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CARDIOVASCULAR JOURNAL OF AFRICA • Volume 30, No 4, July/August 2019
AFRICA
193
Cardiovascular Topics
Ellisras Longitudinal Study 2017: elevated serum
levels of carboxymethyl-lysine, an advanced glycation
end-product, are associated with higher odds of
developing endothelial dysfunction in black South
African patients with type 2 diabetes mellitus (ELS 29)
Motetelo Alfred Mogale, Catherine Martha Mhlanga, Stanley Sechene Gololo, Agustine Adu
Abstract
This case–control study investigated the association between
major types of serum advanced glycation end-products (AGEs)
and selected serum/plasma markers of endothelial dysfunction
in black patients with type 2 diabetes mellitus at Dr George
Mukhari Academic Hospital. Serum AGEs were measured using
either enzyme-linked immunosorbent assay (ELISA) or spec-
trofluoremetry. Serum markers of endothelial dysfunction were
measured using either ELISA or calometry. The correlation and
associations between major types of serum AGEs and markers
of endothelial dysfunction were investigated using the Spearman
correlation coefficient and bivariate logistic regression analysis,
respectively. Although both serum total immunogenic AGEs and
serum carboxymethyl-lysine (CML) were moderately and nega-
tively associated with endothelial dysfunction, only serum CML
was significantly associated with a higher odds for the develop-
ment of endothelial dysfunction (low nitric oxide levels) in our
diabetic subjects. It can therefore be concluded from this study
that high serum levels of CML may predispose to endothelial
dysfunction in black South Africans with type 2 diabetes.
Keywords:
serum AGEs, endothelial dysfunction, markers of
endothelial dysfunction, black South Africans, type 2 diabetes
mellitus
Submitted 11/4/18, accepted 31/10/18
Published online 2/8/19
Cardiovasc J Afr
2019;
30
: 193–197
www.cvja.co.zaDOI: 10.5830/CVJA-2018-060
Clinical and research-based evidence indicates that both type
1 and type 2 diabetes mellitus are associated with long-term
microvascular complications (nephropathy, retinopathy and
neuropathy) and macrovascular complications (myocardial
infarction and cerebrovascular accident).
1,2
Available evidence
also suggests that the pathogenesis of these vascular
complications of diabetes involve endothelial activation or
dysfunction.
3
Endothelial dysfunction, defined as impaired
biosynthesis of endothelium-derived nitric oxide (NO) or
its reduced bioavailability, is an established mediator of the
atherosclerotic process.
3,4
Indeed, most of the traditional and
emerging cardiovascular risk factors are known to promote the
development and progression of vascular atherosclerosis through
their deleterious effect on the endothelium.
4
The development
of endothelial dysfunction in diabetes mellitus is attributable,
among other factors, to the formation and action of advanced
glycation end-products (AGEs).
5,6
AGEs are a heterogeneous group of compounds formed by the
non-enzymatic reaction between reducing sugars such as glucose
and proteins, nucleic acids and lipids.
5
The formation of AGEs
is reported to be enhanced by both chronic hyperglycaemia and
oxidative stress, two conditions that are closely associated with
diabetes mellitus.
2,6
Available evidence also suggests that in diabetes mellitus,
AGEs may promote endothelial dysfunction via a variety
of mechanisms. Firstly, collagen cross-linked AGEs in the
vascular wall may trap and quench NO on its way from the
endothelium to the smooth muscle layer to stimulate their
relaxation.
7
Secondly, the interaction of certain serum AGEs
with the receptor for advanced glycation end-products (RAGE)
on vascular endothelial cells results in the activation and
translocation of nuclear factor kappa B (NF-
κ
B) into the
nucleus.
8
Once in the nucleus, NF-
κ
B up-regulates several genes
whose protein and peptide products are involved in the activation
of the endothelium or endothelial dysfunction.
1,7
Thirdly, serum
AGE/RAGE interaction on the vascular endothelium may result
in deactivation of the enzyme, endothelial nitric oxide synthase
(eNOS), which synthesises NO in the endothelium.
9
Fourthly, the
superoxide anion (O
2
–
) generated during the formation of AGEs
may react with NO to form the peroxy-nitrite ion (ONOO)
-
,
thereby reducing the bioavailability of NO.
9,10
Lastly, AGEs may
Department of Biochemistry, School of Science and
Technology, Sefako Makgatho Health Sciences University,
Pretoria, South Africa
Motetelo Alfred Mogale, MD,
alfred.mogale@smu.ac.zaCatherine Martha Mhlanga, MD
Stanley Sechene Gololo, MD
Department of Internal Medicine, School of Medicine, Sefako
Makgatho Health Sciences University, Pretoria, South Africa
Agustine Adu, MD