A short leucocyte telomere length is associated with development of insulin resistance

Verhulst, Simon; Dalgård, Christine; Labat, Carlos; Kark, Jeremy D.; Kimura, Masayuki; Christensen, Kaare; Toupance, Simon; Aviv, Abraham; Kyvik, Kirsten Ohm; Bénétos, Athanase

doi:10.1007/s00125-016-3915-6

Cited by 77 publications

(70 citation statements)

References 50 publications

(53 reference statements)

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“…Short telomeres are associated with higher concentrations of fasting insulin, which could further increase CHD risk. Our findings were consistent with observational epidemiologic studies, which found associations between shorter telomeres and higher fasting insulin levels, 8,26 and increased fasting insulin as a well-known risk factor for CHD. 27 As already alluded to above, several observational studies have examined the associations between TL and insulin, but also with insulin-like growth factor-1, and diabetes mellitus.…”

Section: Circulation Research July 21 2017supporting

confidence: 92%

“…27 As already alluded to above, several observational studies have examined the associations between TL and insulin, but also with insulin-like growth factor-1, and diabetes mellitus. 8,26,[28][29][30][31] Most of these studies found TL to be inversely associated with insulin or diabetes mellitus, whereas others did not observe this relationship after multivariable adjustments. Conventional explanations for the association, such as shared common causes (oxidative stress and unhealthy lifestyle factors), were based on cross-sectional examinations of these biomarkers.…”

Section: Circulation Research July 21 2017mentioning

confidence: 99%

“…Recently, a longitudinal study for an average of 12-year follow-up time using the Danish Twin Registry found that shorter telomeres affected insulin resistance but not vice versa. 26 Another study suggested that the mechanism for the association might be that short telomeres lead to premature β-cell dysfunction and death, followed by impaired insulin secretion and impaired glucose tolerance. 32 Conversely, elevated insulin secretion could increase oxidative stress and subsequent cardiovascular diseases.…”

Section: Circulation Research July 21 2017mentioning

confidence: 99%

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Exploring the Causal Pathway From Telomere Length to Coronary Heart Disease

Zhan

Karlsson

et al. 2017

Circ Res

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In this study, we aim to examine metabolic risk factors as possible mediators in the causal relationship between genetically determined TL and CHD using a network MR method 12 from summarized genome-wide association study (GWAS) data. The rationale for focusing on metabolic risk factors is based on the following: (1) these metabolic risk factors explain a large proportion Molecular Medicine© 2017 American Heart Association, Inc. Rationale: Observational studies have found shorter leukocyte telomere length (TL) to be a risk factor for coronary heart disease (CHD), and recently the association was suggested to be causal. However, the relationship between TL and common metabolic risk factors for CHD is not well understood. Whether these risk factors could explain pathways from TL to CHD warrants further attention.Objective: To examine whether metabolic risk factors for CHD mediate the causal pathway from short TL to increased risk of CHD using a network Mendelian randomization design. Methods and Results:Summary statistics from several genome-wide association studies were used in a 2-sample Mendelian randomization study design. Network Mendelian randomization analysis-an approach using genetic variants as the instrumental variables for both the exposure and mediator to infer causality-was performed to examine the causal association between telomeres and CHD and metabolic risk factors. Summary statistics from the ENGAGE Telomere Consortium were used (n=37 684) as a TL genetic instrument, CARDIoGRAMplusC4D Consortium data were used (case=22 233 and control=64 762) for CHD, and other consortia data were used for metabolic traits (fasting insulin, triglyceride, total cholesterol, low-density lipoprotein cholesterol, fasting glucose, diabetes mellitus, glycohemoglobin, body mass index, waist circumference, and waist:hip ratio). One-unit increase of genetically determined TL was associated with −0.07 (95% confidence interval, −0.01 to −0.12; P=0.01) lower log-transformed fasting insulin (pmol/L) and 21% lower odds (95% confidence interval, 3-35; P=0.02) of CHD. Higher genetically determined log-transformed fasting insulin level was associated with higher CHD risk (odds ratio, 1.86; 95% confidence interval, 1.01-3.41; P=0.04). Conclusions:

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Section: Circulation Research July 21 2017supporting

confidence: 92%

Section: Circulation Research July 21 2017mentioning

confidence: 99%

Section: Circulation Research July 21 2017mentioning

confidence: 99%

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Exploring the Causal Pathway From Telomere Length to Coronary Heart Disease

Zhan

Karlsson

et al. 2017

Circ Res

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“…In some cases, this is supported by longitudinal evidence (e.g. [45,48,49]) and Mendelian randomization studies [50,51]. Reverse causality may be possible for psychological and behavioural variables too, because short telomere length can change patterns of gene expression [52], with possible consequences for brain function.…”

Section: Discussionmentioning

confidence: 99%

Telomeres as integrative markers of exposure to stress and adversity: a systematic review and meta-analysis

Pepper¹,

Bateson²,

Nettle³

2018

R. Soc. open sci.

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Telomeres have been proposed as a biomarker that integrates the impacts of different kinds of stress and adversity into a common currency. There has as yet been no overall comparison of how different classes of exposure associate with telomeres. We present a meta-analysis of the literature relating telomere measures to stresses and adversities in humans. The analysed dataset contained 543 associations from 138 studies involving 402 116 people. Overall, there was a weak association between telomere variables and exposures (greater adversity, shorter telomeres: r = −0.15, 95% CI −0.18 to −0.11). This was not driven by any one type of exposure, because significant associations were found separately for physical diseases, environmental hazards, nutrition, psychiatric illness, smoking, physical activity, psychosocial and socioeconomic exposures. Methodological features of the studies did not explain any substantial proportion of the heterogeneity in association strength. There was, however, evidence consistent with publication bias, with unexpectedly strong negative associations reported by studies with small samples. Restricting analysis to sample sizes greater than 100 attenuated the overall association substantially (r = −0.09, 95% CI −0.13 to −0.05). Most studies were underpowered to detect the typical association magnitude. The literature is dominated by cross-sectional and correlational studies which makes causal interpretation problematic.

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“…5). Greater changes in telomere length can be attributed to chronic inflammation associated oxidative stress (21,22), which is linked to several diseases for which leukocyte telomere length may be an early risk indicator, i.e., cancer (23), stroke (24), myocardial infarction (24,25), cardiovascular disease (26), type II diabetes (24), insulin resistance (27), and all-cause mortality (28).…”

Section: Discussionmentioning

confidence: 99%

Analytical Validation of Relative Average Telomere Length Measurement in a Clinical Laboratory Environment

Blauwkamp¹,

Fasching²,

Lin³

et al. 2017

The Journal of Applied Laboratory Medicine

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Background Average telomere length in whole blood has become a biomarker of aging, disease, and mortality risk across a broad range of clinical conditions. The most common method of telomere length measurement for large patient sample sets is based on quantitative PCR (qPCR). For laboratory-developed tests to be performed on clinical samples, they must undergo a rigorous analytical validation, currently regulated under CLIA. Methods Whole blood samples from 40 donors were used in the analytical validation of methods for relative average telomere length (rATL) measurement. Three technical replicate DNA samples were extracted from each whole blood sample and placed in three independent wells on a sample plate. Each of these sample plates was assayed 12 times during the validation process. The study was conducted over a 20-day period, once in the morning and once in the evening, using 3 different operators. Results Our process of rATL measurement beginning with DNA extraction followed by qPCR-based assay resulted in repeatability and reproducibility CV of <5% and amplification efficiencies near 100%. The validated assay was used to establish a reference interval derived from 2 cohorts of individuals: (a) San Francisco Bay area (n = 504) and (b) a US cross-sectional, demographic population (n = 357). Conclusions We present advances in the establishment of a highly reproducible analytically validated process for determining rATLs in a CLIA laboratory environment.

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A short leucocyte telomere length is associated with development of insulin resistance

Cited by 77 publications

References 50 publications

Exploring the Causal Pathway From Telomere Length to Coronary Heart Disease

Exploring the Causal Pathway From Telomere Length to Coronary Heart Disease

Telomeres as integrative markers of exposure to stress and adversity: a systematic review and meta-analysis

Analytical Validation of Relative Average Telomere Length Measurement in a Clinical Laboratory Environment

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