Atherosclerosis 206 (2009) 588–593
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journal homepage: www.elsevier.com/locate/atherosclerosis
Leukocyte telomere shortening in elderly Type2DM patients with previous
Fabiola Olivieria,b,∗, Maria Lorenzib, Roberto Antonicellic, Roberto Testad, Cristina Sirollae,
Maurizio Cardellif, Serena Mariottib, Francesca Marchegianif, Maurizio Marrad,
Liana Spazzafumoe, Anna Rita Bonfiglid, Antonio Procopioa,b
aDept. of Molecular Pathology and Innovative Therapies, Polytechnic University of Marche, Ancona, Italy
bCenter of Clinical Pathology and Innovative Therapies, Research Dept. I.N.R.C.A., Ancona, Italy
cCardiologic Unit, I.N.R.C.A. Hospital, Ancona, Italy
dDiabetology Unit, Research Dept. I.N.R.C.A., Ancona, Italy
eStatistical Center, I.N.R.C.A., Ancona, Italy
fLaboratory of Tumor Immunology, Immunology Center, Research Dept. I.N.R.C.A., Ancona, Italy
a r t i c l ei n f o
Received 18 December 2008
Received in revised form 19 February 2009
Accepted 29 March 2009
Available online 5 April 2009
Type2 diabetes mellitus
a b s t r a c t
Objective: We performed a cross-sectional study to examine the differences in leukocyte telomere length
among three groups of subjects: patients with type 2 diabetes mellitus without history of previous
myocardial infarction (Type2DM), patients with type 2 diabetes mellitus with evidence of previous
myocardial infarction (Type2DM+MI), and healthy control subjects (CTR). The main objective of the
present study is to investigate differences in telomere length between the studied groups of subjects,
with the aim to clarify if telomere length could be a reliable marker associated with MI in Type2DM
patients. Secondary end point is the identification of associations between leukocyte telomere length
and selected variables related to glycemic control, pro-inflammatory status and lipidic profile.
Research design and methods: A total of 272 elderly subjects, 103 Type2DM (mean age 70±4 years, 59%
males), 65 Type2DM+MI (mean age 68±7 years, 68% males), and 104 CTR (mean age 69±7 years, 50%
males) were studied. Telomere length, defined as T/S (Telomere-Single copy gene ratio), was determined
(PAI-1) as inflammatory markers; (2) fasting glucose, insulin, glycated haemoglobin (HbA1C) and waist-
to-hip ratio as markers of glycemic control; (3) total-cholesterol, HDL-cholesterol and triglycerides as
markers of lipidic profile, in all sample population. The use of statins and sulfonylurea, as well as the
presence of some relevant diabetes complications (nephropathy and retinopathy) were also assessed.
Conclusion: Type2DM+MI elderly patients have leukocyte telomere lengths shorter than those of
Type2DM (without MI) and healthy CTR. Moreover, glucose, HbA1C and waist-to-hip ratio, variables
related to glycemic control, showed a significant inverse correlation with leukocyte telomeres length.
© 2009 Elsevier Ireland Ltd. All rights reserved.
Telomeres, the tandem repeats of TTAGGG DNA sequence
extending several thousand base pairs (4–20kb in humans) at the
end of the eukaryotic chromosomes, undergo attrition within each
tial of somatic cells . Thus, telomere shortening in proliferative
Research Dept. I.N.R.C.A., Via Birarelli n. 8, 60123 Ancona, Italy.
Tel.: +39 071 8004534; fax: +39 071 206791.
E-mail address: email@example.com (F. Olivieri).
cells is a feature of physiological aging . Many investigations
have used leukocytes, the most readily available proliferative cells
in human, to explore associations between telomere length and
human aging and/or aging-related diseases. Leukocyte telomere
length is however highly variable among individuals, as a conse-
quence of the high inter-individual telomere length variations at
birth and after birth [3,4]. Moreover, at any time during the indi-
vidual’s life span, telomere length and attrition rate reflect birth
telomere length and replicative history of hematopoietic stem cells
(HSCs) and progenitor cells (PCs) . Several lines of evidence sup-
port the hypothesis that the gradual telomere attrition, appearing
to be a normal part of aging, is accelerated in cells that are exposed
to internal or external stressors, which provoke increased cellular
0021-9150/$ – see front matter © 2009 Elsevier Ireland Ltd. All rights reserved.
F. Olivieri et al. / Atherosclerosis 206 (2009) 588–593
proliferation and highest oxidative stress conditions [5–7]. HSCs
ing and accelerated senescence because of their rapid proliferation
and high oxidant species production by phagocytes (granulocytes
could damage telomeres and impair their repair mechanisms .
Thus, the cumulative burden of inflammation and oxidative stress
over the individual’s life span is registered in telomere dynam-
ics of HSCs and their proxies, peripheral leukocytes. Thus, many
epidemiological studies have measured leukocyte telomere length
with the aim to identify associations with aging-related diseases in
for them have been associated with shorter leukocyte telomeres.
However, results on telomere shortening occurring in Type2DM
between glycemic control and telomere attrition [11–13]. In addi-
tion, some Type2DM complications, such as microalbuminuria and
MI, are associated with shorter telomere length [14–18]. Moreover,
is also unclear which clinical-laboratoristic parameters and phar-
to investigate differences in telomere length between healthy sub-
jects, Type2DM and Type2DM+MI patients, with the aim to clarify
if telomere length could be a reliable marker associated with MI in
sible correlations between leukocyte telomere length and selected
biomarkers of pro-inflammatory status (CRP, fibrinogen and PAI-
1), of glycemic control (glucose, insulin, HbA1C, waist-to-hip ratio)
A total of 272 Caucasian subjects, 103 Type2DM patients, 65
Type2DM+MI patients, and 104 healthy control subjects (CTR)
The mean age and % of males were not significantly different in the
three studied groups of samples.
All subjects were enrolled after informed consent was obtained
and the study protocol was approved by the Institutional Eth-
ical Board of the INRCA Institute. Type2DM patients (with and
without previous MI) were recruited among patients consecu-
tively afferent to the Diabetology Unit of INRCA Hospital (Ancona,
Italy) for clinical examinations. Healthy control subjects were
enrolled by the same team (Diabetology Unit of INRCA Hospital)
during a population screening for Type2DM and cardiovascular
diseases prevention. All enrolled subjects were free of malig-
nancy. All participants (Type2DM patients and CTR) underwent
complete physical examination, as well as haematological, bio-
chemical and instrumental examination for the exclusion of
pathologies present at the time of blood collection different from
those reported. They were questioned about previous and current
diseases, use of medications (in particular statins and sulfony-
lurea) and their smoking habits. Ex smokers who had given up
smoking for a period of at least 3 years were considered as
non-smokers. Hypertension was defined as a systolic blood pres-
sure >140mmHg and/or a diastolic blood pressure >90mmHg,
taken when the subject was seated on at least three different
occasions. Patients with previous diagnosis of hypertension and
under pharmacological treatment were considered hypertensive
Information regarding diabetes complications was also col-
lected. Diabetic retinopathy was evaluated by fundoscopy through
dilated pupils, fluorescenceangiography,or both. Diabetic
nephropathy was defined as a urinary albumin excretion rate
Previous MI was defined by clinical history confirmed by ECG
and echocardiogram examination. Type2DM+MI patients had MI
8±7 years before the enrolment for our study.
patients were screened by the Diabetology Unit of INRCA Hospital.
Overnight fasting venous blood samples of all subjects were col-
lected from 8:00 to 9:00a.m. in plain, EDTA and citrate added tubes
(Venoject, Terumo Europe NV); the samples were either analyzed
immediately or stored at −80◦C.
2.2. Laboratory assays
CRP was determined by high sensitive immunoturbidimetric
method (CRP ultrasensitive, Abbott). All the samples were per-
formed with this assay, that has a lower limit of 0.1mg/L and an
upper limit of 160mg/L. The inter- and intra-assays percentage
coefficients of variation of the method were as follows: 3.14mg/L,
1.17%; 3.14mg/L, 2.64%, respectively.
Blood concentrations of total-cholesterol, HDL, triglycerides,
fasting glucose, fibrinogen and glycated haemoglobin were
measured by routine laboratory methods. WBC, lymphocytes,
neutrophils and monocytes counts were performed by standard
An immunoenzymatic method for PAI-1 antigen determination
(Tintelize PAI-1, Biopool, Sweden) was used. This method assays
the whole PAI-1 plasma content, as it is able to detect active and
latent forms of PAI-1 as well as PAI-1 in complex with tissue plas-
minogen activator and urokinase plasminogen activator. Intra- and
inter-assay coefficients of variation of PAI-1 antigen were 3.6% and
2.3. Measurement of telomere length
Telomere length was measured as abundance of telomeric tem-
plate (T) vs. a single gene copy (S) by quantitative real-time PCR as
described by Cawthon . Telomere and single copy gene (36B4)
were analyzed in the same plate in order to reduce inter-assay vari-
T/S ratio respect to a calibrator sample (human genomic DNA from
Roche). Calibrator sample and no-template control sample were
on the iCicler real-time (Biorad). The coefficients of variation (CV)
within triplicates of the telomere and single-gene assay were 2%
on different plates to asses T/S reproducibility. The inter-assay CV
have previously been described .
2.4. Calculation and statistical analysis
Data were analyzed with SPSS/Win program (version 15.0; Spss
Inc., Chicago, IL).
The power analysis was conducted to determine the number of
patients needed to obtain statistically significant results. The crite-
rion for significance has been set at 0.05 and the test is two-tailed.
F. Olivieri et al. / Atherosclerosis 206 (2009) 588–593
Chemical–clinical parameters of 272 subjects.
VariablesCTR (n 104)
69 ± 7
27 ± 4
0.88 ± 0.08
219 ± 40
59 ± 16
107 ± 62
93 ± 7
5.7 ± 0.4
5.8 ± 3.5
6.5 ± 1.7
18 ± 8
5.2 ± 13.5
310 ± 93
Type2DM (n 103)
70 ± 4
29 ± 3
0.94 ± 0.06
206 ± 38
50 ± 13#
152 ± 117
174 ± 50#
7.6 ± 1.1#
6.9 ± 6.2#
6.8 ± 1.6
20 ± 11
3.5 ± 4.1
295 ± 78
Type2DM+MI (n 65)
68 ± 7
29 ± 4
0.96 ± 0.07◦
192 ± 37◦
50 ± 13◦
150 ± 125
175 ± 55◦
7.8 ± 1.4◦
7.1 ± 6.1◦
7.0 ± 1.7
19 ± 9
5.6 ± 12.2
308 ± 75
VariablesCTR (n 104)
Type2DM (n 103)
Type2DM+MI (n 65)
Duration of diabetes (years)
Use of statins
Use of sulfonylurea
Type2DM: non-insulin dependent diabetes mellitus without previous myocardial infarction; Type2DM+MI: non-insulin dependent diabetes mellitus with previous myocar-
dial infarction; CTR: healthy controls. p from general liner model, adjusted for age and sex (continuous variables) and from Chi-square test (dicotomic variables).
◦p<0.01 Type2DM+MI vs. CTR.
#p<0.01 Type2DM vs. CTR.
*p<0.01 Type2DM+MI vs. Type2DM.
The skewed distributions were log transformed before statis-
tical analyses to achieve a normal distribution. CRP, triglycerides
and insulin were log transformed for the analysis. Differences
among groups were compared by univariate analysis using one-
way analysis of variance for continuous variables and ?2test for
categorical variables. Multiple comparisons were applied, when
appropriate. Pearson correlation coefficients were calculated to
analyze the association between leukocyte telomere length (pri-
mary outcome) and the other independent variables. In the first
CTR, Type2DM and Type2DM+MI patients the one-way analysis
of variance was performed. Bonferroni test for multiple compar-
isons was applied. In the second step, the effect of the confounding
factors that affected the leukocyte telomere length was analyzed.
Fig. 1. T/S means and standard deviation in 272 subjects: CTR, Type2DM and
Type2DM+MI. p<0.01 Bonferroni test for multiple comparisons. One-way analysis
of variance adjusted for age and gender, F=34.37, df=2, p=0.005.
The covariance analysis (ANCOVA) was performed to increase the
precision of comparisons between groups by accounting to varia-
that showed a strong or a moderate association with the primary
outcome, such as glucose, waist-to-hip ratio and HbA1C. Contrast
analysis was planned to analyze the differences among groups.
To confirm previous analyses, two multinomial logistic regression
models were performed on the basis of unadjusted assessment and
then adjusted for age, sex, glucose, HbA1C and waist-to-hip ratio,
included as covariates. The strength of the association for the mod-
els was evaluated by Nagelkerke R2ranging from 0 to 1, with higher
values indicating better model fit.
The outcome was defined as 3-level categorical group (control,
T2DM and T2DM+MI). Odds ratio (OR) and 95% CI were estimated
for the T2DM and T2DM+MI with respect to the control group
(comparison group). To perform these analyses T/S value was cate-
gorized according to the 50th percentile (≤0.41 or ≥0.42).
Probability value less than 0.05 was considered statistically sig-
nificant. The reported p-values were two-tailed in all calculations.
Table 1 depicts the characteristics of CTR subjects and
Type2DM/Type2DM+MI patients. Significantly lower levels of
HDL-cholesterol and higher levels of glucose, insulin and HbA1C
were present in Type2DM and Type2DM+MI patients in respect to
CTR. Waist-to-hip ratio was higher in Type2DM+MI patients than
in Type2DM+MI patients, as a consequence of the higher frequen-
cies of use of cholesterol lowering medications, such as statins, in
Type2DM+MI patients than in CTR (Table 1). Moreover, Type2DM,
Type2DM+MI patients and CTR did not differ significantly in terms
F. Olivieri et al. / Atherosclerosis 206 (2009) 588–593
Pearson correlation coefficients between T/S and selected variables (272 subjects).
tion, such as numbers of lymphocytes, neutrophils and monocytes,
was not significantly different among the studied groups (data not
The relative telomere length was inversely correlated with
age overall (Spearman correlation r=−0.05; p=0.374) and in the
control group (Spearman correlation r=−0.12; p=0.23) albeit
non-significantly. Moreover, the relative telomere length was
non-significantly different between male and female overall
(mean±S.D., 0.41±0.19 vs. 0.45±0.19, respectively, age-adjusted
ANOVA p=0.41) and in the control group (mean±S.D., 0.50±0.19
vs. 0.52±0.19, respectively, age-adjusted ANOVA p=0.70). How-
ever, even if age and gender were not significantly different among
studied groups, subsequent analyses were adjusted for age and
gender. In the first step, to analyze the differences of leukocyte
telomere length among CTR, Type2DM and Type2DM+MI, the
one-way analysis of variance was performed. The comparison of
and CTR groups is reported in Fig. 1. Significant differences in
telomere length were observed between the three studied groups
(0.53±0.02 vs. 0.44±0.02 vs. 0.30±0.02, mean±S.E. for CTR,
Type2DM, Type2DM+MI, respectively, F=34.37, df=2, p=0.005).
Type2DM patients as well as Type2DM+MI patients had signifi-
length was shorter in Type2DM+MI patients than in Type2DM
patients. These differences in telomere length between studied
groups are independent by gender. Moreover, difference in leuko-
treatment (data not shown).
In the second step, the effect of the confounding factors that
affected the leukocyte telomere length was analyzed. A correlation
performed in the total sample (Table 2. Glucose (r=−0.28, p<0.01),
significant correlation was observed between inflammatory mark-
ers (hsCRP, fibrinogen and PAI-1), and markers of lipidic profile
(total-cholesterol, HDL-cholesterol and triglycerides) and telom-
ere length. Thus, the ANCOVA was used to adjust the comparison
among groups taking into account the effects of age, sex, glu-
cose, waist-to-hip ratio and HbA1C as covariates. Fig. 2 shows the
adjusted means of T/S in CTR, Type2DM and Type2DM+MI patient
groups. Contrast analysis was applied taking CTR as reference
group. After adjustment, difference in telomere length between
CTR and Type2DM was not significant (adjusted means±S.E.:
0.46±0.03 vs. 0.45±0.04, p=0.66), whereas difference between
tively, remained highly significant (0.31±0.03 vs. 0.46±0.03,
p=0.003 and 0.31±0.03 vs. 0.45±0.04, p=0.005). Moreover, a
multinomial logistic regression was performed to verify whether
leukocyte telomeres length was an independent predictor of MI
Fig. 2. Adjusted T/S means and standard deviation in 272 subjects: CTR, Type2DM
and Type2DM+MI. p<0.01 contrast analysis. ANCOVA with age, gender, HbA1C,
glucose and waist-to-hip ratio as covariates, F=11.07, df=2, p=0.003
Multinomial logistic regression (272 subjects).
aControls is the comparison group.
bThe covariate included in the adjusted model are: age, sex, glucose, HbA1C and
presence in Type2DM. To perform this analysis T/S values were
categorized according to the 50th percentile (≤0.41 or ≥0.42).
Table 3 shows the results obtained performing the unadjusted and
adjusted multinomial logistic regression models. The unadjusted
odds ratio for Type2DM patients was 2.40 (95% IC=1.36–4.25)
and for Type2DM+MI patients was 10.40 (95% IC=4.89–22.12), for
individuals in the 50th percentile with the shortest telomeres as
compared with the other individuals (p=0.003 and 0.002, respec-
and waist-to-hip ratio as covariates, T/S≤0.41 was confirmed as
an independent predictor variable only in Type2DM+MI patients
(OR=24.90, 95% IC=1.63–379.36, p=0.021).
No significant associations between leukocyte telomeres length
and the presence of diabetes complications, such as nephropathy
and retinopathy, were observed.
The main result of the present study is that Type2DM+MI
patients have leukocyte telomere lengths shorter than those of
Type2DM patients and healthy CTR.
From the first step of the analyses, our data showed that
Type2DM patients had leukocyte telomere lengths shorter than
those of healthy CTR, according with previous data showing
a reduced telomere length in leukocytes or monocytes from
Type2DM patients [9,13,15]. Moreover, the inverse correlation
observed in our sample population between leukocyte telomere
lengths and Hb1AC, glucose and waist-to-hip ratio, parameters
to glycemic control, seems to confirm the association between
accelerated telomere attrition and increased oxidative stress. As
F. Olivieri et al. / Atherosclerosis 206 (2009) 588–593
suggested by previous data, the more plausible explanations for
direct damage to telomeres induced by oxidative stress [9,13,15].
However, when the comparison of telomere length between
Type2DM an CTR was adjusted for glycemic control parameters,
such as Hb1AC, glucose levels and waist-to-hip ratio, the differ-
patients enrolled in our study suggests that even if the patients
underwent frequent clinical examinations and use hypoglycemic
drugs, glycemic control was not adequate in the majority of these
patients. About the 70% of elderly Type2DM patients enrolled in
our study show HbA1C levels higher than 7%, a value indicative of a
poor glycemic control. Previous studies have shown that Type2DM
patients with well-controlled diabetes did not have statistically
senescence of these cells .
In addition, most of Type2DM patients enrolled in our study
were affected by hypertension, a parameter recently associated
with leukocyte telomere attrition [21,22].
Interestingly, Type2DM+MI has leukocyte telomere lengths
shorter than those of Type2DM patients and CTR also after cor-
rection for glycemic control parameters, suggesting that telomeres
length was an independent predictor of MI presence in Type2DM
patients. It was reported that in CHD patients with hyperc-
holesterolemia and/or diabetes, telomere length was significantly
shorter than in healthy controls, and that oxidative DNA damage
in CHD patients with metabolic syndrome (MS) was higher than in
those without MS, suggesting a synergistic effect of diabetes and
other CHD risk factors on leukocyte telomere shortening [8,10].
An alternative explanation is the participation of genetic factors
common to both CHD and telomere shortening. Telomere length
is highly heritable and recent findings suggest that inheritance
of shorter telomeres is associated with increased familial risk of
CHD [23,24]. These results support the hypothesis that telomere
shortening is a primary abnormality involved in the pathogen-
esis of CHD, triggering senescent phenotype in leukocyte and
in vascular endothelial and smooth muscle cells [25,26]. Inter-
estingly, leukocytes senescent phenotype was associated with a
pro-inflammatory status . No significant differences of inflam-
matory markers, such as hsCRP, fibrinogen and PAI-1, are observed
between Type2DM and Type2DM+MI patients enrolled in our
study. However, most of the Type2DM+MI patients enrolled in
our study were under statin treatment, having a well-documented
In conclusion, an intriguing hypothesis to explain the leukocyte
telomere shortening in patients affected by age-related diseases,
such as Type2DM and MI, is that leukocyte telomere length hered-
to disease development later in life, and different types of stress
experienced during life could accelerate the effect of this genetic
predisposition. In other words, people who are born with or
acquired shorter telomere may reach the senescent phenotypes in
leukocytes and in endothelial cells earlier.
The fact that adjusting for some glycemic control parameters
attenuated the relationships between telomere length and group
status actually serves as evidence that these may be in the causal
pathway. However, definitive answer to the question if telom-
ere attrition is a primary cause or a consequence of age-related
diseases requires prospective epidemiological studies to ascertain
betes in adulthood independently of well-established risk factors.
ascertain whether augmented rates of telomere attrition in WBCs
are associated with atherosclerosis and diabetes progression. Thus,
prolonged follow-up periods and large cohorts will be required to
Our study has several limitations. The small sample size of
subject groups enrolled in our study is the first limitation. More-
over, a number of factors that may have affected telomere attrition
were not considered in this analysis, including lifestyle, healthy
behaviours, and other factors. Moreover, we observed modest
inverse correlation between telomere length and age. The non-
significant correlation may be due in part to the age range of our
sample and in addition to the intra-individual variability, because
telomere length varies widely even among individuals of the same
age, as reported by other authors .
In addition, we did not observed significant difference in telom-
ere length between male and female sample; changing observed in
postmenopausal period, such as the drop in estrogens, could alter
Moreover, the cross-sectional design of our study does not pro-
vide evidence for a causal relationship between Type2DM+MI
patients and telomere shortening. In fact, we measured leuko-
cyte telomere length in Type2DM patients after Type2DM and MI
diagnosis, thus we cannot provide evidence to define if telomere
attrition is a cause or a consequence of MI in Type2DM patients.
More in general, as our study is a cross-sectional study, only con-
clusion regarding “association” can be made, but not regarding
However, considering the relevance of the findings on telom-
ere biology for a better understanding of human aging and human
aging-related diseases, as well as potential clinical applications in
human age-related diseases, we argue that our preliminary data
merits further study in large, prospective investigations.
may be a possible reliable marker of MI, one of the most frequent
patients, encouraging further studies in this field.
This work was supported by grant from Italian Ministry of
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