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VOLUME 9 NUMBER 1 • MARCH 2012
19
SA JOURNAL OF DIABETES & VASCULAR DISEASE
RESEARCH ARTICLE
mean values in those without vascular complications and the
control group (Table 2).
Upon dividing the diabetic females with vascular complications
according to the type of vascular complication, serum sRAGE and
plasma TBARS mean values were significantly higher in each entity
of micro- and macrovascular types of complications compared to
the group without vascular complications. As for serum TNF-
α
, its
mean value was significantly higher in those with nephropathy,
neuropathy and ischaemic heart disease compared to those without
vascular complications (Table 3).
Discussion
Age, male gender and smoking are considered risk factors for the
overall risk of coronary artery disease (CAD), a major macrovascular
complication of diabetes.
23
Only non-smoking female subjects were
included in our study to nullify such risk factors. Mogensen reported
that 30% of patients with type 2 diabetes had hypertension at the
time of diagnosis, and when nephropathy developed, almost 70%
had high blood pressure.
24
In the present work, 33.33% of the
diabetic patients without vascular complications were hypertensive,
while in the diabetic patients with vascular complications, 53.33%
were hypertensive.
Soluble forms of RAGE are up-regulated in diabetics, particularly
those presenting with vascular complications. The serum sRAGE
mean value in the diabetic females with vascular complications
was significantly higher than the mean in patients without vascular
complications (Table 2). Angiotensin converting enzyme (ACE)
inhibitors are known to be sRAGE inducers,
25
and since 83% of our
diabetic females with vascular complications were receiving ACE
inhibitors, this could partly explain the rise in serum sRAGE in those
with vascular complications. Such high values in the diabetics with
vascular complications represent an attempt by the body to overcome
the toxic effect of the AGEs present in the affected blood vessels.
The relation of sRAGE to duration of diabetes has been addressed
by Challier
et al.
who observed lack of this association in type 1
diabetes patients.
26
We were able to demonstrate a significant
positive correlation (
r
= 0.434,
p
= 0.004) between circulating
sRAGE and the duration of diabetes in the whole group of diabetic
females. The degree of non-enzymatic glycation is determined
mainly by glucose concentration and time of exposure. Therefore a
longer duration of diabetes with associated hyperglycaemia results
in sustained stimulation of the formation of AGEs, with its positive
regulatory effect on RAGE expression.
27
TBARS, end-products of free radicals, are the most popular
molecules used as an indicator of lipid peroxidation.
28
Their mean
plasma values were significantly higher in both groups of diabetic
patients compared to the corresponding control group, and again
significantly higher in those with vascular complications compared
to those without vascular complications (Table 2).
The long-established role of oxidative stress in accelerated
atherosclerosis and its development before late complications
become clinically evident indicates that oxidative stress plays a
crucial role in the pathogenesis of late diabetic complications.
29
This is clearly evident in the positive relation of plasma TBARS
with CIMT (
r
= 0.502,
p
≤ 0.001) and urinary ACR (
r
= 0.437,
p
=
0.003). Furthermore, significant positive relations of TBARS with
both duration of diabetes (
r
= 0.351,
p
= 0.018) and HbA
1c
levels
(
r
= 0.512,
p
< 0.001) in the whole diabetic group emphasise that
prolonged poor glycaemic control potentiates oxidative stress in
diabetic patients.
In agreement with studies demonstrating increased serum levels
of inflammatory markers such as TNF-
α
in type 2 diabetes patients,
where lack of tight glycaemic control increased their serum levels,
30,31
a significantly higher mean serum TNF-
α
value was noted in the
diabetic females with vascular complications compared to those
without vascular complications and the control group. Tanaka
et
al.
proposed that increased TNF-
α
levels in type 2 diabetes patients
may worsen diabetic vasculopathy via RAGE gene induction,
16
yet
no information regarding the effect of TNF-
α
on sRAGE exists.
Regarding microvascular complications, the diabetic females
presenting with nephropathy had higher serum mean values
of sRAGE and TNF-
α
compared to those without microvascular
Table 3.
Serum sRAGE, TNF-
α
, and plasma TBARS mean values in each type of vascular complications present in the diabetic group compared to those without
vascular complications.
Patients without
vascular
complications
Patients with vascular complications (
n
= 30)
Nephropathy
Retinopathy
Neuropathy
Ischemic heart
disease
Peripheral
vascular disease
sRAGE (pg/ml)
(
n
= 15)
(
n
= 27)
(
n
= 19)
(
n
= 17)
(
n
= 14)
(
n
= 8)
Mean
± SD
691
537
1312
772
1420
841
1423
809
1406
966
1554
1021
p
-value
0.006
0.010
0.006
0.027
0.019
TNF-
α
(pg/ml)
(
n
= 15)
(
n
= 26)
(
n
= 19)
(
n
= 16)
(
n
= 14)
(
n
= 8)
Mean
± SD
11.08
6.64
22.15
22.01
25.40
25.10
27.20
27.10
29.90
28.20
21.60
20.30
p
-value
0.022
NS
0.040
0.023
NS
TBARS (μmol/l)
(
n
= 15)
(
n
= 27)
(
n
= 19)
(
n
= 17)
(
n
= 14)
(
n
= 8)
Mean
± SD
3.0
1.9
5.8
1.4
5.7
0.3
6.3
1.4
6.1
1.4
6.0
1.6
p
-value
< 0.001
< 0.001
< 0.001
< 0.001
0.001
p
< 0.05 was considered statistically significant,
p
< 0.001 was considered highly significant.
sRAGE: soluble form of receptor for advanced glycation end products, TBARS: thiobarbituric acid-reactive substances, TNF-
α
: tumour necrosis factor-alpha.