Monocyte Telomere Shortening and Oxidative DNA Damage in Type 2 Diabetes

Abstract

OBJECTIVE -Telomeres are DNA sequences necessary for DNA replication, which shorten at cell division at a rate related to levels of oxidative stress. Once shortened to a critical length, cells are triggered into replicative senescence. Type 2 diabetes is associated with oxidative DNA damage, and we hypothesized that telomere shortening would characterize type 2 diabetes.RESEARCH DESIGN AND METHODS -We studied 21 male type 2 diabetic subjects (mean age 61.2 years, mean HbA 1c 7.9%) selected to limit confounding effects on telomere length and 29 matched control subjects. Telomere length was measured in peripheral venous monocyte and T-cells (naïve and memory) by fluorescent in situ hybridization and oxidative DNA damage by flow cytometry of oxidized DNA bases. Peripheral insulin resistance (homeostasis model assessment) and high-sensitivity C-reactive protein (hsCRP) were measured.RESULTS -Mean monocyte telomere length in the diabetic group was highly significantly lower than in control subjects (4.0 [1.1] vs. 5.5 [1.1]; P Ͻ 0.0001), without significant differences in lymphocyte telomere length. There was a trend toward increased oxidative DNA damage in all diabetes cell types examined and a significant inverse relationship between oxidative DNA damage and telomere length (r ϭ Ϫ0.55; P ϭ 0.018) in the diabetic group. Telomere length was unrelated to plasma CRP concentration or insulin resistance.CONCLUSIONS -Monocyte telomere shortening in type 2 diabetes could be due to increased oxidative DNA damage to monocyte precursors during cell division. This data suggests that monocytes adhering to vascular endothelium and entering the vessel wall in type 2 diabetes are from a population with shorter telomeres and at increased risk of replicative senescence within vascular plaque. Diabetes Care 29:283-289, 2006T elomeres are tandem repeats of the DNA sequence TTAGGG extending over 6 -15 kb at the end of eukaryotic chromosomes and are necessary for both successful DNA replication and chromosomal integrity (1-3). Telomeres in somatic human cells shorten by 30 -200 bp each cell division, and once shortened to a critical length, cells are triggered into replicative senescence, an irreversible cell cycle block in G0/G1 (1-5) where cells function differently (1,2,5,6) and are more likely to undergo apoptosis if exposed to increased oxidative insult (7). Rates of telomere shortening, and therefore telomere length, are highly dependent on oxidatively induced strand breaks in telomeric DNA and on cellular oxidant balance (1)(2)(3)5,6,8,9), and we and others have shown that lymphocyte DNA from subjects with type 2 diabetes is characterized by increased susceptibility to oxidative damage (10 -12). Telomeric DNA is particularly prone to oxidative damage at the GGG sequence (13,14), and it is probable that oxidatively induced single-and double-strand DNA breaks in people with type 2 diabetes (10 -12) would translate into accelerated telomere shortening and a progression to replicative senescence (1-3). Many of the dysf u n c t i o n s...

Telomere length of subcutaneous adipose tissue cells is shorter in obese and formerly obese subjects

“…[4][5][6] Short telomeres in peripheral blood have been described in obese and diabetic patients and in individuals with cardiovascular risk factors, that is, increased blood pressure, increased carotid intima media thickness, smoking as well as in response to psychosocial stress. [7][8][9][10] Telomere length, in vivo as well as in vitro, can be considered as a biological marker for age-and stress-related conditions.…”

Hormone-brain-aging relationships, broadly reactive with imidazole-containing dipeptides: targeting of telomere attrition as an aging biomarker and dynamic telomerase activity flirting

“…Monocyte telomere shortening in type 2 diabetes could be due to increased oxidative DNA damage to monocyte precursors during cell division [102]. These data suggest that monocytes adhering to vascular endothelium and entering the vessel wall in type 2 diabetes are from a population with shorter telomeres and at increased risk of replicative senescence within vascular plaque [102]. Young adult mice that are deficient for the Terc subunit of telomerase exhibit impaired glucose tolerance.…”

“…Shorter TL in leukocytes has been associated cross-sectionally with CVD and its risk factors, including pulse pressure and vascular aging [1,86,[95][96][97], obesity [87,98,99], vascular dementia [88,100], diabetes [98,[101][102][103][104], coronary artery disease (CAD) [1,105,106], myocardial infarction (MI) [107] although not in all studies [108], and cellular turnover and exposure to oxidative and inflammatory damage in chronic obstructive pulmonary disease (COPD) [109]. Leukocyte TL correlates with a subset of measures of cognitive performance, suggesting that it might be a biomarker of cognitive aging in women before the onset of dementia [110].…”

How to survive diabetes

“…The Cardiovascular Health Study estimated that the risk of myocardial infarction or stroke was increased threefold for each kilobase pair reduction in terminal restriction fragment length [49]. Telomere attrition has been reported in both type 1 [50] and type 2 diabetes [51], and the overlap between the determinants of longevity and those of long-term diabetes suggests that this might be a fruitful area for future research.…”