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Diabetes Discoveries & Practice Blog

Putting the Puzzle Pieces Together: Exploring Mechanisms to Understand the Effects of Artificial Sweeteners

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What mechanisms are researchers exploring that may explain the metabolic health effects of artificial sweeteners?

Kristina Rother, MD, MHSc, is conducting research to understand the health effects of artificial sweeteners in healthy individuals and people with diabetes and obesity. She shares her insights below.

Q: What are artificial sweeteners, and what are the main sources of these sweeteners?

A: Artificial, or nonnutritive sweeteners, are low-calorie or calorie-free sugar substitutes. There are 6 FDA-approved artificial sweeteners: sucralose, saccharin, aspartame, acesulfame potassium (Ace-K), neotame, and advantame. These sweeteners can be found in diet sodas and in many juices and other drinks. They’re also added to foods, such as reduced-calorie yogurt and cereal, low-calorie desserts, and condiments. Increasingly, artificial sweeteners are found in foods and beverages along with sugar. Products, such as chewing gum, toothpaste, mouthwash, lip balm, and some medications (especially in pediatric formulations), may also contain artificial sweeteners.

Q: Why are researchers studying the health effects of artificial sweeteners?

A: Artificial sweeteners have been linked to weight gain, metabolic syndrome, stroke, and other negative health outcomes. We’re exposed to ever more artificial sweeteners and don’t necessarily recognize the exposure. Adults have always been the predominant users of artificial sweeteners, but in a recent study we found a 200% increase in artificial sweetener use in children and adolescents during the past decade. We also found that many breast-fed babies are exposed to artificial sweeteners because their mothers consume sweeteners during lactation. Given this increased exposure, we need to better understand the potential health effects of artificial sweeteners.

Q: What mechanisms are researchers exploring?

A: Some of the mechanisms being studied include the microbiome, metabolism, and the brain reward system. Research results are not straightforward and, so far, most studies are short-term. Many studies have only been conducted in animals—fewer involve humans. Researchers are trying to put the pieces of the puzzle together to advance our understanding of the effects of these sweeteners. What we’re learning about the various mechanisms includes

  • Microbiome. Artificial sweeteners have been shown to change the microbiome in animal studies. In one study, researchers fed mice artificial sweeteners and found that the animals’ blood glucose levels increased. The researchers then transplanted the gut microbiome from the mice that were exposed to artificial sweeteners into non-exposed mice that were germ-free (meaning they had no bacteria in their intestines). Shortly thereafter, these mice also developed high blood glucose. This experiment documented that the sweetener-induced changes in the microbiome was the “culprit.”
  • Metabolism. Short-term studies in humans have shown that artificial sweeteners may affect insulin levels. Since insulin is an anabolic hormone, this may promote adipogenesis and potentially increase appetite. The underlying mechanism may be direct stimulation of sweet taste receptors on enteroendocrine cells (releasing more incretins) and/or pancreatic beta cells (releasing more insulin). When we look at epidemiologic studies, it appears that the use of artificial sweeteners is consistently associated with weight gain and obesity, which can lead to cardiovascular disease and worsen health outcomes – especially in patients with type 2 diabetes. However, it’s important to note that “association” means “link” and not “direct cause.”
  • Drug metabolism. We know that various dietary supplements and so-called natural products can change the effectiveness of certain medications. For example, St. John’s wort, a natural antidepressant, increases levels of P-glycoprotein, a transporter in the gut. When this transporter is activated, it blocks the absorption of many commonly used medications. This was found to be the case in patients after kidney transplantation. When patients took both St. John’s wort and cyclosporine, which prevents rejection of the transplanted kidney, cyclosporine levels became so low and ineffective that they lost their kidney transplant. In animal studies, sucralose (the sweetener found in Splenda) also increased this gut transporter, just like St. John’s wort does. Therefore, we are now conducting a human study to find out whether sucralose affects drug absorption and metabolism.
  • The brain reward system. When we eat or drink something that contains sugar, the combination of sweet taste and rising glucose in neurons triggers a good feeling or “reward.” When we eat or drink something sweet that contains no calories, the brain can sense the difference and signals less reward. Investigators have speculated that people therefore keep looking for something else to eat, which may ultimately lead to higher calorie intake. Another issue is human behavior. People have a tendency to reward themselves for “good behavior.” For example, someone who is overweight, has obesity, or has diabetes, choses a diet soda instead of a regular soda and thinks, “I just made a smart choice.” However, a bit later he or she thinks, “Since I just had a diet soda, now I deserve a cookie.” The cookie, however, has 300 calories, compared to a regular soda that would have contained 150 calories.

Q: What do you see as the major research gaps or challenges?

A: We need long-term studies involving humans in which factors such as general nutrition and exercise are well-controlled in order to tease out what artificial sweeteners do. To conduct a good study, we have to keep as many factors stable as possible—and this is obviously difficult to do with people in the real world. It may mean keeping study participants in the research hospital to really control their food intake, exercise, sleep, etc. There are many experimental conditions to be tested, since artificial sweeteners are used in various combinations, at different concentrations, and in the context of a multitude of foods and beverages. Some individuals may be more susceptible to artificial sweetener effects, for example, overweight and obese persons with insulin resistance. In the short term, researchers can design and conduct controlled studies that focus on one specific mechanism, such as the microbiome, using one specific artificial sweetener—and focus on one target group, which is what we do right now: Hispanic and African American women who have obesity.

Do you talk about artificial sweeteners with your patients?

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