Pathways Of Hyperglycemiainduced Damage

As glucose is metabolized, both intra- and extracellular environments are affected by hyperglycemia and endothelial damage can occur. There is a debate (4,6,44) over the pathways through which these hyperglycemia-induced changes in cellular conditions lead to complications. We focus on four major pathways that have been implicated in the process leading to microvascular complications: (i) increased polyol pathway flux, (ii) increased advanced glycation end product (AGE) formation, (iii) activation of protein kinase C (PKC) isoforms, and (iv) increased hexosamine pathway flux. While we will focus on these pathways and their association with microvascular complications, these pathways may be implicated in macrovascular complications as well. Further, these pathways are not mutually exclusive. One or more of the pathways may be operating at a given time, and the progression toward complications may require an interaction among them.

(i) In the presence of a hyperglycemic environment, there is an overproduction of the polyalcohol sorbitol and a decrease in NADPH (used by aldose reductase to reduce glucose to sorbitol). This change in the intracellular environment results in a build up of sorbitol in the cell, which is toxic and alters the redox balance (6). Another result of decreased NADPH is an accumulation of free radicals, which interfere with the mitochondrial production of energy, potentially leading to the formation of AGEs (45).

(ii) AGEs cause tissue damage and have been used to detect damage due to hyper-glycemia (46). AGEs are disruptive to the overall process of glucose metabolism in that these end products tend to accumulate on proteins and modify their functions. Increased levels of AGEs due to hyperglycemia leads to a rise in the RAGE and AGE complex, which

Figure 4 Brownlee's depiction of the four mechanisms and unifying principle. Source: Adapted with permission from Ref. 44.

is a catalyst for an inflammatory process involving activation and production of cytokines and vascular growth factors, contributing to overall vascular pathology (47,48). The AGE pathway from hyperglycemia to microvascular complications is also supported by the findings that an AGE inhibitor, aminoguanidine, slowed the progression of nephropathy in patients with T1D (51,52).

(iii) PKC is a group of proteins with important roles in cell signaling, expression of genes, and control over cell division and differentiation (51). There are at least 12 proteins of the PKC family and 9 have a domain that binds phospholipid diacylglycerol. The majority of PKC are classic forms and in the presence of calcium and diacylglycerol, these forms activate vascular growth and apoptotic processes (51). Hyperglycemia increases the amount of diacylglycerol, thus promoting the activation of PKC (52). With the increased activation of PKC, this signaling pathway between hyperglycemia and tissue damage may occur through several mechanisms (e.g., inhibiting the expression of endothelial nitric oxide synthetase, expression of vascular endothelial growth factor) with resulting vascular damage (53). Use of ruboxistaurin to significantly inhibit PKC activity has been shown to mediate abnormalities in the retinal and renal blood flow in animal models (53). Further, use of this PKC-p inhibitor has been shown to reduce proteinuria and macular edema (54), illustrating a promising approach to the treatment and prevention of microvascular complications associated with T1D (6).

(iv) Hyperglycemia has also been linked to tissue damage, especially in the mesangial cells of the kidney, through hexosamine pathway flux. In general, this process may allow the cell to determine the level of glucose in its extracellular environment. Activation of this pathway increases the activity of transforming growth factor-p1, vascular adhesion molecule-1, and necrosis factor kappa B (NF-kB) enhancer. These proteins are associated with inflammation, which leads to vascular damage. Systematically, the activation of NF-kB in macrophages increases the production of inflammatory factors such as vascular adhesion molecule-1, interleukin-6, and tumor necrosis factor-alpha, furthering possible vascular damage (4,5). It is hypothesized that as the concentration of glucose increases in the extracellular area, the amount of glucose shunted through the glucosamine pathway is increased, thus activating NF-kB and the associated inflammatory processes such as increased expression of the PAI-1 gene (55).

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