Glucose Transporters in Diabetic Kidney Disease—Friends or Foes?

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.

Thirty sweet years of GLUT4

“…The analysis of the role of GLUT4 in metabolism and disease would be incomplete without pointing out its localization in discrete loci outside of muscle and adipose tissues, specifically within areas of the brain (136 -138), cerebellum (139), and kidney (140,141). Undoubtedly, the future will disclose more about the function of the transporter in these areas and its JBC REVIEWS: GLUT4 perspective at 30 impact on whole-body metabolism as well as its potential failure leading to disease.…”

SHIPping out diabetes—Metformin, an old friend among new SHIP2 inhibitors

“…To enhance glucose uptake, PtdIns(3,4,5)P3 transfers signals to downstream molecules including serine/threonine kinase Akt . In the basal state, GLUT4 resides mainly in the cytoplasm and only a small proportion is detected at the plasma membrane, but insulin‐induced activation of Akt induces rapid translocation of GLUT4‐containing vesicles to the cell surface . The trafficking is controlled at various steps with distinct sets of proteins.…”

“…Specifically, the GLUT4‐containing vesicles contain vesicle‐SNAREs (soluble N‐ethylmaleimide‐sensitive factor attachment protein receptors), which interact with target‐SNAREs on the plasma membrane. These together, further aided by sets of accessory proteins, facilitate the translocation, docking and fusion of the GLUT4‐containing vesicles with the plasma membrane leading to uptake of glucose into cells (Figure A) …”

“…It is plausible that the cause of insulin resistance is multifactorial, a combination of genetic defects and environmental factors, or that it is caused by simultaneous lower functional input of multiple components of the pathway, which in the end is insufficient to lead to full activation of the signalling cascade and uptake of glucose into cells . The complex regulation of the trafficking of GLUT4‐containing vesicles via various accessory molecules at different steps makes also the trafficking process a potential site for alterations, which may lead to impaired translocation of GLUT4 to the plasma membrane and consequent insulin resistance (Figure A) …”

“…Defining whether podocytes in patients with DKD are insulin resistant is challenging, and the rarity of normoglycaemic patients who show insulin resistance and develop DKD suggest that development of DKD involves a combination of multiple factors in addition to insulin resistance . Recent reviews summarize in more detail the molecular mechanisms involved in the development of the kidney complication in diabetes, including the role of insulin resistance in the context of the insulin signalling and glucose transporters . The significance of insulin signalling in maintaining the kidney function is supported by intervention studies in both patients with diabetes and experimental animal models of diabetes showing that insulin sensitizers are renoprotective.…”