While the WHO does not say non-nutritive sweeteners are unsafe, it argues that any short-term benefits in the form of weight loss are outweighed by the "possible long-term undesirable effects,” and claims they are often used to make lower sugar versions of 'highly processed' junk foods, rather than encouraging a shift towards a healthier diet.
Ultimately, said the WHO in its July 15, 2022 ‘conditional recommendation’ (which will undergo peer-review by an external expert group) “non-sugar sweeteners [should] not be used as a means of achieving weight control or reducing risk of noncommunicable diseases.”
According to Dr Lustig, this advice may be prudent: “Diet (non-nutritive) sweeteners would seem the obvious alternative to sugar – no calories, no weight gain, right? And this would be true – if weight gain were about calories. It’s not. It’s about insulin. Insulin drives energy into fat for storage.”
“Diet sweeteners increase insulin as well – possibly through the vagus nerve, possibly through GI microbiome changes, possibly through direct effects on fat cells. That’s why there are no long-term human studies demonstrating weight loss with diet sweetener substitution, in fact diet sweetener use is also associated with metabolic syndrome. The WHO has reviewed the same data and has come to the same conclusion.”
Where’s the evidence that diet sweeteners impact insulin?
But where’s the evidence for this, given that the WHO’s recent systematic review of the literature found that randomized controlled trials using diet sweeteners showed small reductions in BMI and body weight “without significant effects” on fasting glucose and insulin?
Similarly, while a handful of studies in the WHO’s review (click HERE, HERE and HERE) suggested that sucralose could decrease insulin sensitivity, the review does not support the conclusion that diet sweeteners (which span everything from stevia and monk fruit to aspartame) uniformly stimulate insulin production.
What are the potential mechanisms by which zero calorie sweeteners might promote metabolic dysregulation?
So what is the evidence to explain how ‘metabolically inactive’ non sugar sweeteners, which typically contribute zero calories, might promote metabolic dysregulation?
According to Lustig: “There is no question that the immediate insulin response to non-sugar-sweeteners is lower than that for sugar. But the point is it's not zero. And in the Tey study [Intl Journal of Obesity, 2017], the insulin response later in the day was larger because of the non-sugar-sweetener preload in the morning, so that the 24-hour insulin response was unchanged.”
His hypothesis includes some of the potential mechanisms outlined in a 2015 review on the metabolic effects of non-nutritive sweeteners conducted by M. Yanina Pepino, PhD at the Center for Human Nutrition at Washington University School of Medicine in St Louis.
1) NNS interfere with learned responses that contribute to control glucose and energy homeostasis
2) NNS interfere with gut microbiota and induce glucose intolerance
3) NNS interact with sweet-taste receptors expressed throughout the digestive system that play a role in glucose absorption and trigger insulin secretion.
In-vitro vs in-vivo studies
According to Dr Lustig: “You drink a soda. The tongue sends a signal to the hypothalamus that says, ‘Hey, sugar is coming, get ready to metabolize it.’ The hypothalamus then sends a signal along the vagus nerve to the pancreas, saying, ‘A sugar load is coming, get ready to release the insulin.’”
If the sugar never comes because the soda is sweetened with, say, sucralose, your pancreas may still produce insulin, he claimed (although other studies have shown no effects of non-caloric sweeteners on insulin production): “The sweet taste alone can both stimulate appetite and insulin release, which drives energy storage.”
He also pointed to an in-vitro study in which human adipocyte (fat) tissue-derived mesenchymal stromal cells were exposed to sucralose, which appeared to promote additional fat accumulation within cells, which researchers at George Washington University speculated may have resulted from increasing glucose entry into cells through increased activity of genes called glucose transporters.
This is an in-vitro study in petri dishes - not a human study (the researchers note that their findings "require further corroborative studies in vivo") - but if sucralose can get across the intestinal mucosa and into the bloodstream, what is the effect on fat cells, asked Lustig?
"Fat cells have receptors for diet sweeteners on them, no one knows why. They bind to receptors on the fat cells and activate the energy storage directly. So maybe you don't even need the insulin, the diet sweetener itself will do it.”
2015 review: ‘There is no irrefutable proof that NNS cause metabolic disorders in human subjects’
According to Dr Pepino’s review: “There is no irrefutable proof that NNS cause metabolic disorders in human subjects. However, data from at least five different mammalian species (rats, mice, pigs, cows, human) show that NNS can be metabolically active. Therefore, the old concept that NNS are invariable metabolically inert no longer holds true.
“More research is needed to elucidate the mechanisms by which NNS may drive metabolic effects and better understand potential effects of these commonly used food additives.”
But ‘the old concept that NNS are invariably metabolically inert no longer holds true’
Dr Pepino noted: “The finding on the effects of non-nutritive sweeteners on the gut microbiome in human subjects is limited to potential effects of saccharin.”
He also observed “inconsistencies between findings from data from animal models and human subjects in regards to whether NNS can acutely affect glycemic responses in vivo, presumably by activating sweet taste receptors in the digestive system.”
“Importantly,” added Dr Pepino, “most of this research in human subjects has evaluated the effects of sucralose, or sucralose in combination with acesulfame-k, and therefore results from these studies should not be extrapolated to all non-nutritive sweeteners.”
International Sweeteners Association: ’The evidence does not support the claim that low/no calorie sweeteners increase or otherwise affect insulin secretion’
Asked for its response to Dr Lustig’s comments, The International Sweeteners Association told us that, “The collective scientific evidence does not support the claim that low/no calorie sweeteners increase or otherwise affect insulin secretion.
“The lack of effect on blood glucose and insulin levels is supported by comprehensive systematic reviews and meta-analyses of all available clinical studies, which confirm that the ingestion of low/no calorie sweeteners, administered either alone or in combination with food, has no effects on postprandial glucose or insulin responses.“
The ISA added: “Actually, low/no calorie sweeteners can be a helpful tool in glycemic control, which is particularly important for people with diabetes. The European Food Safety Authority (EFSA) recognizes that ‘the consumption of foods containing intense sweeteners instead of sugar induces a lower blood glucose rise after their consumption compared to sugar-containing foods’.”
Meanwhile, the claims regarding the potential for sucralose to affect body fat accumulation are “wholly inconsistent with the strong body of evidence based on a wealth of well-controlled human clinical studies, which shows that when used in place of sugar, low/no calorie sweeteners, including sucralose, can help in reduced overall energy intake and weight loss.”
Finally, the in-vitro study referenced by Dr Lustig in which human adipocyte (fat) tissue-derived mesenchymal stromal cells were exposed to sucralose was problematic, claimed the ISA.
“Isolated fat tissue cells were exposed to sucralose out of the human body at concentrations that would never reach the fat tissue in the human organism because sucralose is poorly absorbed, minimally metabolized and thus is excreted primarily unchanged in the feces in humans.”
Calorie Control Council: ‘Substantial body of evidence that clearly demonstrates low- and no-calorie sweeteners do not raise blood glucose or insulin levels’
The Calorie Control Council added: “Though human tissue was used in this particular study, these results cannot be extrapolated to a whole, intact human being where complex metabolic processes and variables not present in the in-vitro setting affect the outcome.”
Reverse causality?
As for the association between non-nutritive sweetener consumption and metabolic syndrome, said the ISA spokesperson, "It is well documented that prospective cohort studies are also at a high risk of residual confounding and reverse causality, as higher consumers of low/no calorie sweeteners may choose these products because they are at greater risk for adverse cardiometabolic outcomes and not the other way around."
Asked about cardiometabolic risk and the WHO's reference to "possible long-term undesirable effects," the spokesperson added: "There is no evidence or plausible mechanism in humans to show that consuming low/no calorie sweeteners can increase cardiometabolic risk.
"In fact, a recent systematic review and meta-analysis of clinical trials showed that substituting sugar-sweetened beverages with drinks containing low/no calorie sweeteners was associated with improvements in cardiometabolic risk factors in addition to reducing body weight and adiposity, without evidence of harm."