Mechanisms of Premature Aging in Diabetes

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The clinical and phenotypic similarities between aging and diabetes suggest that there may be shared biochemical pathways leading to the tissue changes. Glucose is the principal metabolic fuel for many animal species. In general, with few exceptions, the plasma glucose level in various animals is maintained within a narrow range (60-140 mg/dl). It is possible that the lower limit of blood glucose levels is determined by the minimum tissue requirements of metabolic fuel, and the upper limit defines the threshold beyond which glucotoxicity limits survival of the species (Mooradian and Thurman, 1999b). Avian species, especially owls and parrots, are the exception to this generalization. These animals have high blood glucose levels in the range of 250 to 350 mg/dl and yet have a relatively long life expectancy and show no signs of classical diabetic complications. The overall constancy of blood glucose levels across a wide range of animal species suggests that hyperglycemia, except in rare exceptions, is not compatible with healthy living. However, the lack of correlation between the maximum life span of species and the blood glucose levels raises doubts as to the fundamental role of glucose in the rate of aging. Nevertheless, it can be argued that interspecies comparisons are not necessarily relevant to the role of glucotoxicity. In addition, recent clinical studies indicate that there is a continuum in the relationship between tissue toxicity and serum glucose levels rather than there being a threshold of a glucose level beyond which diabetes complications emerge. Such data underscore the fundamental nature of glucotoxicity in animal biology.

The multiplicity of theories of aging makes it difficult to determine with any degree of certainty, the precise mechanism of premature aging in diabetes. However, several sentinel discoveries within the last three decades have shed light on the potential mechanisms of glucose-related toxicity and its effect on degenerative changes of aging. There are several biochemical mechanisms of glucotoxicity (Brownlee, 2001) (see Figure 56.1).

These include the polyol pathway, protein kinase C pathway, glycosylation pathway, and the oxidative pathway. These pathways, although conceptually separate, are interlinked biochemically (Brownlee, 2001). It has been suggested that a unifying hypothesis that incorporates these different pathways of glucotoxicity is hinged upon the mitochondrial generation of free radicals (Brownlee, 2001). According to this hypothesis, excess superoxide (oxidation pathway) partially inhibits the glycolytic enzyme GAPDH, thereby diverting upstream metabolites from glycolysis into pathways of glucose over utilization. This increases the flux of dihydroxyacetone phosphate (DHAP) to DAG, an activator of PKC (PKC activation pathway), and of triose phosphates to methyl-glyoxal, the main intracellular AGE precursor (glycation pathway). Increased flux of fructose-6-phosphate to UDP-N-acetylglucosamine increases modification of proteins by O-linked N-acetylglucosamine (GlcNAc) (hexosamine pathway), and increased glucose flux through the polyol pathway consumes NADPH and depletes GSH, thereby further aggravating the increased oxidative stress (Brownlee, 2001).

Some of the key mechanisms that may contribute to tissue changes in diabetes, and may also be involved in the aging, will be discussed. The relevance of polyol pathway in human disease has been controversial. The hexosamine pathway is an important pathway contributing to the pathogenesis of insulin resistance and diabetes complications. The glycolytic intermediate fructose-6-phosphate (Fruc-6-P) is converted to glucosamine-6-phosphate by the enzyme glutamine:fructose-6-phosphate amido-transferase (GFAT). Intracellular glycosylation of key transcription factors, such as Sp1, by the addition of N-acetylglucosamine (GlcNAc) to serine and threonine, is catalyzed by the enzyme O-GlcNAc transferase (OGT). These changes result in profound alterations in the expression of genes, such as plasminogen activator inhibitor-1 (PAI-1) and transforming growth factor beta-1 (TGF-^1) that are implicated in the emergence of some diabetic complications (Brownlee, 2001). The age-related changes in Sp1 are not concordant with the changes seen in diabetes. Thus, the polyol pathway and hexosamine pathway will not be discussed any further as they appear to be, at the present time, more uniquely related to diabetes rather than to aging.

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