Sweet debate: fructose versus glucose in diabetic kidney disease.

The prevalence of diabetes continues to increase worldwide.1 Renal disease shows the strongest correlationwith excess mortality in diabetes, yet the mechanisms of diabetic kidney disease (DKD) remain poorly understood. It has been repeatedly demonstrated that hyperglycemia plays a crucial role in DKD initiation, both in patients and in animal models. Cells that are unable to downregulate their glucose transporters in response to hyperglycemiawill experience increased intracellular glucoseflux.2 Intracellular glucose is eventually metabolized to pyruvate by a series of enzymatic reactions called glycolysis. Intracellular glucose is first rapidly converted via an energy-dependent mechanism into fructose 6-phosphate and then by the phosphofructokinase to fructose 1,6-phosphate. Phosphofructokinase is a rate-limiting enzyme in glycolysis. Fructose 6-phosphate can also be diverted into the hexosamine pathway to become glucosamine, an important potential mediator of diabetic complications. Increased fructose consumption has been suggested to play a role in obesity, hypertension, and metabolic syndrome development. There is a correlation between the use of high fructose corn syrup and the increase in obesity rates in the United States.3 Dietary fructose mostly enters the cells via glucose transporter-5 and is metabolized, primarily in the liver, by phosphorylation on the 1-position by the hexokinase also known as fructokinase or ketohexokinase (Khk) enzyme, a process that bypasses the ratelimiting phosphofructokinase step in glycolysis. There are slight differences in glucose versus fructosemetabolism because fructose results in trioses that lack phosphate thus need to be phosphorylated formitochondrial oxidation. Hepaticmetabolism of fructose favors lipogenesis because fructose metabolites contribute to triglyceride backbone structure. Furthermore, the ADP formed from ATP after phosphorylation of fructose on the 1-position can be further metabolized to uric acid,4 which utilizes nitric oxide, a key modulator of vascular function. Indeed, an association between fructose intake, uric acid, and triglyceride levels has been observed.3 In addition to dietary fructose, intracellular glucose can be converted into fructose by the aldose reductase enzyme in the polyol pathway.5 Aldose reductase and the polyol pathways play an important role in the development of diabetic complications. Increased accumulation of intracellular reactive oxygen species is considered the final common mechanism that mediates hyperglycemia-induced intracellular biochemical changes and development of diabetic complications. Increased reactive oxygen species generationcancause increasedcell stress andapoptosis and is also shown to turn on the pleiotropic transcription factor NF-kB.6,7 NF-kB is an important regulator of the immune system and its activation has been reported in patient samples and animal models with DKD.8 Increased NF-kB activation is associated with increased expression of proinflammatory cytokines, including monocyte chemoattractant protein-1/chemokine (C-C motif) ligand 29 and TNF-a.10 TNF-a levels positively correlate with and can predict DKD development in patients with type 1 or type 2 diabetes. In addition, genetic ablation or inhibition of monocyte chemoattractant protein-1 significantly ameliorates DKD development in animal models.11 Although DKD was traditionally groupedunder nonimmune-mediated kidneydiseases, recent reports suggest that inflammation and cytokines play an important role in DKD development.12 In this issue of JASN, Lanaspa et al.13 add yet another piece to the complex picture of the metabolic basis of DKD. Lanaspa et al. examined the role of endogenous fructose in the pathogenesis of DKD in vivo, by using a fructokinase-deficient mouse model (Khk). The authors demonstrate that endogenous fructose, produced from glucose in diabetes through the activation of the polyol pathway in the proximal tubule, is involved in development of tubulointerstitial inflammation and renal injury. Wild-type diabetic (streptozotocin-induced) mice developed metabolic characteristics of diabetes and histologic features of diabetic nephropathy.AlthoughKhkknockoutmice developed a similar degree of hyperglycemia, they were relatively protected from renal injury, asmanifested by both laboratory and histologic parameters. Lanaspa et al.13 speculated that a blunted inflammatory response, including a lower expression of inflammatory cytokines and reduced abundance of macrophages in the renal cortex, is responsible for the protective phenotype. The diminished inflammatory response, including decreased NF-kB activation, was also demonstrated in vitro in HK-2 proximal tubule cells, in which KHK expression was silenced. The pathogenic activation of the proinflammatory system in diabetic proximal tubules was induced through the excessive Published online ahead of print. Publication date available at www.jasn.org.