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CARDIOVASCULAR JOURNAL OF AFRICA • Volume 28, No 6, November/December 2017
362
AFRICA
Role of melatonin in glucose uptake by cardiomyocytes
from insulin-resistant Wistar rats
Frederic Nduhirabandi, Barbara Huisamen, Hans Strijdom, Amanda Lochner
Abstract
Aim:
Melatonin supplementation reduces insulin resistance
and protects the heart in obese rats. However, its role in
myocardial glucose uptake remains unknown. This study
investigated the effect of short-term melatonin treatment on
glucose uptake by cardiomyocytes isolated from obese and
insulin-resistant rats.
Methods:
Cardiomyocytes were isolated from obese rats fed
a high-calorie diet for 16 to 23 weeks, their age-matched
controls, as well as young control rats aged four to eight
weeks. After incubation with melatonin with or without
insulin, glucose uptake was initiated by the addition of
2-deoxy-D-[
3
H] glucose and measured after 30 minutes.
Additional control and obese rats received melatonin in the
drinking water (4 mg/kg/day) for the last six weeks of feeding
(20 weeks) and glucose uptake was determined in isolated
cardiomyocytes after incubation with insulin. Intraperitoneal
glucose tolerance and biometric parameters were also meas-
ured.
Results:
Obese rats (fed for more than 20 weeks) developed
glucose intolerance. Cardiomyocytes isolated from these
obese rats had a reduced response to insulin-stimulated
glucose uptake (ISGU) (
p
<
0.05). Melatonin administration
in vitro
had no effect on glucose uptake per se. However, it
increased ISGU by cardiomyocytes from the young rats (
p
<
0.05), while having no effect on ISGU by cardiomyocytes
from the older control and obese groups. Melatonin
in vivo
had no significant effect on glucose tolerance, but it increased
basal (
p
<
0.05) and ISGU by cardiomyocytes from the obese
rats (50.1
±
1.7 vs 32.1
±
5.1 pmol/mg protein/30 min,
p
<
0.01).
Conclusion:
These data suggest that short-term melatonin
treatment
in vivo
but not
in vitro
improved glucose uptake
and insulin responsiveness of cardiomyocytes in obesity and
insulin-resistance states.
Keywords:
cardiomyocytes, glucose homeostasis, glucose uptake,
insulin resistance, melatonin, obesity
Submitted 24/5/16, accepted 4/4/17
Published online 17/5/17
Cardiovasc J Afr
2017;
28
: 362–369
www.cvja.co.zaDOI: 10.5830/CVJA-2017-018
Although food shortage and malnutrition are still endemic in
low- and middle-income countries,
1
excessive food intake and
reduced physical activity associated with modern lifestyles,
as well as night shift-work have led to a dramatic increase in
the worldwide prevalence of obesity.
2,3
This is accompanied
by various metabolic disorders including, among others, type
2 diabetes and cardiovascular diseases.
4,5
The major basis for
this association is the well-known insulin resistance, which is
a fundamental aspect in the development of type 2 diabetes
and a common pathological link between obesity and cardiac
diseases.
6-8
In this condition, the body produces insulin but does
not use it properly due to decreased cellular sensitivity to its
effect on uptake, metabolism and storage of glucose.
9
Melatonin or N-acetyl-5-methoxytryptamine is the hormone
secreted mainly by the pineal gland during the night. Its role in
metabolic diseases has recently attracted many investigators.
10
Several animal
11-15
and epidemiological
16-20
studies support the
role of melatonin in the regulation of glucose homeostasis. Low
melatonin secretion levels are associated with elevated risk for
hyperglycaemia and type 2 diabetes.
12,18
Importantly, removal of
the melatonin receptor (MT1) significantly impairs the ability
of mice to metabolise glucose and induces insulin resistance
in these animals,
14
while melatonin administration improves
glucose homeostasis in insulin-resistant animals.
11,13,21-24
However,
the mechanism underlying the role of melatonin in glucose
homeostasis is complex and not well understood.
25
Impairment of insulin-stimulated glucose uptake is considered
the most consistent change that develops early in the hearts of
animal models of insulin resistance.
26
This change occurs as a
consequence of both reduced glucose transporter 4 (GLUT4)
protein expression and impaired translocation.
27
In this regard,
while melatonin’s effects have been extensively reported in other
insulin-sensitive organs, such as the hypothalamus, skeletal muscle,
liver and adipose tissue,
25,28-30
it is unclear whether melatonin affects
cardiac glucose uptake in the insulin-resistant state.
A previous study showed that melatonin treatment was able
to protect the heart against oxidative damage and restore the
expression of the GLUT4 gene as well as glucose uptake of
cardiomyocytes isolated from hyperthyroid rats,
31
supporting
the ability of melatonin to improve changes in glucose uptake.
Chronic melatonin administration given from the onset of the
obesity-inducing diet was recently shown to prevent the harmful
effects of obesity, such as insulin resistance and dyslipidaemia
and to protect the hearts of obese rats against myocardial
ischaemia–reperfusion injury.
32
In addition, we observed that
Division of Medical Physiology, Department of Biomedical
Sciences, Faculty of Medicine and Health Sciences,
Stellenbosch University, South Africa
Frederic Nduhirabandi, MSc, PhD,
frederndu@gmail.comBarbara Huisamen, MSc, PhD
Hans Strijdom, MD, PhD
Amanda Lochner, PhD, DSc
Biotechnology, Research and Innovation Platform, South
African Medical Research Council, Tygerberg, South Africa
Barbara Huisamen, MSc, PhD