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are the impaired production of insulin by pancreatic islet
-cells and decreased
tissue responses to insulin—the insulin resistance. In the outcome of the
disease, a two- to fourfold increased risk for the development of microvascular
complications such as blindness, gangrene, and kidney failure and macrovas-
cular complications takes place as a result of chronic elevation of circulating
blood glucose levels. Autoxidation of glucose via dicarbonyl intermediates and
protein-bound sugars is proposed to be important for the consequences of
diabetes (225).
There are two main types of diabetes: type 1, which is referred to as insulin
dependent, results from the body's failure to produce insulin. Type 2, which is
referred to as noninsulin-dependent diabetes, results from insulin resistance,
sometimes combined with an absolute insulin deficiency. Diabetes induces
several severe complications in its pathological progression: increased blood
pressure, diabetic retinopathy, diabetic neuropathy, myocardial infarction,
atherosclerosis, stroke, nephropathy, blindness, diabetic foot syndrome, and the
majority of nontraumatic lower extremity amputations. The increased amount
of hyperglycemia-induced oxidative stress, especially in the diabetic neuropa-
thies and atherosclerosis is one of the most important factors in the pathogen-
esis (226-228). This oxidative stress can be followed by an enhanced activity
of the aldose reductase, the formation of AGEs, which are able to induce a
receptor-mediated oxidative stress (229), an increased activity of protein
kinase C (PKC), and a mitochondrial overproduction of superoxide anions.
Oxidative stress may occur via vascular cells and, in particular, in the endo-
thelium (230, 231). Increased lipid peroxidation (LOOH), oxidative damage
to DNA (8-OHdG), and oxLDL have been shown in many studies performed
in human with type 1 and 2 diabetes compared with age-matched control
groups (232-235). In plasma and intracellular environment, protein oxidation
was found to be increased in diabetes tested by protein carbonyls and nitro-
tyrosine (236). De Cristofaro et al. showed high protein carbonyl content of
plasma proteins in 72 patients with type 2 diabetes mellitus compared with
controls (237). In patients with type 1 diabetes, the concentrations of protein
glycation, oxidation, and nitration adduct residues were found to increase up
to threefold in plasma protein and somewhat also in hemoglobin (238). A
decrease in the antioxidative defense in diabetes was also shown by reduced
glutathione (239), reduced vitamin C and E levels (240), and reduced NADPH
formation (241, 242). All these results show the contribution of oxidative stress
in diabetes (243).
Besides these markers for oxidative stress in different targets, proteasomal
degradation as a removal mechanism in protein oxidation has been shown to
be declined in diabetes, affecting the ability to degrade damaged proteins. In
the cytosolic fractions of liver and kidney from rats with streptozotocin-
induced diabetes, proteasome activity was shown to be impaired (244). The
inhibition of proteasome is hypothesized to be dependent on degradation of
insulin by insulin-degrading enzyme. The mechanism of proteasome inhibition
is concluded to be the generation of inhibitory fragments of insulin by the
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