Glucose toxicity.

Glycation of proteins and lipids occurs as a consequence of a nonenzymatic reaction between these entities and glucose. These products are progressively modified, nonenzymatically, to eventually form a stable group of molecules referred to as advanced glycation end products (AGEs). These glucose products, also referred to as glycotoxins, accumulate from aging and the amounts are greatly increased in diabetics as a result of continuous hyperglycemia1. These adducts have deleterious effects on both large and small blood vessels2. Most cells have surface receptors, including mesangial cells, that recognize these adducts. Grouped under the generic title of AGE receptors, these receptors mediate both the uptake of AGEs and mediate cellular responses to AGEs. The responses are multiple, including the release of growth factors and cytokines, changes in extracellular matrix turnover, and alterations in growth control2. Many of these responses are considered to be important in the genesis of diabetic nephropathy. Protein kinase C (PKC) has been shown to be very important in the genesis of glucose-related responses in both mesangial cells and whole glomeruli3,4,5. The importance of the isoform of PKC was recently emphasized in studies showing that inhibition of this isoform ameliorated both retinal and renal lesions in diabetic rats5. AGEs are removed by proteolysis at tissue sites, either nonspecific or receptor-directed release. Since renal excretion is the principal means by which AGEs are eliminated from the body, decreased renal function would be expected to compound the injury because these products accumulate in tissues and body fluids. The senior authors of one study in this issue of Kidney International have provided a series of observations linking early members of the reaction between glucose and proteins, Amadori-glucose adducts, to glomerular mesangial cell responses that favor the development of the accumulation of extracellular matrix6. They have also shown that administering antibodies to these early glucose adducts inhibits the development of nephropathy in db/db mice (a model of spontaneous diabetes mellitus)7. Their current study now expands their observations to include mouse glomerular endothelial cells in vitro, and demonstrates that mouse glomerular endothelial cells also respond to glycated albumin using transforming growth factor-1 (TGF-1) and PKC pathways. Other investigators have focused on the effects of different reactive intermediates in the cascade of chemical moieties formed as a result of glucose-protein interactions, including studies of numerous other tissues. In most studies, the authors focused on the addition of glucose adducts to cells in vitro. Some examined animal tissues after the systemic administration of mixtures of glucose adducts. The use of inhibitors of adduct formation, or breakers of formed adducts, attest to their presence in tissues and their induction of lesions therein8. One issue that should be studied further is that only a fraction of diabetics develop end-organ damage. In the case of the kidney, this amounts to approximately 30% of those at risk. This fact, and the observation that several genes appear to be associated with an increased risk for diabetic nephropathy, supports the hypothesis that genetic susceptibility plays a major role in the development of this complication. Even with the best control of glycemia in either type 1 or type 2 diabetes, the development of nephropathy is not eradicated, even though glycemic control is critical to reduce the risk for nephropathy9. There is a vast difference between individuals and their response to glucose adducts. This has been well documented in experimental animals. For instance, we found that certain mouse strains develop severe glomerulosclerosis after the onset of diabetes, whereas others did not10. Furthermore, the susceptibility of developing glomerulosclerosis was independent of the type of eliciting stimulus. Specifically, nephron reduction in adulthood and toxin exposure in utero or in vitro all elicited an abnormal response resulting in glomerulosclerosis11. Others have observed similar effects in diabetic rats, that is, diabetic BB rats do not develop glomerulosclerosis, diabetic Sprague-Dawley rats develop focal lesions, and diabetic fawn-hooded rats develop diffuse glomerulosclerosis. Finally, it may be necessary to examine cells from animals and patients who either have, or have been shown to develop, diabetic nephropathy, since we have shown that mesangial cells under these conditions have a stable phenotypic change that results in unique responses to agonists12. Chen et al and other investigators have contributed many observations on the biology of TGF-1 responses to hyperglycemia and glucose adducts. Glucose adducts form on both extracellular and intracellular moieties. In fact, there is good reason to suspect that intracellular adducts are at least equally important biologically as those formed in the extracellular milieu, possibly due to their enhancement of oxidative stress13. The advent of new means and avenues of delivering insulin, as well as new pharmacological agents that improve glucose utilization, makes it even more critical to identify those patients at risk of end-organ damage. It is this group of patients who require new investigations and new ideas.