Hyperglycemia Induced Tissue Damage Pathways and Causes

Section on Behavioral and Mental Health Research, Section on Genetics and Epidemiology, Joslin Diabetes Center, Harvard Medical School, Boston, Massachusetts, U.S.A.

Section on Vascular Cell Biology, Joslin Diabetes Center, Harvard Medical School, Boston, Massachusetts, U.S.A.

A. M. Jacobson

Section on Behavioral and Mental Health Research, Joslin Diabetes Center, Harvard Medical School, Boston, Massachusetts, U.S.A.

Since the initial findings from the Diabetes Control and Complications Trial (DCCT) were published in 1993 (1), the intensification of diabetes management to prevent or slow the onset of the complications associated with type 1 diabetes (T1D) has been a hallmark of diabetes treatment. The DCCT findings confirmed the strong link between hyperglycemia and the complications and put to rest a debate about the necessity of tight glycemic control [see (2) and (3) for the history of this debate]. During the past two decades, much attention has been paid to the mechanisms that promote hyperglycemia-induced tissue damage and to the potential ways to modify this process (4-6). The targeted population for intensified diabetes management may well be 2 million adults with T1D in the United States—based on the estimate of 10% of the 20.6 million diabetes patients (7). Further, the incidence of T1D appears to be increasing with a tendency toward younger age at onset (8-10). Taken together, there is a large population of individuals at risk for complications due to T1D with the likelihood of growing numbers in the future.

In this chapter, we discuss the evidence for hyperglycemia-induced tissue damage that results in the occurrence of complications and also address five topic areas: (i) complications that result from T1D, focusing on retinopathy and nephropathy as examples of microvascular complications and noting specific aspects of macrovascular complications, (ii) findings from the DCCT and several epidemiologic studies (11), as they directly relate to complications from T1D, (iii) findings concerning the pathways from hyperglycemia to tissue damage at the molecular level, highlighting the most accepted pathways and common links between them, (iv) the genetic and environmental factors that contribute to chronic hyperglycemia and eventually to long-term complications, and (v) the current momentum and

Accelerating Factors (e.g., hypertension, atherosclerosis)

Figure 1 Pathways and mechanisms of hyperglycemia-induced tissue damage.

the potential future work for finding effective treatments and interventions for preventing or slowing the complications associated with T1D. The conceptual framework that illustrates these associated topic areas is depicted in Figure 1. There are genetic and environmental influences that promote both the occurrence of hyperglycemia as well as the progression to complications. Further, the link between hyperglycemia and complications occurs through several pathways that may be moderated by various accelerating factors.

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