Rise in Insulin Resistance Is Associated With Escalated Telomere Attrition

ArticleinCirculation 111(17):2171-7 · June 2005with23 Reads
DOI: 10.1161/01.CIR.0000163550.70487.0B · Source: PubMed
Abstract
Insulin resistance predisposes to cardiovascular disease and shortens human lifespan. We therefore tested the hypothesis that a rise in insulin resistance in concert with gain in body mass is associated with accelerated white blood cell telomere attrition. We measured white blood cell telomere dynamics and age-related changes in insulin resistance and body mass index in young adults of the Bogalusa Heart Study. Over 10.1 to 12.8 years, the relative changes in telomere length were correlated with the homeostasis model assessment of insulin resistance (r=-0.531, P<0.001) and changes in the body mass index (r=-0.423, P<0.001). These findings provide the first tangible nexus of telomere biology with insulin resistance and adiposity in humans.
    • "However, during times of environmental stress, ROS levels can increase dramatically and result in oxidative stress, leading in the short term to a variety of cellular stressors including mitochondrial dysfunction and in the long term to a pathological state represented by aging, senescence and cardiovascular diseases [68,69]. Clinical and basic science studies have highlighted the importance of short telomeres and impaired mitochondrial function in driving the age-related functional decline in the cardiovascular system [70][71][72]. Telomerase appears to be critically involved in these pathologic changes associated with aging. "
    [Show abstract] [Hide abstract] ABSTRACT: Aging, cancer, and chronic disease have remained at the forefront of basic biological research for decades. Within this context, significant attention has been paid to the role of telomerase, the enzyme responsible for lengthening telomeres, the nucleotide sequences located at the end of chromosomes found in the nucleus. Alterations in telomere length and telomerase activity are a common denominator to the underlying pathology of these diseases. While nuclear-specific, telomere-lengthening effects of telomerase impact cellular/organismal aging and cancer development, non-canonical, extra-nuclear, and non-telomere-lengthening contributions of telomerase have only recently been described and their exact physiological implications are ill defined. Although the mechanism remains unclear, recent reports reveal that the catalytic subunit of telomerase, telomerase reverse transcriptase (TERT), regulates levels of mitochondrial-derived reactive oxygen species (mtROS), independent of its established role in the nucleus. Telomerase inhibition has been the target of chemotherapy (directed or indirectly) for over a decade now, yet no telomerase inhibitor is FDA approved and few are currently in late-stage clinical trials, possibly due to underappreciation of the distinct extra-nuclear functions of telomerase. Moreover, evaluation of telomerase-specific therapies is largely limited to the context of chemotherapy, despite reports of the beneficial effects of telomerase activation in the cardiovascular system in relation to such processes as endothelial dysfunction and myocardial infarction. Thus, there is a need for better understanding of telomerase-focused cell and organism physiology, as well as development of telomerase-specific therapies in relation to cancer and extension of these therapies to cardiovascular pathologies. This review will detail findings related to telomerase and evaluate its potential to serve as a therapeutic target.
    Full-text · Article · Jul 2016
    • "Telomeres are more readily measured in circulating white blood cells, but are also relevant to studies of cultured retinal cells and ocular tissues. There are several studies re- porting: -Shorter telomeres in people with diabetes -Associations of shorter telomeres with the presence of diabetes complications [287, 288] -Predictive power for future nephropathy [289] and mortality [290] However, to the best of our knowledge, there are no specific telomere length-and diabetic retinopathy-related studies. In the West of Scotland Coronary Prevention Study (WOSCOPS), a large clinical study, statins attenuated the cardiovascular risk associated with shorter telomeres [291]. "
    [Show abstract] [Hide abstract] ABSTRACT: There is a global diabetes epidemic correlating with an increase in obesity. This coincidence may lead to a rise in the prevalence of type 2 diabetes. There is also an as yet unexplained increase in the incidence of type 1 diabetes, which is not related to adiposity. Whilst improved diabetes care has substantially improved diabetes outcomes, the disease remains a common cause of working age adult-onset blindness. Diabetic retinopathy is the most frequently occurring complication of diabetes; it is greatly feared by many diabetes patients. There are multiple risk factors and markers for the onset and progression of diabetic retinopathy, yet residual risk remains. Screening for diabetic retinopathy is recommended to facilitate early detection and treatment. Common biomarkers of diabetic retinopathy and its risk in clinical practice today relate to the visualization of the retinal vasculature and measures of glycemia, lipids, blood pressure, body weight, smoking, and pregnancy status. Greater knowledge of novel biomarkers and mediators of diabetic retinopathy, such as those related to inflammation and angiogenesis, has contributed to the development of additional therapeutics, in particular for late-stage retinopathy, including intra-ocular corticosteroids and intravitreal vascular endothelial growth factor inhibitors ('anti-VEGFs') agents. Unfortunately, in spite of a range of treatments (including laser photocoagulation, intraocular steroids, and anti-VEGF agents, and more recently oral fenofibrate, a PPAR-alpha agonist lipid-lowering drug), many patients with diabetic retinopathy do not respond well to current therapeutics. Therefore, more effective treatments for diabetic retinopathy are necessary. New analytical techniques, in particular those related to molecular markers, are accelerating progress in diabetic retinopathy research. Given the increasing incidence and prevalence of diabetes, and the limited capacity of healthcare systems to screen and treat diabetic retinopathy, there is need to reliably identify and triage people with diabetes. Biomarkers may facilitate a better understanding of diabetic retinopathy, and contribute to the development of novel treatments and new clinical strategies to prevent vision loss in people with diabetes. This article reviews key aspects related to biomarker research, and focuses on some specific biomarkers relevant to diabetic retinopathy.
    Article · Dec 2015
    • "In case of longitudinal analyses, a great portion of the variation (37%) was explained by the baseline LTL. Although several studies claimed that this is a biological effect (Gardner et al., 2005; Farzaneh-Far et al., 2010 ), some recently suggested that mathematical coupling is at least partially responsible of these observations (Giltay et al., 2011 ). However, the remaining unexplained variation in LTL clearly indicates that there are other factors, including genetic and physiological, in addition to residual confounding that account for this variation. "
    [Show abstract] [Hide abstract] ABSTRACT: Objective: Telomere length (TL) has been proposed as a biomarker of ageing, which might be used to identify individuals at higher risk of age-related diseases. Obesity is a well-known risk factor for several diseases. This study aims to analyse the associations of BMI with TL and the rate of TL change in older adults. Methods: Leukocyte TL (LTL) was measured by quantitative PCR in blood samples of 3600 older adults aged 50-75years obtained at the baseline examination of a population-based cohort study in Germany. For longitudinal analyses, measurements were repeated in blood samples obtained at 8-year follow-up from 1000 participants. Multivariate linear regression models were used to estimate associations of BMI with LTL and changes in LTL over time. Results: LTL was inversely associated with age (r=-0.090, p<0.0001). BMI and LTL associations varied according to age (p for interaction=0.021). BMI was significantly inversely associated with LTL in those younger than 60years (-6basepairs per 1kg/m(2) difference in BMI). In particular, weight gain during adulthood was inversely associated with LTL in a dose-response manner in this age group, with those having gained ≥30kg having significantly shorter telomeres (-209basepairs) than those who maintained their weight. No clear patterns were observed between any of BMI-related variables and the rate of LTL change. Conclusions: Our cross-sectional analysis supports suggestions that weight gain during adulthood and obesity may contribute to shorter telomere length below 60years of age, but this relationship could not be shown longitudinally.
    Full-text · Article · Nov 2015
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