doi: 10.1111/j.1464-5491.2004.01127.x
Higher carotid-radial pulse wave velocity in healthy
offspring of patients with Type 2 diabetes
Arterial
Original
Article
article
inLtd,
offspring
Oxford, stiffness
Diabetic
DME
Blackwell
1464-5491
20
UK
Medicine
Publishing
Science
Ltd.
2003 of diabetes patients O. D. McEleavy et al.
O. D. McEleavy, R. W. McCallum, J. R. Petrie, M. Small*, J. M. C. Connell, N. Sattar†
and S. J. Cleland
Abstract
Division of Cardiovascular & Medical Sciences,
University of Glasgow, *Department of Medicine,
Gartnavel General Hospital, and †Department of
Pathological Biochemistry, Glasgow Royal Infirmary,
Glasgow, UK
Accepted 16 June 2003
Aims To determine whether carotid-radial pulse wave velocity (crPWV), a
simple non-invasive measurement of muscular artery structure and function,
is increased in offspring of patients with Type 2 diabetes compared with
well-matched controls with no family history of diabetes. Serum levels of intercellular adhesion molecule-1 (sICAM-1) were also examined.
Methods Offspring (n = 19, M = 8) were recruited via contact with patients
attending clinics. Controls (n = 19, M = 8) were recruited by advertisement.
crPWV was measured using COMPLIOR. Blood pressure and heart rate were
determined and fasting blood taken for measurement of metabolic and endothelial parameters.
Results Offspring and controls were well matched [mean (SD)] for age [33.1 (9.6)
vs. 32.8 (9.5) years], body mass index [24.8 (4.9) vs. 24.3 (3.4) kg/m2], waist circumference [78.3 (2.3) vs. 76.3 (2.5) cm], and systolic blood pressure [120 (9.3) vs.
119 (14.2) mmHg]. crPWV was 10% higher in the offspring [9.94 (1.3) m/s]
compared with controls [9.01 (1.2) m/s, P = 0.02] despite similar pulse pressure
[52 (10.5) vs. 53.5 (9.3) mmHg] and resting heart rate [71 (8.7) vs. 69 (14.0)
beats/min]. They also showed a trend toward higher sICAM-1 [217 (55) vs. 188
(40) ng/ml, P = 0.07] concentrations which were also strongly correlated to
crPWV in offspring (r = 0.63, P = 0.004).
Conclusions Vascular dysfunction in the form of increased muscular artery
stiffness is present from an early stage in subjects at higher risk of developing diabetes. This may be secondary to impaired activation of endothelial signalling
pathways in the context of inherited insulin resistance.
Diabet. Med. 21, 262 –266 (2004)
Keywords arterial stiffness, Type 2 diabetes, first-degree relatives, insulin
resistance, endothelial dysfunction, vascular adhesion molecules, nitric oxide
Introduction
Vascular endothelial dysfunction and arterial stiffness are features of insulin-resistant conditions such as Type 2 diabetes
[1–5]. However, it remains unclear whether this vascular dysfunction is linked directly to insulin resistance or indirectly via
Correspondence to : Dr Stephen J. Cleland, Division of Cardiovascular &
Medical Sciences, Western Infirmary, Glasgow G11 6NT, UK. E-mail:
[email protected]
262
other features of the metabolic syndrome such as hypertension,
dyslipidaemia, central obesity, or markers of oxidative stress
and inflammation. In a human model of insulin resistance,
polycystic ovary syndrome, we recently demonstrated increased
arterial stiffness [measured by carotid-radial pulse wave velocity (crPWV)] [6] and elevated levels of circulating C-reactive
protein (CRP) [7] compared with an age- and body mass index
(BMI)-matched control group. In the present study, we have
compared healthy offspring of patients with Type 2 diabetes
with a control group carefully matched for age, BMI, waist
© 2004 Diabetes UK. Diabetic Medicine, 21, 262 –266
Original article
263
Table 1 Subject characteristics of 19 offspring of patients with Type 2
diabetes and 19 control subjects [mean (SD)]
Age (years)
Sex (M/F)
Smoking (Y/N)
South Asian ethnicity (Y/N)
Body mass index (kg/m2)
Waist (cm)
Systolic BP (mmHg)
Pulse pressure (mmHg)
Heart rate (beats/min)
Offspring
Controls
33.1 (9.6)
8/11
4/15
3/16
24.8 (4.9)
78.3 (2.3)
120 (9.3)
52 (10.5)
71 (8.7)
32.8 (9.5)
8/11
4/15
4/15
24.3 (3.4)
76.3 (2.5)
119 (14.2)
53.5 (9.3)
69 (14.0)
circumference and blood pressure (BP). Increased aortic PWV
has previously been demonstrated in offspring of Type 2 diabetic patients [8], but there have been no reports of increased
crPWV in such a group. Given that crPWV, which represents
mainly brachial artery stiffness, is more likely to be influenced
by endothelial nitric oxide (eNO) production than aortic
PWV, and that insulin resistance is functionally linked with
basal eNO production [2], we hypothesized that crPWV
would be increased in this insulin-resistant offspring group.
Based on previous data [6], the study was powered to detect a
10% difference in PWV between the two groups. We also
obtained fasting blood samples in order to test secondary
hypotheses that the endothelial activation marker serum intercellular adhesion molecule-1 (sICAM-1) and the inflammatory
marker CRP would be elevated in the offspring group.
the time between the two pulse upstrokes (e.g. 50 ms) gives the
velocity (e.g. 10 m /s) (Fig. 1).
PWV analyses were performed by a separate investigator blinded
to subject status. Finally, venous blood was sampled, processed
and stored for future measurement of lipid profile, glucose,
insulin, sICAM-1, serum vascular cell adhesion molecule-1
(sVCAM-1) and CRP. The adhesion molecules were assayed
using commercially available ELISAs. All blood samples were
obtained immediately after clinical physiological measurements
in the fasting state.
Subjects and methods
Data analysis
Subjects
Results were compared between groups using Student’s unpaired t-test, with significance for the primary measurements
PWV, sICAM-1 and CRP set at P < 0.05. The significance level
for the secondary measurements was set at P < 0.01 to allow for
multiple comparisons. Pearson’s correlation coefficient was
calculated for the association between PWV and sICAM-1.
Subsequently, stepwise multiple regression was used to examine if the association between PWV and sICAM-1 in offspring
was independent of age, BMI, systolic BP and fasting insulin
resistance index (FIRI: [insulin] × [glucose]/25) [11].
Ethical approval for the study was obtained from the Ethics
Committee, North Glasgow Hospitals University NHS Trust.
Nineteen healthy offspring of patients with Type 2 diabetes
(‘offspring’) were recruited via contact with patients at the Diabetes Centre, Gartnavel General Hospital, Glasgow. Nineteen
volunteers from the same postcode areas with no family history
of diabetes (‘controls’) were recruited by advertisement. The
control group was carefully matched for age, sex, BMI, waist
circumference, BP, smoking habits and ethnicity (Table 1).
Informed consent was obtained from all volunteers.
Clinical procedures
Subjects attended the Clinical Investigation and Research Unit,
Western Infirmary, Glasgow on one occasion having fasted for
10 h and having avoided heavy exercise, alcohol and caffeine in
the preceding 24 h. Subjects rested prone for 15 min prior to
BP/HR recordings in triplicate. Carotid-radial PWV was recorded using COMPLIOR (Colson, Paris, France) [9,10]. Two
sound probes were placed simultaneously over the right carotid
and radial arteries. The probes were adjusted until good-quality
pulse waveforms were generated, 20 of which were captured
for future analysis. Dividing the surface distance (e.g. 50 cm) by
© 2004 Diabetes UK. Diabetic Medicine, 21, 262 –266
Figure 1 Pulse waveform trace recorded by COMPLIOR.
Results
Data are expressed as mean (SD) unless otherwise stated. The
patient demographics are given in Table 1. crPWV was significantly higher in the offspring [9.94 (1.3) m /s] compared with
controls [9.01 (1.2) m /s] (P = 0.02) (Fig. 2).
There were no significant differences between groups for
levels of cholesterol, triglyceride, HDL-cholesterol, VLDLcholesterol, glucose or insulin (Table 2). However, there was a
trend for the offspring group to be more insulin resistant as
reflected by higher FIRI: 3.86 (1.8) vs. 3.11 (0.5), P = 0.10 (Table 2).
Case–control differences in circulating concentrations of
sICAM-1 were near significant [217 (55) vs. 188 (40) ng/ml,
264
Arterial stiffness in offspring of diabetes patients • O. D. McEleavy et al.
BMI, systolic BP, CRP and FIRI (T = 3.35, R2 (adj) = 36.2,
P = 0.004). Geometric mean CRP levels were near double in
cases, but the difference did not attain significance (P = 0.15).
Discussion
Figure 2 Carotid-radial pulse wave velocity (PWV) in 19 offspring of
patients with Type 2 diabetes and 19 control subjects [mean (SD)]. PWV
was 10% higher in the offspring group (*P < 0.05).
Table 2 Glucose, insulin, lipid, serum intercellular adhesion molecule-1
(sICAM-1), serum vascular cell adhesion molecule-1 (sVCAM-1) and Creactive protein (CRP) levels from fasting blood samples in 19 offspring
of patients with Type 2 diabetes and 19 control subjects [mean (SD)]
Glucose/insulin measures
Glucose (mmol/l)
Insulin (pmol/l)
FIRI
Lipids
Cholesterol (mmol/l)
Triglyceride (mmol /l)
HDL-C (mmol/l)
VLDL-C (mmol/l)
Vascular inflammation
sICAM-1 (ng/ml)
sVCAM-1 (ng/ml)
sICAM-1 : sVCAM-1
CRP (mg/dl)*
Offspring
Controls
P-value
4.73 (0.6)
19.79 (7.0)
3.86 (1.8)
4.47 (0.6)
17.48 (3.0)
3.11 (0.5)
0.18
0.20
0.10
4.80 (0.7)
1.15 (0.6)
1.44 (0.3)
0.59 (0.3)
4.59 (0.8)
1.13 (0.5)
1.54 (0.5)
0.78 (0.6)
0.40
0.91
0.45
0.25
217 (55)
298 (58)
0.76 (0.23)
0.64 (2.8)
188 (40)
303 (49)
0.63 (0.14)
0.39 (2.6)
0.07
0.54
0.04
0.15
FIRI, Fasting insulin resistance index (glucose × insulin/25).
*Geometric mean and SD.
Figure 3 Carotid-radial pulse wave velocity (PWV) vs. serum
intercellular adhesion molecule-1 (sICAM-1) in 19 offspring of patients
with Type 2 diabetes (r = 0.63, P = 0.004).
P = 0.074]. There was no difference in sVCAM-1 levels [298
(58) vs. 303 (49) ng/ml, P = 0.54]. There was an increased
sICAM-1 : sVCAM-1 ratio [0.76 (0.23) vs. 0.63 (0.14), P = 0.039]
in the offspring group (Table 2). Correlation analysis revealed
a significant association between PWV and sICAM-1 in offspring (r = 0.63, P = 0.004) but not control subjects (r = 0.14,
P = 0.57) (Fig. 3); stepwise multiple regression showed that
the relationship in offspring persisted after adjustment for age,
© 2004 Diabetes UK. Diabetic Medicine, 21, 262 –266
In this study we have demonstrated, for the first time, that offspring of patients with Type 2 diabetes have increased carotidradial pulse wave velocity, consistent with increased muscular
artery stiffness, when compared with a matched control group.
We have also shown that crPWV in this group is strongly associated with levels of the endothelial activation marker, sICAM-1,
which showed a trend towards elevation in offspring.
First-degree relatives of patients with Type 2 diabetes exhibit
many features of human insulin resistance [12]. Previous
studies in offspring of diabetic patients have shown increased
aortic PWV [8] in comparison with control individuals. Since
aortic PWV has been shown to be associated with cardiovascular risk factors [13] and to predict coronary events in hypertensive patients [14], the elderly [15] and patients with
end-stage renal disease [16], this finding is of importance with
regard to increased cardiovascular risk in the context of inherited insulin resistance. However, while we and others have
demonstrated that insulin resistance is closely associated with
decreased endothelial NO production [2,3], it is unlikely that
central arterial stiffness is increased via this mechanism in insulin resistance, since changes in muscular tone are of less
relevance in large elastic arteries. Associated cardiovascular
risk factors such as dyslipidaemia and hypertension may be of
greater relevance. Therefore, in the current study, we specifically focused on stiffness in a muscular artery, speculating that
any reduction in eNO production in the context of inherited
insulin resistance would have a significant influence on basal
arterial tone, thus increasing stiffness, even in the absence of
traditional cardiovascular risk factors.
In line with the primary hypothesis, we demonstrated increased
crPWV in the offspring group compared with controls, despite
near identical BMI and BP, and similar lipid concentrations.
Although we did not formally measure insulin sensitivity in the
offspring, there was a tendency for this group to have a higher
fasting insulin resistance index (FIRI), consistent with an
inherited tendency to insulin resistance. Thus, any differences
in indirect measures of vascular endothelial function in
comparison with control subjects are of particular interest.
Although we noted no correlation between FIRI and PWV, future
studies should examine this possibility using clamp-determined
insulin sensitivity.
Plasma levels of the endothelial activation marker sICAM-1
have been shown to be associated with cardiovascular risk
factors [17] and BP [18], to correlate with carotid intima-media
thickness [19], and to predict cardiovascular events independent
of other risk factors [20–22]. The ratio of sICAM-1 : sVCAM-1
in early pregnancy has been demonstrated to be useful in predicting pre-eclampsia, a condition characterized by profound
vascular endothelial dysfunction [23]. In addition, sICAM-1
Original article
levels appear to be regulated by insulin [24], possibly via NO
synthesis [25,26], and higher levels are associated with measures of insulin resistance [27,28]. In the present study, there
was a trend towards increased sICAM-1 levels in offspring of
diabetic patients, and this marker of endothelial activation was
also strongly correlated with arterial stiffness, assessed by
PWV. Another marker of inflammation, CRP, which has also
been shown to be an independent predictor of cardiovascular
disease [20] and Type 2 diabetes [29,30] and linked with insulin resistance [7,27], has recently been shown to be correlated
with endothelial NO production [31] and pulse pressure [32].
The causality of links amongst circulating inflammatory markers, including sICAM-1 and CRP, insulin resistance and
endothelial dysfunction, has yet to be elucidated. In the present
study, we could not demonstrate an association between CRP
and PWV in either group, and although CRP concentration
was exactly double in the cases compared with controls, this
difference did not attain statistical significance (P = 0.12).
In summary, we have shown, for the first time, that healthy
offspring of patients with Type 2 diabetes have increased muscular artery stiffness linked to elevated levels of the endothelial
activation marker sICAM-1, in comparison with a control
group matched for age, adiposity and BP. These data suggest
that cardiovascular abnormalities are detectable in subjects
predisposed to insulin resistance prior to the development of
formally defined metabolic syndrome, and may occur as a
result of common underlying pathogenic mechanisms. They
also provide evidence suggesting that vascular dysfunction in
Type 2 diabetes is not solely a consequence of hyperglycaemia
and/or dyslipidaemia. We propose that increased crPWV is a
surrogate marker for decreased basal eNO action in muscular
arteries in the context of insulin resistance and that this may
reflect a primary disorder of insulin signalling.
References
1 Williams SB, Cusco JA, Roddy M-A, Johnstone MT, Creager MA.
Impaired nitric oxide-mediated vasodilation in patients with noninsulin-dependent diabetes mellitus. J Am Coll Cadiol 1996; 27:
567–574.
2 Cleland SJ, Petrie JR, Elliott HL, Small M, Connell JMC. Insulin
action and endothelial function in type 2 diabetes and hypertension.
Hypertension 2000; 35: 507–511.
3 Steinberg HO, Chaker H, Leaming R, Johnson A, Brechtel G, Baron
AD. Obesity/insulin resistance is associated with endothelial dysfunction. Implications for the syndrome of insulin resistance. J Clin Invest
1996; 97: 2601–2610.
4 Lehmann ED, Gosling RG, Sonksen PH. Arterial wall compliance in
diabetes. Diabet Med 1992; 9: 114–119.
5 Westerbacka J, Vehkavaara S, Bergholm R, Wilkinson I, Cockcroft J,
Yki-Jarvinen H. Marked resistance of the ability of insulin to
decrease arterial stiffness characterizes human obesity. Diabetes
1999; 48: 821–827.
6 Kelly CJG, Speirs A, Gould GW, Petrie JR, Lyall H, Connell JM.
Altered vascular function in young women with polycystic ovary
syndrome. J Clin Endocrinol Metab 2002; 87: 742–746.
7 Kelly CJG, Lyall H, Petrie JR, Gould GW, Connell JMC, Sattar N.
Low-grade chronic inflammation in women with PCOS. J Clin
Endocrinol Metab 2001; 86: 2453–2455.
© 2004 Diabetes UK. Diabetic Medicine, 21, 262 –266
265
8 Hopkins KD, Lehmann ED, Jones RL, Turay RC, Gosling RG. A
family history of NIDDM is associated with decreased aortic distensibility in normal healthy young adult subjects. Diabetes Care 1996;
19: 501–503.
9 Asmar R, Benetos A, Topouchian J, Laurent P, Pannier B, Brisac A
et al. Assessment of arterial distensibility by automatic pulse wave
velocity measurement: validation and clinical application studies.
Hypertension 1995; 26: 485–490.
10 Mackenzie IS, Wilkinson IB, Cockcroft JR. Assessment of arterial
stiffness in clinical practice. Q J Med 2002; 95: 67–74.
11 Cleland SJ, Petrie JR, Morris AD, Ueda S, Dorrian CA, Connell JMC.
FIRI: a fair insulin resistance index? Lancet 1996; 347: 770 [letter].
12 Axelsen M, Smith U, Eriksson JW, Taskinen M-R, Jansson P-A.
Postprandial hypertriglyceridemia and insulin resistance in normoglycemic first-degree relatives of patients with Type 2 diabetes. Ann
Intern Med 1999; 131: 27–31.
13 Taquet A, Bonithon-Kopp C, Simon A, Levenson J, Scarabin Y,
Malmejac A et al. Relations of cardiovascular risk factors to aortic
pulse wave velocity in asymptomatic middle-aged women. Eur J
Epidemiol 1993; 9: 298–306.
14 Boutouyrie PT, Anne I, Asmar R, Gautier I, Benetos A, Lacolley P
et al. Aortic stiffness is an independent predictor of primary coronary
events in hypertensive patients: a longitudinal study. Hypertension
2002; 39: 10–15.
15 Meaume S, Benetos A, Henry OF, Rudnichi A, Safar ME. Aortic
pulse wave velocity predicts cardiovascular mortality in subjects > 70
years of age. Arterioscler Thromb Vasc Biol 2001; 21: 2046–2050.
16 Guerin AP, Blacher J, Pannier B, Marchais S, Safar ME, London GM.
Impact of aortic stiffness attenuation on survival of patients in
end-stage renal failure. Circulation 2001; 103: 987–992.
17 Rohde LEP, Hennekens CH, Ridker PM. Cross-sectional study of
soluble intercellular adhesion molecule-1 and cardiovascular risk
factors in apparently healthy men. Arterioscler Thromb Vasc Biol
1999; 19: 1595–1599.
18 Chae CU, Lee RT, Rifai N, Ridker PM. Blood pressure and inflammation in apparently healthy men. Hypertension 2001; 38: 399–
403.
19 Rohde LE, Lee RT, Rivero J, Jamacochian M, Arroyo LH, Briggs W
et al. Circulating cell adhesion molecules are correlated with ultrasoundbased assessment of carotid atherosclerosis. Arterioscler Thromb
Vasc Biol 1998; 18: 1765–1770.
20 Ridker PM, Hennekens CH, Buring JE, Rifai N. C-reactive protein and
other markers of inflammation in the prediction of cardiovascular
disease in women. N Engl J Med 2000; 342: 836–843.
21 Ridker PM, Hennekens CH, Roitman-Johnson B, Stampfer MJ,
Allen J. Plasma concentration of soluble intercellular adhesion molecule 1 and risks of future myocardial infarction in apparently healthy
men. Lancet 1998; 351: 88–92.
22 Malik I, Danesh J, Whincup P, Bhatia V, Papacosta O, Walker M
et al. Soluble adhesion molecules and prediction of coronary heart
disease: a prospective study and meta-analysis. Lancet 2001; 358:
971–976.
23 Clausen T, Djurovic S, Brosstad FR, Berg K, Henriksen T. Altered
circulating levels of adhesion molecules at 18 weeks’ gestation among
women with eventual preeclampsia: indicators of disturbed placentation in absence of evidence of endothelial dysfunction? Am J Obstet
Gynecol 2000; 182: 321–325.
24 Dandona P, Aljada A, Mohanty P, Ghanim H, Hamouda W, Assian E
et al. Insulin inhibits intranuclear nuclear factor [kappa]B and stimulates I[kappa]B in mononuclear cells in obese subjects: evidence for
an anti-inflammatory effect? J Clin Endocrinol Metab 2001; 86:
3257–3265.
25 Aljada A, Saadeh R, Assian E, Ghanim H, Dandona P. Insulin
inhibits the expression of intercellular adhesion molecule-1 by human
aortic endothelial cells through stimulation of nitric oxide. J Clin
Endocrinol Metab 2000; 85: 2572–2575.
266
Arterial stiffness in offspring of diabetes patients • O. D. McEleavy et al.
26 Li L, Crockett E, Wang DH, Galligan JJ, Fink GD, Chen AF.
Gene transfer of endothelial NO synthase and manganese superoxide
dismutase on arterial vascular cell adhesion molecule-1 expression
and superoxide production in deoxycorticosterone acetate-salt
hypertension. Arterioscler Thromb Vasc Biol 2002; 22: 249–255.
27 Hak AE, Pols HAP, Stehouwer CDA, Meijer JK, Amanda J, Hofman
A et al. Markers of inflammation and cellular adhesion molecules in
relation to insulin resistance in nondiabetic elderly: the Rotterdam
study. J Clin Endocrinol Metab 2001; 86: 4398–4405.
28 Chen NG, Holmes M, Reaven GM. Relationship between insulin
resistance, soluble adhesion molecules, and mononuclear cell
binding in healthy volunteers. J Clin Endocrinol Metab 1999; 84:
3485–3489.
© 2004 Diabetes UK. Diabetic Medicine, 21, 262 –266
29 Pradhan AD, Manson JE, Rifai N, Buring JE, Ridker PM. C-reactive
protein, interleukin 6, and risk of developing type 2 diabetes mellitus.
JAMA 2001; 286: 327–334.
30 Freeman DJ, Norrie J, Caslake M, Gaw A, O’Reilly D, Ford I et al.
C-reactive protein is an independent predictor of risk for the
development of diabetes mellitus in the West of Scotland Coronary
Prevention Study. Diabetes 2002; 51: 1596–1600.
31 Cleland SJ, Sattar N, Petrie JR, Farouhi NG, Elliott HL, Connell
JMC. Endothelial dysfunction as a possible link between CRP levels
and cardiovascular disease. Clin Sci 2000; 98: 531–535.
32 Abramson JL, Weintraub WS, Vaccarino V. Association between
pulse pressure and C-reactive protein among apparently healthy US
adults. Hypertension 2002; 39: 197–202.