Telomere Shortening of Peripheral Blood Mononuclear Cells in Coronary Disease Patients with Metabolic Disorders.

Obana, Nobuya; Takagi, Sho; Kinouchi, Yoshitaka; Tokita, Yoshihisa; Sekikawa, Akihiro; Takahashi, Seiichi; Hiwatashi, Nobuo; Oikawa, Shinichi; Shimosegawa, Tooru

doi:10.2169/internalmedicine.42.150

Cited by 61 publications

(29 citation statements)

References 20 publications

(19 reference statements)

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“…Our data are in line with recent studies showing that enhanced telomere attrition is associated with atherosclerosis (23,24). Accelerated telomere erosion was found in diabetic patients (25)(26)(27). This is confirmed here; however, as evidenced by our disease control subjects, acceleration of telomere attrition is independent of type 2 diabetes.…”

Section: Discussionsupporting

confidence: 93%

Lymphocytes of Type 2 Diabetic Women Carry a High Load of Stable Chromosomal Aberrations

Boehm

Möller²,

Högel³

et al. 2008

Diabetes

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OBJECTIVE-Diabetes is associated with an increased risk of death in women. Oxidative stress due to chronic hyperglycemia leads to the generation of reactive oxygen species and loss of chromosomal integrity. To clarify whether diabetes is a premature aging syndrome, we determined telomere erosion dynamics and occurrence of structural chromosomal aberrations in women of the Ludwigshafen Risk and Cardiovascular Health (LURIC) Study.RESEARCH DESIGN AND METHODS-Telomere lengths and karyotypes were examined in peripheral blood mononuclear cells. Regarding these parameters, surviving and deceased type 2 diabetic women of the LURIC study were compared with nondiabetic LURIC women with or without coronary heart disease and with healthy female control subjects.RESULTS-Significantly enhanced telomere attrition was seen in all LURIC subjects compared with healthy control subjects. Although the average telomere-length loss is equivalent to well Ͼ10 years of healthy aging, telomere erosion was not associated with outcome within the LURIC cohort. However, strikingly high numbers of stable chromosomal aberrations were found in type 2 diabetic women but not in LURIC disease control subjects or in healthy individuals. Furthermore, within the younger agegroups, deceased type 2 diabetes patients had significantly more marker chromosomes than the surviving type 2 diabetic patients.CONCLUSIONS-All women at high risk for cardiovascular death have accelerated telomere erosion, not caused by type 2 diabetes per se but likely linked to other risk factors, including dyslipidemia. By contrast, the occurrence of marker chromosomes is associated with type 2 diabetes and is a novel risk factor for type 2 diabetes-related early death. Diabetes 57:2950-2957, 2008 T ype 2 diabetes is characterized by increased morbidity and all-cause mortality (1,2). The combination of excess caloric intake and reduced physical activity leading to obesity, dyslipidemia, and hypertension increases the risk for diabetes and coronary heart disease (CHD). Recent data show that among diabetic men, the mortality rate has decreased significantly, whereas in diabetic women, no such trend was found (3). The all-cause mortality rate difference between diabetic and nondiabetic women is considerable. Therefore, the combination of diabetes with multiple risk factors identifies women at particularly high risk (2,4).The relative risk for morbidity and mortality in women with diabetes is increased compared with nondiabetic control subjects (2,5). Diabetes may therefore be regarded as a premature aging syndrome in which the overall metabolic shift leads to genotoxic stress that results in loss of chromosomal integrity (rev. in 6). Oxidative stress plays a crucial role in the pathogenesis of type 2 diabetes and in diabetes-associated complications. The generation of reactive oxygen species (ROS) is a common downstream mechanism whereby multiple by-products of glucose and (pro)inflammatory molecules exert adverse effects (7-11). DNA damage and telomere attrition can serve as marke...

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Section: Discussionsupporting

confidence: 93%

Lymphocytes of Type 2 Diabetic Women Carry a High Load of Stable Chromosomal Aberrations

Boehm

Möller²,

Högel³

et al. 2008

Diabetes

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“…In addition, several studies have demonstrated a relationship between telomere length in peripheral blood leukocytes (PBL) and the onset of certain diseases associated with aging. Such studies in nonneoplastic diseases have shown that PBL telomere lengths can provide predictive information on the risk of developing atherosclerosis (87,88) and on overall mortality (89). In aggregate, these data indicate that although telomerase plays a clear role in malignant progression, telomere-induced checkpoints also contribute to certain aspects of human aging.…”

Section: Figurementioning

confidence: 94%

Telomeres, stem cells, senescence, and cancer

Sharpless¹,

DePinho²

2004

J. Clin. Invest.

416

187

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“…One strength of this study is that the diabetic group was selected to limit confounding by variables that influence telomere length such as age, sex, ethnicity, drug therapy, smoking, and inflammatory processes such as established vascular disease or hypertension, which make clinical studies on telomere length less easy to interpret (1)(2)(3)(15)(16)(17)(18)(19)23,24). Monocyte-endothelial cell adhesion is enhanced in type 2 diabetes (35), and in other studies we have shown that monocytes from type 2 diabetic subjects demonstrate increased adhesion molecule expression during glycemic excursions and increased expression of the LDL scavenger receptor, CD36 (36,37).…”

Section: Determinants Of Telomere Length In Control Subjectsmentioning

confidence: 99%

Monocyte Telomere Shortening and Oxidative DNA Damage in Type 2 Diabetes

et al. 2006

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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...

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Telomere Shortening of Peripheral Blood Mononuclear Cells in Coronary Disease Patients with Metabolic Disorders.

Cited by 61 publications

References 20 publications

Lymphocytes of Type 2 Diabetic Women Carry a High Load of Stable Chromosomal Aberrations

Lymphocytes of Type 2 Diabetic Women Carry a High Load of Stable Chromosomal Aberrations

Telomeres, stem cells, senescence, and cancer

Monocyte Telomere Shortening and Oxidative DNA Damage in Type 2 Diabetes

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