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Does diet soda make people gain weight?

This question originally appeared on Quora. Answer by Tirumalai Kamala, Immunologist.

Sweet taste without the calories sounds like a perfect example of no pain, all gain but unfortunately cumulative data suggests otherwise. A poster child for unintended consequences, diet soda ( Diet drink) typically contains a type of non-caloric artificial sweetener, Sugar substitute called Aspartame, for example NutraSweet or Equal (sweetener). Unintended consequences in the form of not just weight gain but also increased risk of Cardiovascular disease, Diabetes mellitus type 2, Hypertension, Metabolic syndrome, all vigorously disputed of course (see some examples in references 1, 2), which brings us to the glaring caveat we need to keep front and center when considering the science about artificial sweeteners. Historically the food and beverage industry has funded nutrition research so substantially, the ensuing entrenched conflict of interest renders the phrase 'nutrition science' an oxymoron ( 3).

North America currently leads in sales and consumption of diet beverages (see below from 4).

Soda Sales
Soda sales in North America. Photo courtesy of Tirumalai Kamala, Quora

Artificial sweetener consumption patterns tend to change rapidly in response to widespread perception of harm attendant to one type of artificial sweetener or another. US artificial sweetener consumption for example moved from cyclamate in the 1960s to Saccharin, e.g., Sweet'n Low, to aspartame which reigned supreme for several decades until being upstaged in the 2010s by Sucralose, e.g., Splenda, mainly because it's highly stable in food (5) while Acesulfame potassium (Ace-K), for example, Sunett, Sweet & Safe, Sweet One, is also increasing in use. Pepsi embodies such rapid change. In 2015 it changed its US Diet Pepsi formulation replacing aspartame with sucralose and Ace-K ( 6) but for reasons best known to itself announced in 2016 it was bringing aspartame back while also retaining the reformulated products ( 7). Meantime so-called natural sweeteners like Stevia aka Truvia are also rapidly increasing in prevalence (4).

"If you can avoid taking in more food, does diet soda still somehow make you gain weight?'

Weight gain without increased food intake is in fact a strikingly consistent observation in many animal model studies on artificial sweeteners ( 8, 9, 10). How does this happen? Problem with understanding how these artificial sweeteners affect human metabolism and health long-term is each artificial sweetener is different in chemistry, biology and pharmacokinetics (11, 12, 13, 14, see below from 4, 15). Obviously each will induce different metabolic and health effects.

Artificial Sweeteners
Diet soda artificial sweeteners. Photo courtesy of Tirumalai Kamala, Quora

For long, uncertainty dogged epidemiological studies on artificial sweeteners. Do they cause cancer or not? Do they increase risk of diabetes and/or obesity or not? Do they play a role in metabolic syndrome or not? And so on. Given the big bucks riding on ensuring people continued to guzzle at least diet soda even as the tide turned against sodas in general ( 16), unsurprising really that much of this data is conflicting, mostly due to avoidable study design flaws such as assessing artificial sweetener consumption in conditions far removed from how they're consumed in real life, which is as part of a typical unhealthy "Western" diet replete in highly processed food and as part of a highly sedentary lifestyle. Few studies included children or elderly or minorities or low income, few examined long-term/chronic/habitual artificial sweetener consumption.

In other words, vast chasm between such studies and real life artificial sweetenerconsumption patterns. Most importantly, since different artificial sweeteners are used in different processed foods and drinks and since studies rarely address a single artificial sweetener specifically, we essentially don't understand how each artificial sweetenerinfluences metabolism and health long-term ( 17).

The few studies such as the San Antonio Heart ( 18) and Longitudinal Study of Aging ( 19) that examined elderly and minorities long-term (7 to 9 years follow-up) found substantial weight and waist circumference gain with artificial sweetenerconsumption (in soda, coffee or tea), even without increased food intake, which echoes animal model studies. Increased abdominal fat is of course now a well-known risk factor for cardiovascular disease and type II diabetes.

How to make at least minimal sense of artificial sweetener-related data? Same way as other prickly scientific issues, by looking at conclusions of systematic reviews and meta-analysis. However, given the entrenched practice of the food and beverage industry funding a massive amount of nutrition research, not meta-analyses by just anyone but rather by those not funded by them. Since publication bias, such as, overweening dominance of studies with statistically significant results, is widespread, such reviews and analyses will naturally also be hobbled by the same drawback. However, since they use a set of objective criteria to assess a wide variety of individual studies ranging from cross-sectional to interventional to observational to prospective to randomized, placebo-controlled trials, they're still far more robust and objective than individual studies claiming to find in favor of one or other hypothesis.

One such review ( 20) was conducted by federally funded Purdue University researcher Susan E. Swithers. It assessed differences between diet soda non-consumers and consumers among more than 450,000 participants across 14 independent prospective cohort study, including the San Antonio Heart Study ( 18), with an average 16-year followup. It concluded that regardless of baseline weight in the two groups, regardless naturally or artificially sweetened, soda consumption increased risk of not just weight gain but also cardiovascular disease, hypertension, metabolic syndrome and type II diabetes ( 20). Typically, bad news about artificially sweetened stuff is discredited by arguing overweight people tend to choose it in the first place trying to lose weight, i.e., by arguing reverse causality ( 21). In other words, arguing drinking artificially sweetened stuff doesn't cause weight gain, rather overweight people drink it to try to lose weight. This review ( 20) found that not to be the case.

Swithers concluded ( 20), "Recent data from humans and rodent models have provided little support for artificially sweetened beverages in promoting weight loss or preventing negative health outcomes such as type 2 diabetes, metabolic syndrome and cardiovascular event. Current findings suggest that caution about the overall sweetening of the diet is warranted, regardless of whether the sweetener provides energy directly or not."

No surprise these conclusions were vigorously disputed on the grounds that (22): "Robust scientific evidence demonstrates benefits of artificial sweeteners."

In her authoritative rebuttal (23), Swithers points out the American Heart Association (AHA) and American Diabetes Association (ADA) themselves stated in 2012 lack of robust scientific data about artificial sweeteners ( 24, emphasis mine): "Paucity of data from well-designed human trials exploring the potential role of (non-nutritive sweeteners) in achieving and maintaining a healthy body weight and minimizing cardiometabolic risk factors."

In other words, these products have been unleashed indiscriminately on society, making their way into thousands upon thousands of food and drinks that billions consume and yet we apparently don't know enough to conclude if they're beneficial or not. Sounds like a recipe for a slow motion disaster, which the modern-day global obesity epidemic indeed is, with both sugars and artificial sweeteners obviously playing leading roles. Another systematic review of 18 studies by US NIH researchers found association between consumption of artificial sweetened beverages and weight gain in children and teens ( 25).

Future artificial sweetener research will likely coalesce around at least 3 aspects:

  1. How artificial sweeteners influence Gut flora composition and metabolism.
  2. How they drive behavioral & metabolic compensation.
  3. Biomarkers to identify those at highest risk of sugar/replacer-induced weight gain and/or metabolic disruption.
  4. Artificial sweetener effect on Gut flora composition and metabolism.

Since most artificial sweetener studies focus on their effect on body weight, important aspects about their metabolism remain under-studied. This is because they were for longconsidered inert, passing through the GI tract, untouched, unused, little perturbed and little perturbing. Turns out that's not the case at all (26).

In a mouse model study ( 27), maximal daily accepted doses of saccharin, sucralose and aspartame in their drinking water for five weeks induced mouse gut microbiota changes and Impaired glucose tolerance. How this happens is still not clear, especially since aspartame is fully digested to its constituent amino acids in the small intestine unlike saccharin and sucralose. Study found similar results in human volunteers as well. Since most of its experiments involved saccharin, this study's major caveat is limited relevance for diet sodas, which mostly contain aspartame. Obviously similar, larger study needs to examine aspartame effect separately. In a rat model study ( 28), aspartame exposure led to gut microbiota changes and elevated fasting glucose and reduced insulin-stimulated glucose consumption.

Caveat common to all fecal microbiota studies, not just this one: Fecal samples mostly represent distal colon microbiota. Different parts of the GI tract obviously harbor different microbial populations (29). This is especially pertinent for diet verses weight gain since most nutrient digestion and absorption is in the small intestine, whose microbial composition is still rather a black box.

Implications of artificial sweetener-induced gut microbiota change :

  • Are such changed microbiota better at nutrient harvesting? Better at driving adipose tissue energy storage?
  • These would help explain weight gain even without increased food intake.
  • Are they more harmful to gut's long-term health, making it more leaky, intestinal permeability, triggering systemic inflammation?
  • This would help explain the long-term harmful consequences such as metabolic syndrome and attendant increased risk of cardiovascular disease and type II diabetes.

Hypothesis: Atificial Sweeteners Drive Behavioral and Metabolic Compensation:

Since the 1990s, Purdue University researcher Susan E. Swithers has pioneered animal model studies to explore how artificial sweeteners could uncouple sweet tastes from their metabolic consequences and thus distort ability to predict the latter. In other words,artificial sweeteners may alter how the brain processes reward for sweet taste. Her reviews refer to several such experimental studies ( 30, 31) by hers and other groups.

Biomarkers to identify those at highest risk of sugar/replacer-induced weight gain and/or metabolic disruption

Biomarker are measurable, often quantifiable biological indicators of some condition. As with anything diet-related, some seem to gain weight no matter what or how much they eat, some don't while most of the rest fall somewhere in between. How to proactively identify those at highest risk of weight gain and/or metabolic disruption from artificial sweeteners?

The US Scientific Report of the 2015 Dietary Guidelines Advisory Committee advises ( 32), "Future experimental studies should examine the relationship between ASSD [artificially sweetened soft drinks] and biomarkers of insulin resistance and other diabetes biomarkers."

Only when we have data from such studies will we be able to delve into genetic markers, specific gut microbiota composition, etc., that differentiate those most at risk from the harmful effects of artificial sweeteners, something we have no clue of at present.


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