Prevention Of Tissue Damage And Complications

There appear to be several approaches to preventing or slowing the progression of complications associated with T1D. In this chapter, we have highlighted the research on hy-perglycemia as the number one culprit in the development of long-term complications. However, as we have demonstrated, the etiology of hyperglycemia is multifactorial. In addition, once hyperglycemia is present, the molecular pathways that ultimately lead to complications are varied and may or may not rest on a unifying link. Taken together, our chapter highlights that multiple methods are necessary in order to prevent the long-term complications commonly associated with T1D. One method concerns a focus on stopping hyperglycemia before it happens by identifying the risk across multiple factors (e.g., genetics, lifestyle, and emotional factors) and intervening early, before these factors can cause prolonged hyperglycemia. A second method is aimed at attacking hyperglycemia on the molecular level through novel pharmacologic approaches.

The attainment of near-normoglycemia from very early on in the onset of the disease to protect or delay complications was illustrated in the DCCT and confirmed with long-term data from the EDIC study and other epidemiologic studies (1,11,13,18,19). If the knowledge of such findings was enough, clinical investigators would no longer search for ways to promote near-normoglycemia. For example, less than two-thirds of a large sample of adults with T1D monitor blood glucose levels at the rate prescribed by the American Diabetes Association (79). Various psychological programs have attempted to improve monitoring as well as co-occurring areas of poor adherence, showing promise for the promotion of self-management (96,97). However, the direct link with glycemic control is not always apparent. Thus, while there are established programs that promote diabetes and other health-related outcomes, work remains in order to reduce the exposure to hyperglycemia that many individuals with T1D experience.

Researchers examining the molecular pathways between hyperglycemia and tissue damage have proposed several methods for both the prevention of the adverse effects of hyperglycemia and its prevention. Sheetz and King (6) offer a selection of approaches to prevent complications resulting from hyperglycemia. They describe the first approach as a "classic" one in which the glucotoxins are neutralized, thus protecting the cell from the destruction commonly associated with hyperglycemia. As noted earlier, Ceriello (57) merges several avenues of current and potential work on antioxidants to suggest several methods for the role of reactive oxygen species. In the second approach, the one they refer to as a "promising" approach, the activity within the common signaling pathways are identified and normalized to counter the effects of glucose and glucotoxins created by hyperglycemia (6). Certainly, there is mounting evidence that PKC plays a pivotal role in this approach.

Brownlee (44) also advocates several therapeutic approaches on the molecular level. For example, one approach stems from the overproduction of superoxide (56) and includes transketolase activators. A simplistic description of this complex process is that trans-ketolase is activated and the concentration of problematic metabolites is decreased, thus reducing the flux across the hyperglycemia-induced pathways (98). Through the administration of a thiamine derivative, Brownlee and colleagues were able to activate transketolase and decrease activation in the hexosamine pathway, decrease AGE formation and PKC activation (98). In animal studies, they have demonstrated beneficial effects from this novel therapy. Likewise, Brownlee (44) highlights promising work around poly(ADP-ribose) polymerase inhibitors and certain catalytic antioxidants such as endothelial nitric oxide synthetase.

In sum, we have described a multifactorial view of hyperglycemia-induced tissue damage. The pathways leading to the occurrence of hyperglycemia due to a number of relevant factors are just as important as the molecular pathways that cause the tissue damage ultimately leading to complications. Our review of the current state of the field suggests that many investigators are conducting promising work aimed at changing the causes of hyperglycemia and diminishing the effects of long-term exposure to high blood glucose values. The accumulation of research findings in some areas is substantial compared to others, but targeting both the causes and molecular pathways of vascular damage will ultimately lead to methods to prevent the onset of complications associated with T1D.

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