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Aspartame: Should Individuals with Type II Diabetes be Taking it?

  • All India Institute of Medical Science Raebareli

Abstract and Figures

Background: Individuals with type II diabetes (T2D) have to manage blood glucose levels to sustain health and longevity. Artificial sweeteners (including aspartame) are suggested sugar alternatives for these individuals. The safety of aspartame in particular, has long been the centre of debate. Although it is such a controversial product, many clinicians recommend its use to T2D patients, during a controlled diet and as part of an intervention strategy. Aspartame is 200 times sweeter than sugar and has a negligible effect on blood glucose levels, and it is suggested for use so that T2D can control carbohydrate intake and blood glucose levels. However, research suggests that aspartame intake may lead to an increased risk of weight gain rather than weight loss, and cause impaired blood glucose tolerance in T2D. Objective: This review consolidates knowledge gained from studies that link aspartame consumption to the various mechanisms associated with T2D. Method: We review literature that provides evidence that raise concerns that aspartame may exacerbate T2D and add to the global burden of disease. Result: Aspartame may act as a chemical stressor by increasing cortisol levels, and may induce systemic oxidative stress by producing excess free radicals, and it may also alter gut microbial activity and interfere with the N-methyl D-aspartate (NMDA) receptor, resulting in insulin deficiency or resistance. Conclusion: Aspartame and its metabolites are safe for T2D is still debatable due to a lack of consistent data. More research is required that provides evidence and raise concerns that aspartame may exacerbate prevalence of pathological physiology in the already stressed physiology of T2D.
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Aspartame: Should Individuals with Type II Diabetes be Taking it?
Arbind Kumar Choudhary*
Department of Physiology, School of Medicine, Faculty of Health Sciences, University of Pretoria, Pretoria, Gauteng,
South Africa
Received: April 06, 2017
Revised: May 25, 2017
Accepted: May 29, 2017
Abstract: Ba ckground: Individuals with type II diabetes (T2D) have to manage blood glucose levels to
sustain health and longevity. Artificial sweeteners (including aspartame) are suggested sugar alternatives
for these individuals. The safety of aspartame in particular, has long been the centre of debate. Although it
is such a controversial product, many clinicians recommend its use to T2D patients, during a controlled diet
and as part of an intervention strategy. Aspartame is 200 times sweeter than sugar and has a negligible
effect on blood glucose levels, and it is suggested for use so that T2D can control carbohydrate intake
and blood glucose levels. However, research suggests that aspartame intake may lead to an increased
risk of weight gain rather than weight loss, and cause impaired blood glucose tolerance in T2D.
Objective: This review consolidates knowledge gained from studies that link aspartame consumption to
the various mechanisms associated with T2D.
Method: We review literature that provides evidence that raise concerns that aspartame may exacerbate
T2D and add to the global burden of disease.
Result: Aspartame may act as a chemical stressor by increasing cortisol levels, and may induce systemic
oxidative stress by producing excess free radicals, and it may also alter gut microbial activity and inter-
fere with the N-methyl D-aspartate (NMDA) receptor, resulting in insulin deficiency or resistance.
Conclusion: Aspartame and its metabolites are safe for T2D is still debatable due to a lack of consistent
data. More research is required that provides evidence and raise concerns that aspartame may exacerbate
prevalence of pathological physiology in the already stressed physiology of T2D.
Keywords: Aspartame, type II diabetes, glucose, insulin, weight gain..
Artificial sweeteners are low-calorie substitutes for sugar
used to sweeten a wide variety of foods, has health contro-
versy over perceived benefits [1]. The use of artificial sweet-
eners has increased concomitantly with a rising incidence of
diabetes and allows type-II diabetics Individuals (T2D) to
control carbohydrate intake and maintain blood glucose
level, however artificial sweeteners have been linked to an
increased risk of extreme weight gain, metabolic syndrome
and cardiovascular complication [2-5].
“Lite or diet” carbonated soft drinks contain 150-200 mg
of aspartame per serving (12 oz or 360 ml) and noncarbon-
ated beverages usually contain 140 mg per serving (8 oz or
240 ml) [6, 7]. The European Food Safety Authority estab-
lished acceptable daily intake (ADI) of aspartame by humans
at 40 mg/ [8].The U.S. Food and Drug Admini-
stration (FDA) established an ADI of 50 mg/ [9].
*Address correspondence to this author at the University of Pretoria, Fac-
ulty of Health Sciences, Department of Physiology, Private Bag x323,
Arcadia, 0007, South Africa; Tel: +27 12 420 2535; Fax: +27 12 420 4482;
Some authorities suggest that it is particularly useful for per-
sons with T2D to use aspartame (up to ADI levels), as it has
no significant effect on plasma glucose levels or blood lipids
[10]. Aspartame may not influence on food intake, satiety
levels or postprandial glucose levels, it may not have an ef-
fect on postprandial insulin levels compared to natural
sweeteners such as sucrose [11]. Whilst aspartame consump-
tion may assist with weight management by reducing caloric
intake compared to sucrose [12], but there is evidence that
rats may compensate for the reduction in calories by over
eating, resulting in increased body weight and adiposity [13].
It is well-known that there is a concerning relationship be-
tween T2D and obesity [14] and that the increases in T2D
prevalence are on the rise, even with governments and pri-
vate sectors spending and increasing percentage of their
funds on treating and caring for these individuals. Although
the side-effects of aspartame are well-known such as neu-
roendocrine imbalances [15, 16], neurophysiological symp-
tom [17], gut dysbiosis along with impaired blood glucose
level [18, 19], altered liver function [20-22] and metabolic
consequences [23]. However, people insist on its usefulness
in particular T2D. Therefore, in this paper regarding the ef-
fect of aspartame [24, 25] we critically evaluate the mecha-
2 Current Diabetes Reviews, 2017, Vol. 13, No. 0 Arbind Kumar Choudhary
nism of aspartame consumption in obese T2D (Fig. 1) and
raise important concerns regarding the safety of aspartame
Aspartame is rapidly metabolized upon ingestion by gut
enzymes (esterase and peptidase) into its metabolic compo-
nents: phenylalanine (50%), aspartate (40%) and methanol
(10%) [26]. Aspartame and its metabolites may cause the
deregulation of blood glucose levels (see (Fig. 1) by:
1) Interruption of neuroendocrine balances [15, 16],
(2) Alteration of N-methyl D-aspartate (NMDA) receptor
(3) Impairment of liver function [20]
(4) Alteration of gut microbes [18].
The role of aspartame to maintain normal blood glucose
level is controversial, in human [11, 28, 29] and animal stud-
ies [30-32] (Table 1). As, no significant differences were
observed in blood glucose level [11, 29] , however it also
failed to maintain normal level and raised blood glucose
level [19, 30, 32] . Aspartame has also been linked to weight
gain and hyperglycemia in common zebra fish nutritional
model [32]. The chronic exposure of aspartame (50
mg/, for first five months (mature adulthood) of life,
deteriorates insulin sensitivity [30], and produces changes in
blood glucose parameters and adversely impacts spatial
learning and memory in mice [31]. It has also been found
that aspartame exposure may cause behavioral differences
and learning impairment in rodents [33-36]. Literature states
that, learning impairments suggested to be linked to glucose
homeostasis and insulin sensitivity, which affects neuronal
survival and synaptic plasticity [37].
2.1. Aspartame and the Neuro-endocrine Balance
The disruptive effect of aspartame has been observed in
the brains of aspartame treated mice [38]. The neuro-
endocrine system maintains glucose homeostasis [39]. Glu-
cose receptors (GLUTS) are mainly present in the liver, pan-
creas and brain [40]. The hypothalamic–pituitary–adrenal
(HPA) axis maintains glucose homeostasis by augmenting
liver glycogenolysis and gluconeogenesis [39]. Aspartame is
a chemical stressor to the HPA axis and produces excess
corticosterone (cortisol) [16]. Disrupted glucose homeostasis
may cause hyperglycemia leading to insulin resistance [41].
A mild condition of unchecked hyperglycemia may be in-
dicative of pre-diabetes; defined as having an impaired fast-
ing glucose (IFG) (glucose level 100 mg/dL but 125
mg/dL) or impaired glucose tolerance [42] .
Aspartame may further affect glucose homeostasis
by increasing muscarinic receptor density by 80% in the
brain, including the hypothalamus [35]. The activation of
muscarinic and ACh-receptive neurons (mAChRs) in the
hypothalamus triggered an elevation in rodent plasma glu-
cose levels, and reduced by the mAChRs antagonist, atro-
pine, suggesting a role for hypothalamic mAChRs in glucose
homeostasis [43].
2.2. Aspartame and the N-methyl D-aspartate (NMDA)
N-methyl D-aspartate (NMDA) receptors are distributed
throughout the central nervous system including the hypo-
thalamus, amygdala and hippocampus, regulating vital meta-
bolic and autonomic functions including energy homeostasis
[44], glucose sensing [45] and non-insulin mediated hepatic
glucose uptake [46]. Aspartate, a component of aspartame,
may activate the NMDA receptor and occupy binding sites
Fig. (1). Aspartame consumption may lead to alteration of (a) neuroendocrine balances (b) N-methyl D-aspartate (NMDA) receptor (c) liver
function, (d) gut microbes; this may result in impairment of blood glucose level in diabetic patients.
Aspartame: with Type II Diabetes Current Diabetes Reviews, 2017, Vol. 13, No. 0 3
for glutamate [26]. During hypoglycemia, central excitatory
amino acids through activation of NMDA receptors, result-
ing in stimulation of the sympathoadrenal as well as hypo-
thalamic–pituitary adrenal axis and appears to play an impor-
tant role in the sustained elevation in hepatic glucose produc-
tion [47]. Hence drinking aspartame sweetened drinks whilst
in a hypoglycemic state may interfere with the glucoregula-
tory response.
2.3. Aspartame and the Liver Function
The liver maintains normal glucose concentrations during
fasting and after eating, and it is a major site of insulin clear-
ance [48]. Hepatic glucose production and glycogenolysis
may result in hyperglycemia when insulin is absent or when
the liver is insulin resistant [49]. Aspartame consumption at
the safety dosage (40mg/ may cause abnormal
hepatocellular function [20-22, 32, 50]. The alteration of
hepatic function is associated with a decline in hepatic insu-
lin sensitivity and impairment of blood glucose level [51].
2.4. Aspartame and Changes in Appetite and Weight
It was previously noted that aspartame may actually
stimulate appetite, increase carbohydrate cravings, stimulate
fat storage and increase weight gain [5].
Whilst aspartame is recommended to assist with weight
management by reducing food intake and controlling calo-
ries [12]. The observed weight gains in aspartame fed rats,
that consumed the same amount of calories as water fed rats,
could be due to a decrease in energy expenditure or increases
in fluid retention [13]. Higher BMI was observed in human
with consumption of diet carbonated beverages containing
aspartame [52, 53]
The body may use sweet taste to predict the caloric con-
tents of food [54]. The sweet taste, regardless of caloric con-
tent, enhances our appetite [55]. The calories contained in
natural sweeteners trigger biological responses to keep over-
all energy consumption constant. Non-caloric sweeteners
may promote excessive intake and body weight gain by cor-
rupting the predictive relationship between sweet taste and
the caloric consequences of eating [5]. The unbalanced pre-
dictive relationship may lead to a positive energy balance
through increased food intake and/or diminished energy [56].
Defective appetite control mechanisms may trigger food
cravings [56]. Weight gain has been linked to the widespread
use of non-caloric artificial sweeteners, such as aspartame
(e.g., Diet Coke) in food products [5]. The effects of aspar-
tame on weight gain are summarized in (Table 2).
Energy balance is regulated through the manufacture of
leptin (satiety hormone) by adipose cells and by inhibiting
ghrelin, (the hunger hormone). Both hormones act on the
receptors in the arcuate nucleus of the hypothalamus to regu-
late appetite [57]. Interestingly, research showed that the
arcuate nucleus of the hypothalamus in adult mouse brains is
damaged markedly by aspartame (0.5 mg/g) [36]. It is sug-
gested that aspartame usage may upset appetite regulation
and lead to weight gain, as aspartame do not activate the
food reward pathways in the same fashion as natural sweet-
eners but encourage sugar craving and sugar dependence,
leading to gain weight [5]. Usually, the changes in weight
are related to changes in insulin receptor or insulin resistance
[58]. Weight gain is related to increased insulin and glucose
levels [59]. Chronically elevated insulin levels are associated
with a decrease in insulin sensitivity [60] and may lead to
eventual insulin resistance [58]. It is proposed that insulin
resistance is associated with impaired blood sugar, triglyc-
erides, blood clots, sleep, as well as cardiovascular and neu-
rological disorder [61-63] (Fig. 2).
Table 1. Aspartame and studies looking at the maintenance of normal blood glucose levels.
At week 11, induced dysbiosis and glucose intolerance!
Aspartame elevated fasting glucose levels
Postprandial glucose and insulin levels at 20 min after consump-
tion were significantly lower compared to the sucrose condition!
Significant increase in fasting blood glucose together with re-
duced insulin sensitivity during an Insulin Tolerance Test (ITT)
zebra fish
Remarkable increase in serum glucose level after 12 days
No significant differences were observed in blood glucose level at
5, 10, and 15 min post-consumption.!
Aspartame ingestion was followed by blood glucose declines (40
% of subjects), increases (20 %), or stability (40 %). This varied
blood glucose responses after aspartame support the controversy
over its effects
4 Current Diabetes Reviews, 2017, Vol. 13, No. 0 Arbind Kumar Choudhary
Fig. (2). Aspartame consumption may alter food habits (satiety
signal), leads to weight gain, increase free fatty acid, which may
inhibit glucose utilization and promotes glucose production and
results in insulin resistance or deficiency. Insulin resistance is asso-
ciated with impaired blood sugar, trigly cerides, blood clots, sleep,
as well as cardiovascular and neurological disorders.
2.5. Aspartame and Gut Dysbiosis with Insulin Resis-
tance or Deficiency
Gut microbes modulate main host biological systems that
control energy homoeostasis and glucose metabolism in T2D
[64] and plays a significant role in the development of insu-
lin resistance [65]. The intestinal bacterial population unique
to T2D may produce toxins causing systemic inflammation,
affecting overall metabolism and insulin sensitivity [66].
Low dose aspartame (5–7 mg/kg/day) consumption in drink-
ing water over eight weeks resulted in elevated fasting glu-
cose levels and impaired insulin tolerance in diet-induced
obese rats and the fecal analysis of gut microbiota showed
aspartame to increase the abundance of Enterobacteriaceae
[18]. Mice that drank water with 4% aspartame and con-
sumed a high fat diet for eleven weeks had higher glucose
excursions after a glucose load, these changes were associ-
ated with a metabolic phenotype change caused by alteration
of the gut microbiota [19] and dysregulated microbiota-gut-
brain axis may explain aspartame metabolic and other side
effects [67].
Generally, it is well-known that glucose intolerance is a
precursor to T2D [68]. T2D is a heterogeneous disease with
large variation in the relative contributions of insulin resis-
tance and beta cell dysfunction [69]. Insulin is synthesized
and released from pancreatic β- cells in response to increases
in plasma glucose concentrations [70]. Increases in amino
acids can influence insulin biosynthesis and secretion [71].
The amino acid; phenylalanine, may stimulate insulin secre-
tion and glucagon concentration [72]. The insulin response
can be substantially increased by phenylalanine, and has
high insulinotropic potential in T2D [73]. The amino acid;
phenylalanine (50%), is a major aspartame component,
which may lead to insulin resistance or deficiency.
2.6. Cortisol Pathway to Insulin Resistance
The cortisol pathway plays an important role in the de-
velopment of insulin resistance, and literature suggests that
aspartame (75mg/, may act as a chemical stressor
and result in the production of excess corticosterone (corti-
sol) after 90-days of oral administration in rats [16]. In gen-
eral, cortisol has been linked to insulin resistance through the
following mechanisms:
1. Cortisol decreases the translocation of GLUT-4
transports and associated glucose uptake [74, 75].
2. Cortisol inhibits the release of insulin from the beta
cells of pancreas in mice [76].
3. Cortisol facilitates insulin resistance by increasing the
production of glucose and accumulation of lipids in
the cell [74, 75].
Rats given the safety dosage of aspartame
(40mg/ for 90-days, showed a significant increase
in coticosterone level but no significant changes in blood
Table 2. Research showing the effects of aspartame on weight gain.
Higher BMI was observed with consumption of diet carbonated beverages.
Increased diet soda consumption was associated with higher BMI in school children.
Zebra fish
Aspartame may promote weight gain and hyperglycemia in a zebra fish nutritional model
A positive association between aspartame intake and body weight in C57BL/6J mice.
Aspartame can cause greater weight gain than sugar, even when the total caloric intake remains similar.
Aspartame: with Type II Diabetes Current Diabetes Reviews, 2017, Vol. 13, No. 0 5
glucose level [50]. However, prolonged exposure to excess
levels of cortisol may affect blood glucose levels in T2D
[77]. Excess levels of cortisol may induce insulin resistance
or decrease insulin action [78] (Fig. 3A and B) which de-
creases both hepatic and extra hepatic (peripheral) sensitivity
to insulin and increase blood glucose levels [74] (Fig. 4A).
Cortisol also increases the rate of gluconeogenesis and gly-
cogenolysis in liver, and decreases the activity of the GLUT-
4 transporter and related glucose uptake in skeletal muscle.
Furthermore, it increases lipolysis and decreases the activity
of lipoprotein lipase; both of which increase free fatty acid
levels in the cell and compete with glucose for oxidative
metabolism (Fig. 4A) [74, 75]. Cortisol action therefore di-
rectly opposes insulin action and can be described as a
diabetogenic hormone, that fundamentally and possibly
directly contributes to insulin resistance (Fig. 3A and B) [74,
Insulin resistance is a state of impaired biological re-
sponse to normal or elevated serum insulin concentrations
[79] and occurs when the body does not respond properly to
Fig. (3). The link between aspartame and cortisol. A) Aspartame may act as a chemical stressor and its intake may lead to hormonal imbal-
ance and produce excess cortisol; this may induce insulin resistance or deficiency, and result in increased blood sugar, increase blood pres-
sure, decrease immune response, decrease serotonin and pain sensation and impaired memory and mental attention. 3B) Increased cortisol or
aspartame component, methanol, may lead to hormonal imbalance (increase appetite and food intake, decrease energy expenditure and in-
crease fatigue) and increase sympathetic activity (result in sleep loss) may lead to weight gain, insulin resistance and increase cardiov ascular
risk. In addition, increased cortisol or aspartame component: phenylalanine and aspartic acid, may affect platelet function, result into
prothrombotic state, vascular dysfunction and increase cardiovascular risk.
6 Current Diabetes Reviews, 2017, Vol. 13, No. 0 Arbind Kumar Choudhary
insulin. Insulin resistance may also be the cause of abnor-
mally high blood glucose levels in T2D [80] due to (a) re-
duced early insulin secretory response to oral glucose, (b)
decreased glucose-sensing ability of the cell, (c) reduced the
ability of the cell to compensate for the degree of insulin
2.7. Hypercortisolism and its Other Complications
Augmented cortisol may also increase sympathetic activ-
ity, result in sleep loss; a risk factor for weight gain, insulin
resistance, [81] and cardiovascular risk [82] (see Fig. 3A and
B). Aspartame ingestion result in sympathetic dominance
with loss of vagal tone and impaired cardiac function in rats
[83, 84]. Mostly, Hypercortisolism is associated with central
obesity, insulin resistance, dyslipidemia, and alterations in
clotting and platelet function [85] (see Fig. 3A and B). The
duration of cortisol excess correlates with increases the syn-
thesis of several coagulation factors, stimulating endothelial
production of von Willebrand factor and concomitantly in-
creasing factor VIII [86] and may also enhance platelet and
reduce plasma fibrinolytic capacity [87, 88]. Increased corti-
sol or aspartame component phenylalanine after aspartame
usage may affect platelet function and both fibrin formation
and platelet activation in an animal model were found to be
to changed fibrin packaging by aspartame administration
[89]. Pathological functioning of both platelets and fibrin,
closely associated with hypercoagulability, is known to be a
hallmark of T2D, and therefore aspartame usage would add
to this pathological hypercoagulability in T2D and also in all
other inflammatory conditions.
Cortisol may influence the insulin receptor by (a) de-
creasing binding affinity and receptor number [90], (b) de-
creasing binding affinity without decreasing numbers [91],
(c) increasing receptor number without affecting affinity [92]
or (d) having no effect on receptor affinity or number [93].
Insulin receptors are made up of 2 α and 2 β glycoprotein
subunits connected by disulphide bonds and are situated in
the cell membrane[94] (Fig. 4B). Insulin binds to the ex-
tracellular α subunit, causing a conformational change, al-
lowing ATP to bind to the intracellular component of the β
subunit [79]. ATP binding in turn activates phosphorylation
of the β subunit convening tyrosine kinase activity. This en-
ables tyrosine phosphorylation of intracellular substrate pro-
teins known as insulin responsive substrates (IRS) (Fig. 4B).
The phosphorylated IRS proteins bind with enzymes, such as
phosphatidylinositol 3-kinase (PI 3-kinase). The PI 3-kinase
acts via serine and threonine kinases, such as Akt/protein
kinase B (PKB), protein kinase C (PKC) and PI dependent
protein kinases 1& 2 (PIPD 1 and 2). The PI 3-kinase medi-
ates insulin’s metabolic effects [94] by translocation of glu-
cose transporter proteins (GLUT), synthesis of glycogen,
lipid and protein, anti-lipolysis and hepatic gluconeogenesis
[79] (Fig. 4B). Cortisol may cause insulin resistance by de-
creasing transcription of insulin IRS-1/ IRS-2 in skeletal
muscle [95], adipose tissue [96] and liver[97]. Excess corti-
sol may act as an insulin antagonist in the insulin resistant
condition. Hence excess cortisol after chronic aspartame
consumption may promote to insulin resistance, however,
the particular mechanism has to be explored further with
more scientific studies.
Cortisol also exerts bi-phasic regulation of inflammation
Fig. (4A). Insulin and cortisol on peripheral and central glucose uptake. The GLUT 4 is expressed principally in skeletal muscle and lipopro-
tein lipase principally in adipose tissue. Actions of cortisol (brown color) and insulin (green color) are shown either as stimulate (+) or inhibit
(×).The major effects of cortisol may be to reduce translocation of GLUT 4 to the cell surface and enhance lipolysis, thereby increasing free
fatty acid competition with pyruvate for mitochondrial oxidative metabolism. In liver, insulin and glucocorticoids oppose each other’s ac-
tions, particularly on gluconeogenesis and oxidative glycolysis.
Aspartame: with Type II Diabetes Current Diabetes Reviews, 2017, Vol. 13, No. 0 7
in humans and either suppresses or stimulates the inflamma-
tory response in a concentration and time-dependent manner
[98]. It is unclear if aspartame consumption causing cortisol
production has a pro-inflammatory or anti-inflammatory
The CNS regulates the peripheral metabolism, including
energy expenditure, glucose and lipid metabolism, through
changes in autonomic sympathetic, parasympathetic, and
hormonal outputs[99]. Any aspartame dose consumed by
humans will elevate brain phenylalanine much more than it
elevates tyrosine, since the human liver converts phenyla-
lanine to tyrosine relatively slowly than in rats[100]. Pheny-
lalanine, rather than tyrosine is the amino acid that is known
to be associated with suppression of brain catecholamine
synthesis[101] . Aspartame (0.625-45mg/kg) consumption
may exert a dose-dependent inhibition of brain serotonin,
noradrenaline, and dopamine[38] that may result in a
changed neurological function.
Phenylalanine, an aspartame component, competes with
tryptophan, the serotonin precursor, for the same channel
(NAAT) through the blood-brain barrier[26]. Phenylalanine,
penetrates the brain and suppresses serotonin levels [26].
Large doses of phenylalanine can block important neuro-
transmitters including serotonin, which helps to control sen-
sations of satiety. Serotonin regulates the appetite mecha-
nism and converts into melatonin to induce sleep and sero-
tonin deficiencies can cause depression, upset the appetite
mechanism and lead to weight gain [101]. Serotonin may
also play a role in glucose homeostasis[102]. The central
serotonin 2C receptors in the pro-opiomelanocortin (POMC)
neurons in the arcuate nucleus of hypothalamus regulate en-
Fig. (4B). Insulin and cortisol on insulin receptor (adapted from [79]). Insulin receptors are made up of 2α and 2β glycoprotein. Insulin binds
to the extracellular α subunit, subsequent conformational change, allowing ATP to bind to the intracellular β subunit, phosphorylation of the
β subunit convening tyrosine kinase activity, and this phosphorylation of insulin responsive substrates (IRS), The phosphorylated IRS pro-
teins bind with enzymes phosphatidylinositol 3-kinase (PI 3-kinase). The PI 3-kinase acts via Akt/protein kinase B (PKB), protein kinase C
(PKC) and PI dependent protein kinases 1& 2 (PIPD 1&2). The PI 3-kinase mediates further insulin’s metabolic effects by translocation of
glucose transporter proteins (GLUT), synthesis of glycogen, lipid and protein, anti-lipolysis actions of cortisol (brown color) and insulin
(green color) are shown either as stimulate (+) or inhibit (×) and hepatic gluconeogenesis.
8 Current Diabetes Reviews, 2017, Vol. 13, No. 0 Arbind Kumar Choudhary
ergy and glucose homeostasis [103-105]. The arcuate POMC
neurons respond to circulating glucose, and if the KATP
channels present in POMC neurons are blocked by a com-
pound, such as phenylalanine, may result in impaired glu-
cose tolerance [99, 106]. POMC neurons are also involved in
the control of lipid metabolism [107].
People with low levels of serotonin are often compelled
to consume more sugar in a bid to increase serotonin produc-
tion and this often results in a sugar addiction[108], which in
turn can lead to insulin resistance (high levels of insulin
cause receptors for insulin to shut down by means of ‘down-
regulation) [109]. Aspartame consumption in both higher
doses [16] and safety doses [110, 111] were shown to induce
oxidative stress in the hypothalamus, leading to neuronal
death (apoptosis). The glucose regulatory role of the hypo-
thalamus would thus be impaired. Recent research has tar-
geted the serotonin 2C receptors for the treatment of Diabe-
tes /obesity [112]. The activation of this receptor reduces
elevated insulin levels and improves glucose tolerance and
insulin sensitivity in both genetically obese mice and in mice
with diet-induced obesity [113].
An imbalance between pro-oxidants and anti-oxidants
determines oxidative stress and causes cellular disruption
and damage [114]. Aspartame induces excess free radical
production, in particular, reactive oxygen species (ROS) and
reactive nitrogen species (RNS). These free radicals result in
systemic oxidative stress [23] such as in blood cells [50, 89,
115-117], brain cells [16, 110, 111, 118, 119], liver and kid-
ney cells [20, 22, 120], heart cells [83, 84] and immune or-
gans [15, 121-123] (Fig. 5).
Systemic oxidative stress is associated with insulin re-
sistance [124]. Oxidative activity among diabetes patients
Fig. (5). Aspartame usage may result in systemic inflammation and leads to insulin resistance. A spartame consumption produces excess free
radicals (ROS/RNS) production; result in oxidative stress and can trigger pro-inflammatory factor (TNF-α, NF-Κb, IL-6, CRP, FFA), or
subsiding adiponectin, lead to systemic inflammation which may result in insulin resistance or impaired glucose transport. [Tumor necrosis
factor (TNF-α), nuclear factor kappa B (NF-kβ), C-reactive protein (CRP), Free fatty acid (FFA)].
Aspartame: with Type II Diabetes Current Diabetes Reviews, 2017, Vol. 13, No. 0 9
[125] contributes to both the onset and the progression of
diabetes as well as its late complications [126]. Oxidative
stress increases with fat accumulation [127]. Oxidative
stress may also lead to insulin resistance by stimulating the
expression of several pro-inflammatory cytokines [128].
The particular link between oxidative stress and impaired
insulin signaling is not completely understood, but several
mechanisms have been proposed. ROS/RNS may impair
insulin signalling [129-131] by (a) inducing IRS ser-
ine/threonine phosphorylation, (b) upsetting cellular redis-
tribution of insulin signaling components, (c) declining
GLUT4 gene transcription or (d) altering mitochondrial
ROS can trigger signal transduction pathways, primarily
through nuclear factor κB (NFκB), promoting the produc-
tion of tumor necrosis factor α (TNFα) [132] and increasing
the production of pro-inflammatory cytokines, IL-6 [133]
and C-reactive protein [128]. Inflammation is recognized as
a manifestation of oxidative stress and is important in the
development and progression of diabetic complications
[134, 135]. Increased oxidative stress may cause insulin
resistance by inhibiting insulin signals and deregulating
adiponectin [127, 136] and other adipocyte-derived factors
such as TNF-α [137], leptin [138] and free fatty acids
(FFAs) [139](Fig. 5). Hence, systemic oxidative stress in-
duced by aspartame usage may exacerbate insulin resis-
tance and impaired glucose tolerance and may increase
complications in T2D (Fig. 5).
In summary, aspartame usage by T2D may lead to insulin
deficiency or resistance by (a) alteration of food habit may
lead to weight gain, (b) acting as chemical stressor by in-
creasing plasma cortisol level,(c) inducing excess free radi-
cal production, result in systemic oxidative stress, (d) altera-
tion of gut microbes, (e) disrupt neurotransmitter or NMDA
receptor [N methyl D-aspartate (NMDA)], finally, result in
impaired glucose tolerance and may increase complications
in diabetic patients; see (Fig. 6).
The benefit of aspartame usage as part of regarding
weight management and blood glucose regulation in T2D
has not been confirmed. To the contrary, many studies link
adverse outcomes to aspartame consumption and various
systems that are important to diabetic individuals. There
are limitations to this review. In particular, data from hu-
man studies are limited especially the lack of good quality
study design and small sample sizes. In addition, self-
reported consumption has not been validated as an accurate
measure of aspartame consumption. Unfortunately, results
from animal data may not be directly transferable or appli-
cable to human.
We conclude that aspartame use in T2D, may lead to
weight gain, rather than weight loss. Aspartame consumption
may furthermore act as a chemical stressor, increasing corti-
sol levels, which interferes with insulin pathways. Moreover,
aspartame consumption may induce systemic oxidative stress
by producing excess free radicals, leading to inflammation
that may exacerbate T2D complications.
More research is required that provides evidence and
raise concerns that use of aspartame in T2D is a challenge,
and we suggest that aspartame consumption regulations
should be revisited and international guidelines reviewed to
add further to the already challenged health burden of T2D.
Fig. (6). Aspartame usage to insulin resistance. Aspartame u sage by type-II diabetic individuals may lead to insulin deficiency or resistance
by (a)alteration of food habit (or weight gain), (b) increase cortisol, (c) systemic oxidative stress, (d)alteration of gut microbes, (e) disrupt
neurotransmitter or NMDA receptor [N-methyl D-aspartate (NMDA)], and finally result in impaired glucose tolerance.
10 Current Diabetes Reviews, 2017, Vol. 13, No. 0 Arbind Kumar Choudhary
I would like to thank the funder, the UP (University of
Pretoria) Funding Post-Doctoral Fellowship.
Not applicable.
The authors confirm that this article content has no con-
flict of interest.
Declared none.
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DISCLAIMER: The above article has been published in Epub (ahead of print) on the basis of the materials provided by the
author. The Editorial Department reserves the right to make minor modifications for further improvement of the manuscript.
PMID: 28571543
... Aspartame consists of aspartic acid and phenylalanine amino acids, and its ingestion stimulates the secretion of insulin [16]. Thus, the intake of aspartame also can interfere with the aspartate receptor resulting in insulin resistance or deficiency [17]. One study found that the patients who consumed artificial sweetener had higher insulin resistance when compared to patients who had no artificial sweeteners [10], which contradict the present study's results that said no significant difference between healthy and diseased patients at all time points. ...
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Background Human beings have an attraction to sweet items: desserts, fruits, honey, etc., which stimulate the sense of taste. However, sweet things tend to have many calories, thus contributing to issues with obesity. Moreover, those with diabetes must strictly limit their consumption of sugar to maintain their blood glucose levels within acceptable limits. Artificial sweeteners contain substances from several distinct chemical classes. The effects of artificial sweeteners on clinically relevant outcomes such as insulin, blood glucose, and lipids have been incompletely studied. Objective This study aims to assess the effects of artificial sweeteners on blood glucose, triglycerides, and insulin in healthy, non-diabetic, and diabetic type 2 patients. Material and method Levels of glucose, triglycerides, and insulin in serum samples from 25 patients with confirmed Diabetic type 2 disease and 30 normal controls were determined at 30, and 60 after the ingestion of the drinks. Results Levels of glucose, triglycerides, and insulin were notably higher in patients with diabetic Mellitus compared with the normal group. Both triglycerides and insulin (60 min) were elevated significantly above baseline after the intake of the artificial sweeteners in diabetic patients; however, values for all other conditions across time were very stable. Conclusion There is no reason to suppose that a higher consumption would result in an elevation in these measures. Any noted insulin resistance linked to a high intake of artificial sweeteners is likely a function of the excess calories and processed ingredients often included within artificially sweetened food and beverage products.
... In addition, aspartame is not recommended for phenylketonuria patients due to its phenylalanine content [117]. However, several studies have shown that aspartame has no negative effects on blood pressure and is a suitable replacement for type 2 diabetes [118]. A similar controversial situation is available for sucralose, saccharin, and acesulfame-K. ...
The use of natural ingredients in food formulation has been facing an increasing demand worldwide. Aiming to preserve the consumer’s health and provide better guidance to the food industry, regulatory agencies must propose precise definitions and establish safe limits of use for additives of natural origin. In this book chapter, we discuss the lack of specific regulations for natural additives and list the substances currently approved by two important regulatory agencies in the globe: the European Food Safety Authority (EFSA) and the Food and Drug Administration (FDA) from the United States. Other regulatory documents from Asia, Australia, and South America are briefly mentioned. Clearly, there is a need for an international regulatory consensus to minimize ambiguity around the term ‘natural’ with a better understanding of what the term “natural” meant and how it can be applied to food labelling and international trade.
... The non-nutritive sweeteners (such as aspartame) which have zero-to-negligible caloric load have been suggested for clinical use in the obese and diabetic individuals to aid in controlling their carbohydrate intake and blood glucose levels. However, a number of clinical studies have led to the suggestion that the intake of the non-nutritive sweeteners, aspartame in particular, may actually cause impaired blood glucose tolerance in DM patients, often accompanied by increased risk of weight gain rather than weight loss [457,458]. This intriguing clinical finding is actually not surprising in the light of the proposed MFF hypothesis. ...
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Hyperglycemia in diabetic patients is associated with abnormally-elevated cellular glucose levels. It is hypothesized that increased cellular glucose will lead to increased formation of endogenous methanol and/or formaldehyde, both of which are then metabolically converted to formic acid. These one-carbon metabolites are known to be present naturally in humans, and their levels are increased under diabetic conditions. Mechanistically, while formaldehyde is a cross-linking agent capable of causing extensive cytotoxicity, formic acid is an inhibitor of mitochondrial cytochrome oxidase, capable of inducing histotoxic hypoxia, ATP deficiency and cytotoxicity. Chronic increase in the production and accumulation of these toxic one-carbon metabolites in diabetic patients can drive the pathogenesis of ocular as well as other diabetic complications. This hypothesis is supported by a large body of experimental and clinical observations scattered in the literature. For instance, methanol is known to have organ- and species-selective toxicities, including the characteristic ocular lesions commonly seen in humans and non-human primates, but not in rodents. Similarly, some of the diabetic complications (such as ocular lesions) also have a characteristic species-selective pattern, closely resembling methanol intoxication. Moreover, while alcohol consumption or combined use of folic acid plus vitamin B is beneficial for mitigating acute methanol toxicity in humans, their use also improves the outcomes of diabetic complications. In addition, there is also a large body of evidence from biochemical and cellular studies. Together, there is considerable experimental support for the proposed hypothesis that increased metabolic formation of toxic one-carbon metabolites in diabetic patients contributes importantly to the development of various clinical complications.
... For example, there is a concern about aspartame's carcinogenic potential, despite no evidence to conclusively prove it (Mallikarjun & Sieburth, 2015). There are also concerns that artificial sweeteners could affect glucose metabolism, body weight, diabetes, (Pepino et al., 2013;Choudhary, 2018) and gut microflora (Abou-Donia et al., 2008;Pang, Goossens & Blaak, 2020), etc. Recent epidemiological studies have shown an association between consumption of artificial sweeteners and adverse cardiovascular events-in particular ischemic stroke, coronary heart disease, and all-cause mortality (Malik et al., 2019;Mossavar-Rahmani et al., 2019;Chazelas et al., 2020). ...
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Background Recent epidemiological cohort studies have suggested that consumption of artificial sweeteners (AS) is associated with adverse cardiovascular events and mortality. However, these population association studies cannot establish a causal relationship. In this study we investigated the effect of long-term (1-year) consumption of AS (Equal and Splenda, two commonly used AS) on cardiovascular health and survival in rats. Methods Adult Sprague-Dawley rats (both sexes, 4–5 months old) were randomized into the following 3 groups: control ( n = 21), AS Equal ( n = 21) and Splenda ( n = 18). In the AS groups, Equal or Splenda was added to the drinking water (2-packets/250 ml), while drinking water alone was used in the control rats. The treatment was administered for 12 months. Cardiovascular function and survival were monitored in all animals. Results It was found that rats in the AS groups consistently consumed more sweetened water than those in the control group. AS did not affect body weight, non-fasting blood cholesterol, triglycerides, blood pressure or pulse wave velocity. There were no significant differences in left ventricular wall thicknesses, chamber dimension, cardiac function or survival. AS did not affect heart rate or atrial effective refractory period. However, rats in both Equal and Splenda groups had prolonged PR intervals (63 ± 5ms in Equal, 68 ± 6 ms in Splenda, vs 56 ± 8 ms in control, p < 0.05) and a tendency of increased atrial fibrillation inducibility. Conclusion Long-term consumption of AS does not affect cardiovascular structure, function or survival but may cause some electrophysiological abnormalities with prolonged PR intervals and a tendency of increased atrial fibrillation inducibility in rats.
... animal-derived clothing and plastic bottles) (Katsanis, 1994;Wilson & West, 1995). In previous studies, some authors have claimed uncommon products as controversial, such as pawnbroking, that is the act of offering a loan secured by the pledge of an item of value (Edwards & Lomax, 2017), aspartame (Choudhary, 2018), palm oil (Sodano, Riverso, & Scafuto, 2018), e-cigarettes (Maclean, Oney, Marti, & Sindelar, 2018), recycled water (Tsagarakis, Menegaki, Siarapi, & Zacharopoulou, 2013), and American alligator leather accessories (Xu, Summers, & Belleau, 2004). ...
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Purpose: investigate the offensiveness of controversial products in Brazil, especially the influence of the field of study. Design/methodology/approach: a questionnaire with 11 controversial products was conventionally answered by a sample of 368 college students from the three most popular fields of study in Brazil (i.e. Human Sciences, Biological and Health Sciences, and Exact and Technological Sciences). The offensiveness of each controversial product was measured and compared across those fields of study through t-tests. Findings: Controversial products did not easily offend respondents being guns, weight-loss medicine, and female underwear the most offensive ones. In general, students of Human Sciences are the most easily offended and those of Exact and Technological Sciences the least offended. In addition, results showed differences and similarities between people from each field of study. Originality/value: Improvement of our knowledge about controversial products in Brazil, especially about the influence of the field of study in the offensiveness of controversial products.
Frontiers in Clinical Drug Research-Diabetes and Obesity is a book series that brings updated reviews to readers interested in advances in the development of pharmaceutical agents for the treatment of two metabolic diseases - diabetes and obesity. The scope of the series covers a range of topics including the medicinal chemistry, pharmacology, molecular biology and biochemistry of natural and synthetic drugs affecting endocrine and metabolic processes linked with diabetes and obesity. Reviews in this series also include research on specific receptor targets and pre-clinical / clinical findings on novel pharmaceutical agents. Frontiers in Clinical Drug Research - Diabetes and Obesity is a valuable resource for pharmaceutical scientists and postgraduate students seeking updated and critically important information for developing clinical trials and devising research plans in the field of diabetes and obesity research. The seventh volume of this series features 6 reviews on diabetes related topics for both medical specialists and pharmacologists. Clinical and diagnostic implications of glycated albumin in diabetes mellitus Development of novel therapeutic groups and bioactive compounds from herbs for diabetes management Aspartame as a sugar substitute Mental health, adherence, and self-management among children with diabetes Cardioprotective effects of new generation anti-diabetic and lipid-lowering agents Epidemiology, pathophysiology, and treatment of diabesity
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Functional foods have been developed as a response to the demands from modern society for a heathy life style. In this way, synthetic colorants have been replaced by natural counterparts. The potential use of several natural pigments such as anthocyanins, betalains, carotenoids, annatto, β-carotene, lycopene, lutein, paprika, carminic acid, chlorophylls, and curcumin as food colorants have been explored in recent years. These pigments can be used to impart different colors in foods such as red, pink, orange, blue, green, and yellow, among others. Most of these natural colorants can be isolated from vegetal sources, with exception of lutein which can be also isolated from animal sources. However, natural pigments are sensitive to heat, oxygen, and light, as well as to modifications of pH, limiting their use as food colorants. This chapter reviews the state of the art with regard to the sources and properties of natural colorants, as well as their food applications.
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Objective: We aimed to investigate the associations between maternal serum aspartame/sucralose levels and metabolic health during pregnancy. Methods: A nested population-based case-control study was conducted in 109 women with and without gestational diabetes mellitus (GDM). Serum aspartame and sucralose levels were assessed using an ultraperformance liquid chromatography coupled to a tandem mass spectrometry system. Results: We detected the presence of circulating aspartame and sucralose in all participants at fasting. No differences in serum aspartame or sucralose levels were observed between GDM and non-GDM groups. In the fully-adjusted linear regression models, serum aspartame levels were positively associated with insulin resistance index, total cholesterol, and LDL cholesterol. In the fully-adjusted logistic regression models, higher serum aspartame levels were positively associated with elevated HbA1c, insulin resistance, hypercholesterolemia, and hyper-LDL cholesterolemia. In the GDM group, the significant associations between higher serum aspartame levels and elevated HbA1c, insulin resistance, and hypo-HDL cholesterolemia persisted, while positive associations were found between higher serum aspartame levels and insulin resistance and hyper-LDL cholesterolemia in the non-GDM group. Serum sucralose levels were negatively associated with HbA1c. Conclusions: The study found that maternal serum aspartame levels were positively associated with insulin resistance index, total cholesterol, and LDL cholesterol during pregnancy. This finding provides the different effects of specific NNS on metabolic health during pregnancy.
The prevalence of obesity has risen dramatically over recent years, and so has the prevalence of adverse obesity-associated pregnancy outcomes. To combat obesity, the calorie contents of many foods and beverages may be reduced by the use of artificial sweeteners, such as aspartame. However, animal studies suggest that aspartame and its metabolites may exhibit toxicity, and the effects of aspartame on pregnancy are largely unknown. In this study, we treated pregnant mice with aspartame by oral gavage and found that the treatment decreased fasting blood glucose level, whereas systolic blood pressure was elevated. Importantly, the aspartame-treated animals also had low placenta and fetus weights, as well as reduced thickness of the placenta decidua layer. Moreover, aspartame decreased the expression of epithelial-mesenchymal transition proteins and manganese superoxide dismutase (MnSOD) in mouse placentae. In order to clarify the mechanisms though which aspartame affects placenta, we performed experiments on 3A-sub-E trophoblasts. In the cells, aspartame treatments induced cell cycle arrest and reduced the proliferation rate, epithelial-mesenchymal transition, migration activity and invasion activity. We also found that aspartame increased reactive oxygen species (ROS) levels to hyper-activate Akt and downregulate MnSOD expression. Pretreatment with antioxidants or sweet taste receptor inhibitors reversed the effects of aspartame on trophoblast function. We also found that the aspartame metabolite phenylalanine similarly induced ROS production and affected proliferation of trophoblasts. Taken together, our data suggest that aspartame consumption during pregnancy may impact the structure, growth and function of the placenta via sweet taste receptor-mediated stimulation of oxidative stress.
The main goal of this study was to investigate the molecular changes in pancreatic progenitor cells subject to high glucose, aspartame, and metformin in vitro. This scope of work glucose, aspartame, and metformin were exposed to pancreatic islet derived progenitor cells (PID-PCs) for 10 days. GLUT1’s role in beta-cell differentiation was examined by using GLUT1 inhibitor WZB117. Insulin+ cell ratio was measured by flow cytometry; the expression of beta-cell differentiation related genes was shown by RT-PCR; mitochondrial mass, mitochondrial ROS level, cytoplasmic Ca2+, glucose uptake, and metabolite analysis were made fluorometrically and spectrophotometrically; and proteins involved in related molecular pathways were determined by western blotting. Findings showed that glucose or aspartame exposed cells had similar metabolic and gene expression profile to control PID-PCs. Furthermore, relatively few insulin+ cells in aspartame treated cells were determined. Aspartame signal is transmitted through PLCβ2, CAMKK2 and LKB1 in PID-PCs. The most obvious finding of this study is that metformin significantly increased beta-cell differentiation. The mechanism involves suppression of the sweet taste signal’s molecules T1R3, PLCβ2, cytoplasmic Ca+2, and AKT in addition to the direct effect of metformin on mitochondria and AMPK, and the energy metabolism of PID-PCs is remodelled in the direction of oxidative phosphorylation. These findings are very important in terms of determining that metformin stimulates the mitochondrial remodeling and the differentiation of PID-PCs to beta-cells and thus it may contribute to the compensation step, which is the first stage of diabetes development.
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Aspartame is a synthetic dipeptide artificial sweetener, frequently used in foods, medications, and beverages, notably carbonated and powdered soft drinks. Since 1981, when aspartame was first approved by the US Food and Drug Administration, researchers have debated both its recommended safe dosage (40 mg/kg/d) and its general safety to organ systems. This review examines papers published between 2000 and 2016 on both the safe dosage and higher-than-recommended dosages and presents a concise synthesis of current trends. Data on the safe aspartame dosage are controversial, and the literature suggests there are potential side effects associated with aspartame consumption. Since aspartame consumption is on the rise, the safety of this sweetener should be revisited. Most of the literature available on the safety of aspartame is included in this review. Safety studies are based primarily on animal models, as data from human studies are limited. The existing animal studies and the limited human studies suggest that aspar-tame and its metabolites, whether consumed in quantities significantly higher than the recommended safe dosage or within recommended safe levels, may disrupt the oxidant/antioxidant balance, induce oxidative stress, and damage cell membrane integrity, potentially affecting a variety of cells and tissues and causing a deregulation of cellular function, ultimately leading to systemic inflammation.
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Purpose The current review aimed to summarize the available literatures, specifically in the following areas: (1) metabolic and other side effects of aspartame (2) microbiota changes/dysbiosis and its effect on the gut-brain axis (3) changes on gut microbiota as a result of aspartame usage (4) metabolic effects (weight gain and glucose intolerance) of aspartame due to gut dysbiosis (5) postulated effects of dysregulated microbiota-gut-brain axis on other aspartame side-effects (neurophysiological symptoms and immune dysfunction). Design/methodology/approach Aspartame is rapidly becoming a public health concern because of its purported side-effects especially neurophysiological symptom and immune dysregulation. It is also paradoxical that metabolic consequences including weight gain and impaired blood glucose levels have been observed in consumers. Exact mechanisms of above side-effects are unclear and data are scarce but aspartame and its metabolites may have caused disturbance in the microbiota-gut-brain axis. Findings Additional studies investigating the impact of aspartame on gut microbiota and metabolic health are needed. Originality/value Exact mechanism by which, aspartame induced gut dysbiosis and metabolic dysfunction, requires further investigation.
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Aspartame is most commonly found in low calorie beverages, desserts and table top sweeteners added to tea or coffee. It is widely consumed by humans who are diabetic and who are under weight loss regime. Aspartame is rapidly and completely metabolized in humans and experimental animals to aspartic acid (40%), phenylalanine (50%) and methanol (10%). Methanol, a toxic metabolite is primarily metabolized by oxidation to formaldehyde and then to formate these processes are accompanied by the formation of superoxide anion and hydrogen peroxide. This study focus is to understand whether the oral administration of aspartame (40 mg/ for 15 days, 30 days, and 90 days have any effect on membrane bound ATPase's and oxidant-antioxidant imbalance, neutrophils function and humoral immunity. To mimic human methanol metabolism, folate deficient animals were used. After 15 days of aspartame administration, animals shows a significant change in membrane bound ATPase's and showed a significant increase in lipid peroxidation and nitric oxide level along with the increase in free radical production as indicated by the increase in both enzymatic (superoxide dismutase, catalase, glutathione peroxidase) and non-enzymatic (reduced glutathione and vitamin C) antioxidant level. However, after repeated long term administration (30 days and 90 days) the generation of reactive free radicals overwhelmed the antioxidant defense as indicated by an increase in lipid peroxidation with the decrease in antioxidants level. This study concludes that administration of aspartame (40 mg/ causes oxidative stress by altering the oxidant/antioxidant balance in blood cells, which also alter the neutrophil function and humoral immunity of aspartame treated wistar albino rats.
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Aspartame is a non-nutritive sweetener that is used predominantly in various ‘diet’ and ‘low-calorie’ products, such as beverages, instant breakfasts, desserts, breath mints, sugar-free chewing gum, vitamins, and pharmaceuticals, consumed by millions of people who are attempting weight loss, young adults and diabetic persons. On a weight basis, the metabolism of aspartame generates approximately 50% phenylalanine, 40% aspartic acid and 10% methanol. The detailed mechanisms of the effects of aspartame on the electrophysiological response are still unclear; therefore, this study was designed to clarify whether longer-term aspartame consumption has any effect on the electrophysiological response in Wistar albino rats. The oral administration of aspartame in a safe dose of 40mg/kg bodyweight/day (as recommended by EFSA, 2012) was tested in Wistar Albino rats for a longer period (90 days). Electrophysiological responses, including heart rate variability (HRV) and electroencephalogram (EEG) pattern, were assessed in a folate-deficient animal model along with control animals using BIOPAC and EEG equipment (model RMS EEG–24 brain new- plus: RMS- Recorder and Medicare systems). In this study, the folate-deficient animal model was used to mimic human methanol metabolism in rats. After 90 days of aspartame treatment, a significant alteration was observable in the time domain [Mean RR (ms) SDNN (ms) RMSSD (ms) PNN50 (%)] and the frequency domain [LF, HF, and LF/HF ratio] with significantly impaired frequency and amplitude of the fronto-parietal and occipital EEG waves at p ≤ 0.05. The results of this study clearly indicate that the oral consumption of aspartame reduced HRV, with sympathetic dominance and loss of vagal tone, and altered sympathovagal activity along with impairment of learning and memory, showing an additional effect on health within this study duration. The aspartame metabolites methanol and formaldehyde may be the causative factors behind the change observed.
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Though several studies on toxic effect of aspartame metabolite have been studied, there are scanty data on whether aspartame exposure administration could release formate, a methanol metabolite thereby inducing oxidative stress and neurodegeneration in brain discrete region. To mimic the human methanol metabolism, the methotrexate (MTX) treated folate deficient rats were used. Aspartame was administered orally to the MTX treated animals and was studied along with controls and MTX treated controls. Oral intubations of FDA approved 40 mg/kg b.wt aspartame were given daily for 90 days. The locoemotor activity and emotionality behavior in the aspartame treated animals showed a marked increase in the immobilization, fecal bolus with a marked decrease in ambulation, rearing, grooming. The anxiety behavior in the aspartame treated animals showed a marked decrease in percentage of open arm entry, percentage of time spent in open arm and number of head dips. It is appropriate to point out, formal-dehyde and formate could have led to an increased formation of free radical in the aspartame treated animals resulting in altered neurobehavioral changes owing to neuronal oxidative damage. Aspartame induced ROS may be also linked to increased neuronal apoptosis. In this study the aspartame treated animals showed an up regulation in the apoptotic gene expression along with protein expression in the respective brain region indicating the enhancement of neuronal cell death. This study intends to corroborate that chronic aspartame consumption can alter the behavior and neurodegeneration in brain discrete regions.
Aspartame (α-aspartyl-l-phenylalanine-o-methyl ester), an artificial sweetener, has been linked to behavioral and cognitive problems. Possible neurophysiological symptoms include learning problems, headache, seizure, migraines, irritable moods, anxiety, depression, and insomnia. The consumption of aspartame, unlike dietary protein, can elevate the levels of phenylalanine and aspartic acid in the brain. These compounds can inhibit the synthesis and release of neurotransmitters, dopamine, norepinephrine, and serotonin, which are known regulators of neurophysiological activity. Aspartame acts as a chemical stressor by elevating plasma cortisol levels and causing the production of excess free radicals. High cortisol levels and excess free radicals may increase the brains vulnerability to oxidative stress which may have adverse effects on neurobehavioral health. We reviewed studies linking neurophysiological symptoms to aspartame usage and conclude that aspartame may be responsible for adverse neurobehavioral health outcomes. Aspartame consumption needs to be approached with caution due to the possible effects on neurobehavioral health. Whether aspartame and its metabolites are safe for general consumption is still debatable due to a lack of consistent data. More research evaluating the neurobehavioral effects of aspartame are required.
Aspartame (non-nutritive sweetener) is consumed by millions of people in products like beverages, instant breakfasts, desserts, breathe mints, sugar free chewing gum, vitamins, and pharmaceutical. On a weight basis, metabolism of aspartame generates approximately 50% phenylalanine, 40% aspartic acid and 10% methanol. The detailed mechanisms of their effects on cardiac tissue are still unclear. The present study aimed to clarify whether longer time aspartame consumption has any effect on heart of Wistar albino rats. Animals were randomly divided into 4 groups of 6 animals (group-1: control, group-2: folate deficient diet fed animals, group-3: control animals treated with aspartame, group-4: folate deficient diet fed animals treated with aspartame). Aspartame was given orally (40 mg/kg·bw/day), dissolved in normal saline and for 90 days. Since human beings have very low hepatic folate content, the folate deficient diet fed animals were used to mimic the human methanol metabolism. Aspartame consumption increased significantly plasma corticosterone level, suggesting that aspartame may act as a chemical stressor. There was a significant increase in lipid peroxidation, nitric oxide and protein carbonyl, and significant decrease in protein thiol, cardiac membrane bound ATPases (Na+, K+, Ca++, Mg++), enzymatic (SOD, CAT, GPX, G6PD, GR) and non-enzymatic antioxidants (GSH, Vit-C, Vit-E) as well as a significant increase in heart rate and heart marker enzymes (CK and CK-MB). It may be due to excessive generation of free radicals, which impairs cardiac function. Aspartame metabolite methanol or formaldehyde may be the causative factors behind these changes. However, up regulation of Hsp70 in immunohistochemical analysis of cardiac tissue might be a protective response to oxidative stress induced by aspartame metabolites and structural damages in cardiac tissue.