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

Abstract

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.

Full text

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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
A R T I C L E H I S T O R Y
Received: April 06, 2017
Revised: May 25, 2017
Accepted: May 29, 2017
DOI:
10.2174/1573399813666170601093336
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..
1. INTRODUCTION
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/kg.bw/day [8].The U.S. Food and Drug Admini-
stration (FDA) established an ADI of 50 mg/kg.bw/day [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;
E-mail: arbindchoudhary111@gmail.com
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
usage.
2. ASPARTAME AND BLOOD GLUCOSE LEVELS
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
[27].
(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/kg.bw), 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)
Receptor
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/kg.bw/day) 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.
Species
Study design
Observation
Refer-
ences
Mice
Aspartame (4g/kg.bw) dissolved in water and given to
C57Bl/6 mice!
At week 11, induced dysbiosis and glucose intolerance!
[19]!
Rat
Aspartame (5–7 mg/kg/d in drinking water) for 8 week.
Aspartame elevated fasting glucose levels
[18]
Human
Aspartame (290 kcal), preload 20 min before the lunch and
dinner meal in healthy and obese individuals.!
Postprandial glucose and insulin levels at 20 min after consump-
tion were significantly lower compared to the sucrose condition!
[11]!
Mice
Aspartame alone (50 mg/Kgbw/day) and as well as with
combination of Monosodium Gluta-
mate (120 mg/Kgbw/day) were given to C57BL/6 J mice.
Significant increase in fasting blood glucose together with re-
duced insulin sensitivity during an Insulin Tolerance Test (ITT)
[30]
zebra fish
Aspartame (3 mM) were fed in the diet of hyperlipidemia,
zebra fish nutritional model
Remarkable increase in serum glucose level after 12 days
[32]
Human
Aspartame-sweetened beverage (8 oz) was randomly as-
signed to drink in Sixty-four fasted participants.!
No significant differences were observed in blood glucose level at
5, 10, and 15 min post-consumption.!
[29]!
Human
Ten healthy volunteers consumed one of three isovolumet-
ric drinks (aspartame, 1 MJ simple carbohydrate, and 1 MJ
high-fat; randomized order)
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
[28]

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/kg.bw/day), 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/kg.bw/day) 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.
Species
Observation
References
Human
Higher BMI was observed with consumption of diet carbonated beverages.
[53]
Human
Increased diet soda consumption was associated with higher BMI in school children.
[52]
Zebra fish
Aspartame may promote weight gain and hyperglycemia in a zebra fish nutritional model
[32]
Mice
A positive association between aspartame intake and body weight in C57BL/6 J mice.
[29]
Rat
Aspartame can cause greater weight gain than sugar, even when the total caloric intake remains similar.
[13]

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,
75].
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
A)
B)
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
resistance.
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
action.
3. NEUROTRANSMITTER ALTERATIONS WITHIN
BRAIN TO INSULIN RESISTANCE
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].
4. OXIDATIVE STRESS TO INSULIN RESISTANCE
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
activity.
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).
LIMITATION AND CONCLUSION
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
FUNDING
I would like to thank the funder, the UP (University of
Pretoria) Funding Post-Doctoral Fellowship.
CONSENT FOR PUBLICATION
Not applicable.
CONFLICT OF INTEREST
The authors confirm that this article content has no con-
flict of interest.
ACKNOWLEDGEMENTS
Declared none.
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PMID: 28571543