucose transporters (GLUTs), which mediate the uptake of glucose into cells. Podocytes express several GLUTs, including GLUT1, GLUT2, GLUT3, GLUT4, and GLUT8. Of these, the most studied ones are GLUT1 and GLUT4, both shown to be insulin responsive in podocytes. In the basal state, GLUT4 is preferentially located in perinuclear and cytosolic vesicular structures and to a lesser extent at the plasma membrane. After insulin stimulation, GLUT4 is sorted into GLUT4-containing vesicles (GCVs) that translocate to the plasma membrane. GCV trafficking consists of several steps, including approaching of the GCVs to the plasma membrane, tethering, and docking, after which the lipid bilayers of the GCVs and the plasma membrane fuse, delivering GLUT4 to the cell surface for glucose uptake into the cell. Studies have revealed novel molecular regulators of the GLUT trafficking in podocytes and unraveled unexpected roles for GLUT1 and GLUT4 in the development of DKD, summarized in this review. These findings pave the way for better understanding of the mechanistic pathways associated with the development and progression of DKD and aid in the development of new treatments for this devastating disease.
Highlights
Diabetic kidney disease (DKD) is the serious complication of diabetes
We summarize insulin signaling in podocytes in the context of glucose uptake and concentrate in describing the current knowledge on the glucose transporters (GLUTs) and the regulation of GLUT trafficking in podocytes
Additional work is needed to investigate whether the function of GLUT4 in podocyte is independent of insulin signaling, as a study suggests that GLUT4 may directly regulate actin remodeling [82]
Summary
Diabetic kidney disease (DKD) is the serious complication of diabetes. Clinically, DKD manifests as progressive albuminuria and gradual decline in estimated glomerular filtration rate. Hyperglycemia plays a central role, and insulin resistance is a risk factor for DKD and contributes to the development of the disease [3]. This is supported by studies showing that insulin resistance correlates with microalbuminuria in diabetic [4,5,6,7] and non-diabetic subjects [8]. Insulin resistance has been proposed as one of the key mechanisms that associates with the development and progression of DKD [12] This raises interest in the pathways that regulate insulin sensitivity of podocytes and in the perturbations in these pathways leading to the development of insulin resistance of these specialized cells. We summarize insulin signaling in podocytes in the context of glucose uptake and concentrate in describing the current knowledge on the glucose transporters (GLUTs) and the regulation of GLUT trafficking in podocytes
Sign-in/Register to view highlights & summary Sign-in/Register to access full text options 
Free) 
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a call
