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SA JOURNAL OF DIABETES & VASCULAR DISEASE
RESEARCH ARTICLE
VOLUME 16 NUMBER 2 • NOVEMBER 2019
57
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
Correspondence to: Motetelo Alfred Mogale
Department of Biochemistry, School of Science and Technology, Sefako
Makgatho Health Sciences University, Pretoria, South Africa
e-mail:
alfred.mogale@smu.ac.zaCatherine Martha Mhlanga, Stanley Sechene Gololo
Department of Biochemistry, School of Science and Technology, Sefako
Makgatho Health Sciences University, Pretoria, South Africa
Agustine Adu
Department of Internal Medicine, School of Medicine, Sefako Makgatho
Health Sciences University, Pretoria, South Africa
Previously published in
Cardiovasc J Afr
2019;
30
: 193–197
S Afr J Diabetes Vasc Dis
2019;
16
: 57–61
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 spectrofluoremetry. 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 negatively
associated with endothelial dysfunction, only serum CML
was significantly associated with a higher odds for the
development 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
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 cerebro-
vascular accident).
1,2
Available evidence also suggests that the patho-
genesis 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 establishedmediator 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 impair Ca
2+
signalling in endothelial cells, thereby interfering with several
endothelial cell processes, including the biosynthesis of NO.
11
Racial/ethnic disparities in endothelial dysfunction have been
observed in a number of studies. For example, African-Americans