Artificial Sweeteners Alter Signaling In The Brain and Pancreas

“Safe” Sugars Act As Endocrine Disruptors



Not all artificial sweeteners aka (nonnutritive sweeteners (NNSs) or low-calorie sweeteners (LCS)) are bad. 

Use of artificially sweetened foods (ASFs) has increased in the past 50 years in the USA and there are clear parallels with changes in the prevalence of obesity and NNSs usage. R

Some NNSs have been deemed safe by government organizations like the FDA.

Just because something is deemed as “safe” by the FDA, does not make it safe for humans.

In this post, I will break down the effects of artificial sweeteners on the body (easy reading is in bold) and give an alternative list to which ones are “safer” or even beneficial. 


  1. Basics
  2. List Of Artificial Sweeteners
  3. How Artificial Sweeteners Affects The Body
  4. Caveats
  5. Natural Alternatives
  6. Genetics
  7. Mechanism Of Action
  8. More Research


Not all NNSs are created equal.

They have been around for centuries, starting with the Stevia plant family. R

Then commercial production of chemically synthesized NNSs began with saccharine in 1879 (discovered by Constantine Fahlberg at Johns Hopkins). R R

They were originally made by pharmaceutical companies to make drugs taste better and later as a sugar substitute for diabetic patients. R

And since, there has been a rise in obesity and sugar has been deemed as “bad” by mainstream healthcare, calling on professionals to encourage sugar replacements as a feasible replacement. R R R R R

This has led to a high variety of “light” products across the globe including water- and fat-based desserts, certain alcoholic beverages, sandwich spreads, cereals, marinades, chewing gums, drugs, etc. R R R R

All ages from various populations are now consuming NNSs (even preschoolers). R R R R R

They are quite revolutionary as most NNSs have no or are in low calories, but the problem with them lies in the fact that they change our perception of taste and cause a negative feedback for our brain to crave more food (more discussed below). R

Not only this, but NNSs may cause changes to hormone regulation, alterations in gut biome, DNA and methylation problems, and obesity.

List Of Artificial Sweeteners

A simple list of artificial sweeteners: R

  • Acesulfame K (Ace-K, Sunette, Equal Spoonful, Sweet One, Sweet ‘n Safe)
  • Advantame
  • Alitame
  • Aspartame (Equal, NutraSweet, NatraTaste Blue)
  • Cyclamate
  • Dulcin
  • Glucin
  • Glycerol
  • Hydrogenated Starch Hydrolysate (HSH)
  • Lactitol
  • Lactisole
  • Lead Acetate
  • Maltitol
  • Mannitol
  • Monellin
  • Neohesperidin Dihydrochalcone (NHDC) 
  • Neotame
  • P-4000
  • Polydextrose
  • Rebaudioside
  • Saccharin (Sweet ‘N Low, Sweet Twin)
  • Sorbitol
  • Sucralose (Splenda)
  • Tagatose
  • Xylitol

How Artificial Sweeteners Affect The Body

1. Change Your Perception of Taste



NNSs may have an addictive physiological response in our body (similar to Pavlov’s theory on classical conditioning). R R

Sweet tastes evoke many physiological responses that help the body maintain energy homeostasis. R

When the mouth senses sweet tastes, it tells the that there is sugar (energy) about to enter the body, so the body prepares for it. R

Because of this, consuming NNSs may impair energy and body weight regulation by diminishing the ability of sweet taste to evoke these physiological responses. R

So this may make consuming sugar along with NNSs more harmful for the body by blunting they body’s natural response to sugar. R

NNSs can also make sugar taste different or too sweetR

Not only this but consuming NNSs may make you crave sugar and binge eat sugar since NNSs activate the body’s pleasure system. R R

For example, children that were fed a diet high in NNSs craved sugar more than those who don’t consume artificial sweeteners. R

This effect is of course greater when hungry. R

Oxytocin may reverse or inhibit the changes of taste buds by NNSs. R

2. Cause Altered Pancreatic Signaling

NNSs may increase the chance of developing type 2 diabetes and metabolic disorders. R R R

For example, middleaged men and women consuming more than 1 serving of diet soft drinks per day had 30% higher risk of developing metabolic syndrome over 9 years of follow-up. R

One ways this happens is by messing with with glucose/insulin homeostasis. R

For example, saccharin, sucralose and aspartame can all impair glucose tolerance. R R R

NNSs work together with glucose to enhance glucagon-like peptide-1 (GLP-1) release into the body. R

NNSs can cause insulin or incretin (a GLP-1 hormone) release and it’s release is even greater when added with other sugars. R

For example, those drinking Splenda (sucralose) with sugar had a 20% higher increase in insulin after consumption than those who had sugar alone. R

Also, in another study, obese women that ate sucralose had higher glucose and insulin levels post consumption. R

High doses of NNSs given to patients can induce insulin resistance within 7 days. R

Low doses of NNSs can induce insulin resistance in 2 months. R

These effects of NNSs also disrupt the brain-gut axis. R

Saccharin may increase hemoglobin A1c (HBA1C). R

In clinical trails and meta-analyses, it appears NNSs have very little effect on hepatic steatosis and non-alcoholic fatty liver disease (NAFLD). R R

Although they may not cause NAFLD or scarring, they may deplete the liver of antioxidants like gluathione causing liver damage. R

Some NNSs may protect against liver injury. R

For example, in mice neohesperidin dihydrochalcone (NHDC) can lower damage to the liver by reducing oxidative stress, inflammation, and cell death when exposed to the the liver-toxic chemical paraquat (PQ). R

Stevia may also be able to reduce inflammation and oxidation in the liver and kidneys as well. R

3. Affect Brain Homeostasis and The Nervous System

Binge eating NNSs decreases alertness and cognition. R

Aspartame can also create metabolites (phenylalanine and aspartic acid) which may decrease or inhibit the synthesis and release of neurotransmitters like dopamine, norepinephrine and serotonin in the brain (probably won’t have an effect at normal consumption dosages). R

Aspartame may also induce oxidative stress and damage in the brain as well as increase cortisol levels. R

Aspartame may also destroy the myelin sheath of neurons. R

NNSs may also affect glucose homeostasis in the brain, which is a known factor of Alzheimer’s Disease. R

As discussed earlier, NNSs work synergistically with sugars. R

For example, NNSs + Koolaid can increase motivation in patients with eating disorders. R

NNSs can also induce headaches and migraines. R R

Sucralose increases the perception of bladder fullness and may act as a diuretic. R

Acesulfame potassium, cyclamate and saccharin ingestion may reduce seizures in epilepsy. R R

NNSs may also contribute to the prevalence of stroke and dementia. R R R

4. Increase Obesity

Use of NNSs may contribute to fat accumulation and obesity. R

NNSs stimulate food intake in humans and animals by reducing the body’s ability to compensate for energy provided by caloric sweeteners in the diet, which may lead to increased feeding and overproduction of fat accumulation hormones. R R

For example, NNSs are used in animal feed in the agriculture industry to make animals fatter. R

Mice that are fed aspartame in utero or Ace-K in vivo have increased weight gain and decreased insulin sensitivity. R R

In humans, saccharin use is associated with weight gain. R

Weight gain by sucralose tends to be more prevalent at very low dosages or very high (chronic consumption) ones. R

Also, pregnant mothers that drank NNSs beverages had a higher rate of having children with obesity and birth-size defects. R R R

Children that are obese do better when eliminating both sugar and NNSs from their diet. R

5. Affect Development



During breastfeeding, some NNSs (like sucralose, aspartame, ace-K, and saccharin) can pass through breast milk, not only affecting the child’s microbiome, but also the development of their brain. R R R

NNSs may also cause the child to be born prematurely and increase the risk of the child developing asthma. R

NNSs also cause developmental problems in aquatic animals (needs more research in relation to humans). R

6. May Increase Chances of Developing Heart Disease

A Northern Manhattan study of 2,500 multiethnic adults with a 10 year follow-up measured diet soda vs normal soda consumption. R

They found that cardiovascular events were higher in those who drank diet sodas, whereas regular soft drink intake was not associated with any cardiovascular events. R

I would not take this as conclusive evidence since another study measuring 43,000 men over the period of 22 years showed a positive association between sugar-sweetened beverage intake and chronic heart disease (CHD) risk, and no association with NNSs. R

7. Alter The Immune System

Saccharin can decrease oral tolerance. R

It may play a role in inducing food allergies. R

Aspartame activates the immune system and increases oxidative stress in rats. R

8. Alter DNA and May Increase Cancer Progression

Aspartame has shown to have carcinogenic properties (inducing lymphomas, leukemias, liver, and lung cancers). R 

Sucralose and saccharin may induce DNA damage in the stomach, colon, and kidneys. R R R R

Also, (shown in a lymphoma assay) sucralose mutated DNA and progressed lymphoma. R

For example, mice that were fed sucralose at birth and chronically throughout their life, developed hematopoietic neoplasias (tumors that affect the blood, bone marrow, lymph, and lymphatic system). R

Sucralose in humans may not cause cancer, but heating or cooking sucralose may. R R

Cooking sucralose at high temperatures can generate chloropropanols (see more in Caveats). R R

Chemicals in the same group of NNSs have shown to make genetic changes that travel over generations. R

Stevia may protect against some cancers by altering the gut biome (more discussed below). R

9. Affect Sleep and Circadian Rhythms

Saccharin may cause sleep such as insomnia and light sleep. R

Mice that were fed saccharin had altered sleep cycles and harder times falling asleep. R

10. Change The Microbiome

Saccharin, sucralose and aspartame may cause dysbiosis. R R

Some NNSs (similar to resistant starches) aren’t digested by the human gut, but instead digested by the gut bacteria. R

Sucralose reduces beneficial bacteria in the gut. R

Sucralose can also increase serotonin and can cause gut contractions. R

Saccharin may increase ammonia in the gut. R

Saccharin may inhibit intestinal protein digestion leading to increased metabolism by bacteria, which may be carcinogenic. R

Both saccharin and sucralose can reduce short chain fatty acid (SCFA) levels of propioate, butyrate, and valerate. R R

Xylitol increases SCFAs such as butyrate in the gut. R

Xylitol and erythritol decrease gut contractions. R

The slowing of gut motility and increase in SCFAs may be the reason why gums and foods containing xylitol can make you gassy or bloated. R

Stevia can decrease and inhibit the growth of lactobacillus reuteri. R

Xylitol may benefit with the oral microbiome by decreasing dental plaque buildup and tooth decay. R

11. Fight Pathogens



Stevia has shown to have anti-microbial effects against Borrelia Burgdorferi (Lyme)R

Saccharin has anti-microbial effects against Streptococcus Mutans. R

Saccharin also inhibits the growth of Proteus VulgarisR

Saccharin has also shown to have anti-microbial properties against E. Coli. R

Aspartame, saccharin, stevioside, and sucralose have anti-fungal properties against Candida Albicans. R

Sucralose can fight oral pathogens such as Aggregatibacter actinomycetemcomitans and Porphyromonas gingivalis. R

Other NNSs may reduce the GI effects of Cryptosporidium parvum infection. R

12. May Affect Sex Organs and Hormoes

In vitro, steviol, a metabolite of stevia, can decrease the activity of the progesterone receptor. R

This may affect progesterone and progestagen levels. R

Additionally, steviol affected progesterone receptors in sperm (CatSper). R

Saccharin may induce oxidative stress on sperm cells. R

13. May Affect Fatigue and Exercise

NNSs alone may decrease exercise output and increase perceived exertion (study was compared to caffeine). R

NNSs when combined with sugar and used as a mouth rinse may improve performance. R


Do not heat artificial sweeteners past 119ºC, as their byproducts (chloropropanols) are toxic (genotoxic, carcinogenic, and tumorigenic). R R R R R R

This holds true to alternative tobacco products like e-cigs. R

Do not take aspartame if you have phenylketonuria (PKU), R

Also, sucralose may interact with drugs that require P-gp and CYP3A for detoxification. R

Saccharin interacts with P450 enzymes and may interact with drugs that use that pathway. R

Taking organic ion transporters (e.g., anti-HIV therapeutics, antitumor drugs, antibiotics, antihypertensives, and anti-inflammatory agents) can interfere with saccharin excretion. R

Natural Alternatives

Here is a list of the amount of sweeteners added to common sodas. -> R

Reducing your intake of both sweeteners and NNSs will probably be the most healthy action to take. R

  • Fruit – Fructose (levulose)
  • Milk – Galactose and Lactose
  • Starchy Veggies – Glucose (dextrose)

NNSs Alternatives and Prebiotics:

Protection When Consuming NNSs:


Bitterness with Ace-K:

  • Regardless of age, more participants with 1 or no copies than with 2 copies of the TAS2R31 WMVI haplotype liked Ace-K (p = 0.01). R
  • Ala187 homozygotes (n = 37) reported less bitterness from Ace-K than heterozygotes (n = 55) (Tukey–Kramer P = 0.011) and the Val187 homozygotes (n = 13). R
  • Val240Ile (rs10772423) was significantly associated with the bitterness of AceK. R
  • Ala227Val (rs10845293) the logged bitterness ratings for the Val227 homozygotes (n = 33), Ala/Val heterozygotes (n = 49), and Ala227 homozygotes (n = 19). R
  • Val187Ala )rs374184) associated with bitterness from Ace-K. R

Mechanism Of Action


  • Artificial sweeteners are perceived to be a lot sweeter by taste receptors, which can increase GLP1 hormones like incretin to be released into the body.
  • The may also change signaling of satiety hormones and when combined with sugars can result in a positive feedback system to eat more sugar. 
  • They also change the gut biome to favor dysbiosis which may lead to lower amounts of SCFAs.
  • Lastly, using NNSs may use up the body’s natural antioxidants and cause for supplementation of methylation enhancers.  


  • Most artificial sweeteners “taste” sweeter than other natural sugars. R
  • For example, sucralose is 385- to 650-fold higher than sucrose, aspartame is 200x sweeter than sucrose, saccharin is 200–700 times sweeter than sucrose, thaumatin is about 2000x higher than sucrose. R R R
  • Natural sugars and NNSs are sensed by receptors in taste buds. R
  • NNSs activate transient receptor potential vanilloid-1 (TRPV1) receptors, and, moreover, they sensitize these channels to acid and heat.R
  • They also activate TIR2 (T2R) bitter and TIR1 (T1R) sweet taste receptors, which are coupled through G-proteins, alpha-gustducin and transducin, to activate phospholipase C beta2 and increase intracellular calcium concentration. R R
  • Sweet-taste receptors (T1R family and α-gustducin) respond not only to caloric sugars such as sucrose but also to artificial sweeteners, including sucralose (Splenda) and acesulfame-K. R
  • These receptors and functions are also found in/influenced by the gut, pancreas, hypothalamus and basolateral nucleus of the amygdala. R R
  • For example, supplementing ruminant diets with artificial sweetener in feed leads to a 7-fold increase in the intestinal protein expression of the sodium-dependent glucose transporter 1 (SGLT1). R
  • This transporter, located on the apical surface of the small intestine, is highly sensitive, is responsible for active glucose transport in enterocytes and is linked to the secretion of the incretin hormones glucagon like peptide (GLP-1, GLP-2) and gastric inhibitory polypeptide (GIP). R R
  • They do this synergistically. R
  • When NNSs increases expression of TIR2 in the hypothalamus (mediated by hepatic ChREBP increasing production of FGF21 from the liver), it may affect appetite regulation by providing an inaccurate signal regarding the actual levels of extracellular glucose in the brain and inaccurately activate ERK1/2-ribosomal proteins in the pancreas. R R R R
  • Because of this, sucralose alone can increase gastric inhibitory polypeptide (GIP), Peptide YY (PYY), and cholecystokinin (CCK). R
  • Sucrose, as well as fructose (may be even stronger) activates dopaminergic midbrain areas related to reward or pleasantness, whereas sucralose alone results in reduced activation in other taste-related pathways and this may affect brain dopaminergic homeostasis. R R
  • Sucralose may increase ghrelin secretion as well as leptin expression in the arcuate nucleus. R R
  • Sucralose elevates cyclic AMP (cAMP), activates phospholipase C (PLC) and stimulates Ca2+ entry by a Na+-dependent mechanism in MIN6 cells (in pancreas). R
  • Sucralose at low dosages increases P-gp (barrier against toxins) and CYP P450 enzymes, but at higher doses P-gp decreases, acting similarly to organochlorine and other pesticides. R R 
  • Sucralose passes through breast milk into the infant’s body, which infants have low amounts of P-gp. R
  • P-gp is also expressed in the brain and may enhance the cross of sucralose (as well as ace-K, asparatme, mannitol, and saccharin) into the blood brain barrier (BBB), which may be excitotoxic for the baby’s brain, including the hypothalamus. R R R
  • GLP1 is an incretin hormone that induces glucose-dependent stimulation of insulin by the pancreas, reduces glucagon secretion by the liver, delays gastric emptying, and increases satiety. R
  • Bing eating glucose + saccharin, decreases orexin and pCREB expression. R
  • Saccharin + glucose will increase dopamine in the brain more than glucose alone, possibly creating a feed-back loop to eat more. R
  • Artificial sweetener use may affect amygdala and insula response to sugar. R 
  • In the gut biome, sucralose reduces anaerobes, bifidobacteria (77.7%), lactobacilli (79%), Bacteroides (77.5%), clostridia, and total aerobic bacteria, as well as increases fecal pH. R
  • Saccharin increases Enterobacteriaceae, Deltaproteobacteria, and Actinobacteria phylum. R
  • SUCRAM (neohesperidin dihydrochalcone (NHDC) and saccharin} may increase Lactobacillus 4228. R
  • Concerning cancer and DNA mutations, sucralose is slowly hydrolyzed to its two constituent OC monosaccharides 4-CG and 1,6-DCF in acidic solutions (e.g., sodas) over time. R
  • 1,6-DCF was found to be weakly mutagenic in both human DNA and bacterial DNA. R R
  • Some NNSs (like sucralose) are organochlorine compounds, which can cause epigenetic changes and alter DNA methylation patterns, which may be transmitted transgenerationally. R R R R R R R
  • Saccharin may act as a CA-IX inhibitor, acting synergistically in the formation of cancer cells. R
  • Aspartame may increase cortisol levels, free radicals, and interfere with NMDA receptor signalling. R R
  • Aspartame (L-Aspartyl-L-phenylalanine methyl ester is also hydrolyzed in the gut to its constituent amino acids, aspartate, and phenylalanine, as well as methanol which are all absorbed into the portal circulation. R R
  • Methanol is then converted to formaldehyde, diketopiperazine (a carcinogen) and subsequently oxidized into formic acid. R R
  • During sleep, saccharin increases non–rapid eye movement sleep during the active phase, increases wakefulness during the sleep phase and decreases free-moving activity during the active phase. R
  • Xylitol and erythritol increase in CCK and GLP-1 and both decrease gastric emptying. R
  • In the liver, NHDC significantly inhibited PQ-induced nuclear factor-kappa B (NF-κB) expression and mitochondrial-driven apoptotic signaling. R
  • Aspartame down-regulates glutamate cysteine ligase and decreased cysteine levels. R
  • Aspartame also blockades the trans-sulphuration pathways. R
  • For example, mice that were chronically given aspartame had increased alanine aminotransferase (ALT) and aspartate aminotransferase, as well as reduced glutathione (GSH), oxidized glutathione (GSSG),  γ-glutamylcysteine (γ-GC), cysteine, S-adenosylmethionine (SAM), and S-adenosylhomocysteine (SAH).
  • Sucralose may affect cellular lipid packing, decreasing microviscosity and increasing membrane fluidity. R
  • In the immune system,  aspartame increases hsp70 expression, alters bcl-2 and bax mRNA transcription and protein expression level. R

More Research

  • Water treatment facilities can effectively remove artificial sweeteners from sewage, but doesn’t appear to work well in Spain. R R R
  • Acesulfame when oxidized may not get treated from the water. R 
  • UV will eventually break down some (not all) artificial sweeteners. R
  • Young children with PKU and CMPA have higher relative average intakes of artificial sweeteners than healthy young children. R
  • Artificial sweeteners affect micro-algae and increase their toxic load of heavy metals. R
  • Diet teas have less of a calming effect than regularly sugared teas. R
  • When alcohol is combined with NNSs, breath alcohol concentrations increase. R