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RESEARCH ARTICLE
SA JOURNAL OF DIABETES & VASCULAR DISEASE
66
VOLUME 14 NUMBER 2 • DECEMBER 2017
Role of melatonin in glucose uptake by cardiomyocytes
from insulin-resistant Wistar rats
Frederic Nduhirabandi, Barbara Huisamen, Hans Strijdom, Amanda Lochner
Correspondence to: Frederic Nduhirabandi
Division of Medical Physiology, Department of Biomedical Sciences, Faculty
of Medicine and Health Sciences, Stellenbosch University, South Africa
e-mail:
frederndu@gmail.comBarbara Huisamen, MSc, PhD
Biotechnology, Research and Innovation Platform, South African Medical
Research Council, Tygerberg, South Africa
Hans Strijdom, MD, PhD
Department of Biomedical Sciences, Faculty of Medicine and Health
Sciences, Stellenbosch University, South Africa
Amanda Lochner, PhD, DSc
Department of Biomedical Sciences, Faculty of Medicine and Health
Sciences, Stellenbosch University, South Africa
Previously published in
Cardiovasc J Afr 2017;
28
:
online publication
S Afr J Diabetes Vasc Dis
2017;
14
: 66–73
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-[3H] 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 measured.
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
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 short-term melatonin consumption also
reduced systemic insulin resistance and conferred cardioprotection.
33
However, whether melatonin treatment affects myocardial insulin
sensitivity and glucose uptake remains unknown.