12-10-2016, 10:46 AM
COMPARATIVE EVALUATION OF DIABETOGENIC AND MUTAGENIC POTENTIAL OF ARTIFICIAL SWEETENERS ASPARTAME, ACESULFAME-K AND SUCRALOSE
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Abstract :
Objectives: Artificial sweeteners provide the sweetness of sugar without calories. Since from discovery, safety of artificial sweeteners
has been controversial as they directly or indirectly link to induce carcinogenic and genotoxic risks. Hence the present study was
undertaken to compare the diabetogenic and mutagenic potential of most widely using artificial sweeteners; aspartame, acesulfame-K,
and sucralose.
Methods: Diabetic potential is assessed by ascending repeated dose study in which acceptable daily intake (ADI) dose of artificial
sweeteners after converting human dose to animal dose using a standard reference table and administered up to 13 weeks with 3
different phases in an ascending manner on experimental rats. Mutagenic potential was accessed by Ames test with and without
metabolic activation using Salmonella typhimuriumstrains TA 97 and TA1535.
Results: At ADI doses between 0-3 weeks, no significant changes but after 13 weeks significant increase was observed in the levels of
fasting blood glucose, glycated haemoglobin, total cholesterol, triglyceride, LDL and VLDL in all artificial sweetener groups. Sucralose
showed comparatively less increase which was supported by histology reports. In Ames mutagenic assay aspartame, acesulfame-K and
sucralose gave negative results.
Conclusion: Aspartame, acesulfame-K and sucralose were found to exhibit diabetogenic effect at higher dose levels but they were safer
to use at ADI doses and non mutagenic compounds. Comparatively sucralose is safer than aspartame and acesulfame-K. Hence these
artificial sweeteners should be used with caution and over usage is not appreciated.
Introduction :
Artificial sweeteners include substances from several
different chemical classes that interact with taste receptors
and typically exceed the sweetness of sucrose by a factor of
30 to 13,000 times but have no or low calories. They
provide only sweetness but not the daily calorie needs [1].
Due to their intense sweetness they are needed in small
quantity and hence are
economical. Currently FDA
a p p r o v e d a rti f i c i a l
s w e e t e n e r s f o r
c o n s u m p t i o n a r e
acesulfame-K, aspartame,
neotame, saccharin, and
sucralose, out of which most extensively used sweeteners are aspartame,
sucralose and acesulfame-K [2]. As the artificial sweeteners
provide the sweetness of sugar without calories, public
health attention has turned to reversing the obesity
epidemics in the individuals of all ages by choosing to use
the products containing artificial sweeteners. Hence the
use of low-calorie, sugar-free products tripled in the last
two decades of the 20th century. In the United States
alone, more than 150 million people use these products
regularly. However safety of these artificial sweeteners is
unresolved and controversial.
Diabetes mellitus has now assumed epidemic proportions
in many countries of the world. With the present
population of 19.4 million diabetics, and approximately 60 million by the year 2025, India would rank first in its share
of the global burden of diabetes. When a portion of the
population suffers from a disease in which sucrose is the
initiating culprit, the treatment choices are to either
eliminate the source of glucose or add/regulate the
amount of insulin available to the bloodstream [3]. So, in
lieu of ridding the diet of sweet, science went looking for a
sweet replacement by the artificial sweeteners. But,
however recent epidemiologic studies showed the
association between diet soda consumption (which
contains artificial sweeteners) and the risk of development
of obesity, metabolic syndrome and Type 2 diabetes [4,5].
The earlier studies linked artificial sweeteners to
carcinogenic and genotoxic risk. Aspartame exhibited
carcinogenicity on prolonged use, sucralose in mouse
lymphoma assay showed positive mutation frequency at
higher doses and acesulfame-K caused slight chromosomal
aberration indicating that these artificial sweeteners not
entirely safe even though they are FDA approved [6-9].
Aspartame, acesulfame-K and sucralose are not entirely
safe as they were artificially synthesized and their
metabolites may yield to toxic chemicals. Most
importantly, the risk-benefit ratio of artificial sweeteners is
unclear. Recent study also shows health risk even below
the acceptable daily intake (ADI) doses after the long term
consumption. So, further studies are essential to assess the
safety of these three artificial sweeteners. Hence present
study was undertaken to access the diabetogenic and
mutagenic potentials of the artificial sweetenersaspartame,
acesulfame-K and sucralose.
Materials and Methods :
Chemicals
Aspartame, acesulfame-K and sucralose were procured by
Highmedia Bombay, India. HbA1C (glycated haemoglobin)
kit, total cholesterol kit, triglyceride kit, etc, were procured
from Agappe diagnostics Ltd, Kerala. And all other
chemicals were of analytical grade and used as received.
Animals
All the experiments were carried out with Sprague-Dawley
rats weighing 150-200g. Animals were kept in the animal house of NGSM Institute of Pharmaceutical Sciences,
Mangalore under controlled conditions of temperature
(23±2ºC), humidity (50±5%) and 12 h light-dark cycle.
Animals were fed pellet diet (Venkateshwara enterprises,
Bangalore) and water ad libitum. All the animals were
acclimatized for seven days before the study. The
experimental protocol was approved by institutional
animal ethical committee (approval number:
Reg.No.KSHEMA/AEC/39/2010)
Selection of Drug Doses
The human ADI of aspartame, sucralose and acesulfame-K
was 50 mg/kg, 15 mg/kg and 15 mg/kg respectively. The
ADI doses were converted to animal doses as per the
conversion chart and used for the study [10].
Assessment of diabetogenic potential [11,12]
Experimental design:
Diabetic potential accessed by ascending repeated dose
study up to 13 week in 3 phases on rats. Study involved 4
groups with 6 animals each. Drugs were administered
orally through oral gavage.
ã Control group
ã Aspartame treated group
ã Acesulfame-K treated group
ã Sucralose treated group
Phase ?(0-3 weeks- ADI dose):
• Control group: administered with distilled water for 0-
3 weeks.
• Aspartame treated group: administered with 315
mg/kg rat
• Acesulfame-K treated group: administered with 94.5
mg/kg rat
• Sucralose treated group: administered with 94.5
mg/kg rat
Phase ІІ (3-7 weeks- 2 x ADI dose):
• Control group: administered with distilled water
• Aspartame treated group: administered with 630
mg/kg rat
• Acesulfame-K treated group: administered with 75.6 mg/kg rat
• Sucralose treated group: administered with 75.6
mg/kg rat
Phase ІІІ (7-13 weeks- 4 x ADI dose):
• Control group: administered with distilled water
• Aspartame treated group: administered with 1260
mg/kg rat
• Acesulfame-K treated group: administered with 151.2
mg/kg rat
• Sucralose treated group: administered with 151.2
mg/kg rat
At the end of 3rd, 7th, 13th week rats were fasted for 18
hour and the fasting blood glucose (FBG) levels were
measured. Blood was collected by retro orbital sinus
method [13] and centrifuged at 2500 rpm. Serum was
separated and lipid profiles like total cholesterol,
triglyceride, LDL and VLDL was measured along with the
HbA1C levels which are measured only at the end of the
13th week.