Sweeteners Part I: Sensation & Metabolism

snappa_1467865068We as humans are literally born loving sweet things. Newborn babies are naturally drawn to sweet tastes. This preference appears to be deeply rooted in our evolutionary history. Neonatal apes and monkeys, who are the closest genetic relatives to humans, have been found to exhibit a similar response.

If we take a look at the natural environment in which humans and other great apes evolved, it is not hard to see why. Most wild apes have historically derived a tremendous amount of their calories from fresh fruit, as well as other plants. Taste provides useful information about the nutritional attributes of such foods. For example, apes universally gravitate to ripe fruits – which are loaded with nutrients and sugar – over unripe fruits. Prior to ripening, fruits are often not only less nutritious, but contain compounds like tannins to deter animals from eating them. If you’ve ever bitten into an unripe Hachiya persimmon (something I do not recommend), you are all too familiar with this chemical defense mechanism.

In general, the presence of intense sweetness in the foods that we encounter is suggestive of energy density, and a relative lack of toxic compounds. For instance, mangoes are significantly higher in sugarnoun_260064 (and calories relative to volume) than kale, and are indeed sweeter and more rewarding to most people. In this way, our sweet tooth is quite adaptive, and guides our food choices toward the best immediate payoff (from the perspective of energy efficiency).

Food processing, production, and other aspects of the modern environment have dramatically altered our feeding patterns. But the predisposition toward sweetness persists. Consequently, a state of overnutrition (i.e., too many calories) – due to constant access to super tasty energy-rich foods – is now a bigger problem for much of the world population than is starvation.

This tension between our natural desire for sugary foods and our goals of long-term health has driven demand for low-calorie products, which would ostensibly fulfill our hedonic preferences while avoiding the pitfalls of excessive sugar consumption. One such example is sugar substitutes. These additives have existed for more than a hundred years but have consistently been subject to controversy. Studies and media reports come out every year attributing them to a wide array of health hazards. Yet government organizations have declared them to be safe.

In this article series, we will examine some of the evidence surrounding these sugar substitutes, and try to determine the safest and most effective way to use them.


How we sense sweetness

Our experience of sweetness begins, unsurprisingly, in the tongue.

Humans, like other omnivores, can detect five distinct tastes: bitter, salty, sour, umami (savory) and sweet. Each of these tastes is detected by various classes of taste receptors, which are located on cells in the taste buds. Scientists have identified taste receptors that are specialized to respond to sweet substances.

Artificial sweeteners, such as saccharin and sucralose (Splenda), activate sweet taste receptors, just like sugar. In fact, saccharin and sucralose are 300 and 600 times sweeter than sucrose respectively. But many people also find certain artificial sweeteners to have bitter aftertastes. This is because of subtle differences in the shape and structure of non-nutritive sweeteners, which allow them to bind to both sweet and bitter receptors on the taste buds. These little alterations in chemical structure are part of why so much research has been dedicated to determining what other ways sweeteners may be interacting in the body when they are consumed.

The process of identifying specific receptors that are involved in the sensation of sweet substances has led to the revelation that sweet receptors are not only expressed on the tongue – they are actually found throughout the body. Over the past fifteen years, scientists have discovered that taste receptors are situated in the digestive tract, pancreas, fat tissue, skeletal muscle, and possibly other tissues.


Sweet taste receptors in the gut

Within the gut, sweet taste receptors are found in the enteroendocrine cells. These cells play an important role in sensing the nutrient contents of the digestive tract and secreting hormones that help regulate metabolism and nutrient uptake. Activation of sweet taste receptors in the gut appears to precipitate the release of hormones called incretins. Incretins are metabolic hormones that trigger a rise in the amount of insulin released from pancreatic beta cells, which regulates blood glucose levels.

In the context of a sugary meal, this process makes a lot of sense as a means to anticipate an incoming spike in blood glucose.

But what happens when these receptors are stimulated by sweeteners that do not actually produce a rise in blood glucose? It has been hypothesized that non-nutritive sweeteners may produce an inappropriate rise in insulin, due to the sweeteners conveying a sort of “false alarm” to the pancreatic beta cells about the incoming levels of blood sugar.

It is plausible that this could result in hypoglycemia, and perhaps a cascade of undesirable long-term metabolic effects associated with high insulin levels. One would expect this to be particularly likely in the context of something like a diet soda – in which the subject experiences sweet taste but no concurrent glucose intake.

There have indeed been some interesting findings in rodent models and in human cell lines that are supportive of this hypothesis. However, the data investigating whether artificial sweeteners actually trigger a pathological rise in insulin in vivo (in a living organism, as opposed to isolated cells or tissues) has been inconsistent at best so far, with many studies finding no significant effect in human subjects.


Sweet taste receptors in the pancreas

Interestingly, sweet taste receptors are also found in the pancreas. This makes some sense if you consider one of the major roles of the pancreas, which is to secrete hormones that regulate blood sugar. Beta cells in the pancreas, which release the hormones insulin and amylin to control blood sugar levels, need to be able to detect sugar and anticipate blood sugar rises in order to respond appropriately. This is likely why there are indeed sweet taste receptors located on the beta cells to assist in this role.

In theory, these sweet taste receptors could also be influenced by artificial sweeteners to release insulin. However, as we discussed above with respect to the taste receptors in the gut, the actual impact of non-nutritive sweeteners on insulin response in living organisms remains unclear.

It is important to bear in mind that a lot of studies that appeared to support a metabolic impact of noun_13582artificial sweeteners via taste receptors were done in vitro – with non-caloric sweeteners being applied directly to tissues or cells in a laboratory setting. For this reason, it is questionable to what extent the in vitro findings related to artificial sweeteners can translate to what happens in living tissues, when such additives are ingested orally. Research has suggested that levels of non-nutritive sweeteners in the bloodstream is actually rather low – probably too low to activate insulin secretion as has been suggested. This isn’t terribly surprising. Most artificial sweeteners are not broken down and transported throughout the body in the blood in the same way that dietary sugars are, which really limits the usefulness of many in vitro studies. How these sweeteners are metabolized is important to consider when interpreting studies that have been done on them.


Metabolism of sweeteners

Sugar is the preferred energy source of the body. All cells in the body can convert glucose into ATP, which is used to power many chemical reactions and cellular processes.

In contrast to most naturally occurring sweeteners, most artificial sweeteners cannot be metabolized by the body. Substances like saccharin and sucralose are not usable as an energy source, and instead pass through the body unchanged – thus contributing no calories to the diet. Let’s take a quick look at a few of the most common artificial sweeteners and how they are processed.


Saccharin was first discovered in 1879 by Constantin Fahlberg, a chemist at Johns Hopkins snappa_1467864286University who was working on coal tar derivatives. He noticed the sweet flavor of the residue on his hand, and eventually realized its potential commercial appeal.

Saccharin is chemically stable but tends to have a harsh metallic aftertaste – because it is also able to stimulate bitter taste receptors. Like most sweeteners, saccharin goes through the body largely unmetabolized, and exits through the urine.



Sucralose (also referred to by the commercial name ‘Splenda’) was discovered serendipitously in 1976 by snappa_1467864480Shashikant Phadnis at King’s College in London, while he was researching ways to employ sucrose (table sugar) for industrial use. Phadnis was instructed to test a chlorinated sugar compound. He misunderstood, and thought he was asked to taste it (this is a pretty serious no-no in organic chemistry labs, at least in my experience). Fortunately, he suffered no ill effects, and observed that the compound was extremely sweet. The researchers came to recognize its utility as a non-nutritive sweetening agent.

Sucralose is a chlorinated disaccharide. The substitution of hydroxyl groups on sucrose with chlorine renders the molecule unrecognizable as a sugar to the body, and thus it passes through the body unchanged. Studies have shown that 65-95% of sucralose is excreted in feces, and the remaining portion is thought to be passed through urine.

Due to its chemical structure, it is more stable than some other sweeteners. This permits it to last longer on the shelf and allows it to be used in baking.


Acesulfame potassium (Ace-K) has a chemical structure very similar to saccharin. Like snappa_1467864733saccharin, acesulfame potassium is not broken down in the body and is largely excreted in urine.

Acesulfame potassium is stable under conditions of high heat and for this reason is often used in baked goods. Similarly to saccharin, this sweetener sometimes seems to convey a nasty aftertaste, due to its affinity for the bitter taste receptors, and therefore is often combined with other sweeteners.



Aspartame was discovered by accident (I’m definitely noticing a trend here) by a chemist in Illinois who was trying to develop a drug to treat ulcers. It is unique among artificial sweeteners in that it is composed from molecules found in natural foods and is therefore rapidly metabolized. This is part of why direct injection of aspartame (or direct application to cells in vitro) is not necessarily useful for gauging safety when ingested.


Aspartame is broken down in the small intestine into methanol, and the amino acids phenylalanine and aspartic acid. These components are absorbed, resulting in measurable elevations of amino acids in the blood and brain.

In most individuals, however, transient elevations in plasma levels of phenylalanine and aspartic acid are benign, and are not associated with detrimental health effects. One obvious exception would be people with phenylketonuria, a rare genetic disorder that results in dangerous elevations in the amino acid phenylalanine and therefore must avoid products with aspartame.

The other constituent of aspartame, methanol, is readily metabolized into formaldehyde. This sounds scary at first, but as with all things in toxicology, the dose makes the poison.

Formaldehyde is produced by the body every day in amounts that are thousands of times greater than one would ever get from consuming aspartame. Studies have been conducted to see if consumption of extraordinary amounts of aspartame (up to 200 mg / kg) can affect blood methanol concentrations and formaldehyde levels, and have found no medically relevant impact.


Finally, one lingering area of possible ambiguity is the question of how non-caloric sweeteners may interact with other molecules inside the body. Some preliminary evidence has suggested that specific combinations of food additives – which are fairly ubiquitous in processed foods – may have unique detrimental effects when they are consumed simultaneously.

As an example, one recent study examined the effects of different combinations of trans-fatty acids, monosodium glutamate (MSG), and aspartame on young mice who were predisposed to diabetes and obesity.

The investigators found that mice fed diets rich in trans-fatty acids and MSG gained 26% more visceral fat than mice fed the same amount of trans-fat alone. Curiously, mice fed a combination of trans-fats, MSG, and aspartame gained 55% more visceral fat – despite consuming roughly the same amount of food and water as the other groups.

These findings suggest that at least in mice, certain additives common in processed foods – including aspartame – could result in synergistic toxicity. This effect likely also depends on timing and dosing – the amount of aspartame given to the mice in this study was rather large. And to the extent that this does occur, it would be expected to be most pronounced during critical windows of development, like in utero or childhood, as was observed in the aforementioned mouse study.

As with any toxicology studies that deal exclusively with isolated rodent models, these findings should obviously be treated cautiously. I would not be super worked up about this specific concern until it can be replicated in trials using human participants, and with doses that resemble typical consumption patterns. If nothing else, it does strike me as yet another good reason to perhaps steer clear of highly processed foods.

In the next installment in this series, we will take a closer look at how the consumption of sweeteners actually affects hunger and satiety.



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  • steve

    Dan, Can you also comment on Stevia? Since it’s used in ways similar to these sweeteners, it would be interesting to include it as part of this series.

    • Virginia Robards

      Hi Steve! I think that’s a good idea. We kind of arbitrarily decided to look at the artificial sweeteners for this. But given the recent popularity of stevia as a sugar substitute, I think it would be appropriate to address. Thanks for the suggestion.