Saturday, December 14, 2013

Sucralose, Hazardous or Innocent? A Review of the Review - Part I: Glucose, Insulin & GLP1 | Sucralose & Diabetes?

Sweet, low and unhealthy? Is sucralose as bad as a recent review would suggest?
I guess I could say "I've written more than enough about artificial sweeteners!" and simply ignore the sensational press release about the "bioactivity" of this increasingly common artificial sweetener you've read on the SuppVersity Facebook News, yesterday (check it out). In view of the fact that most of my previous artificial sweetener articles revolved around a possible impact on body weight / insulin sensitivity, ca. 90% of the claims in the press release are actually "news" - even for SuppVersity readers. Ample reason to take another, closer look at the study outcome and analyze both the "real" results, what the press release made of it and whether or not the panic that's already spreading on the Internet is warranted.

First things first: What are we talking about?

As the press release informs us, an "extensive review published by Taylor & Francis"... stop, so here is our first hint. The authors of the press release are people from Taylor & Francis and have a vested interest in writing it in a way that will have people share the text and their name on the Internet (that worked pretty well, as you can see - even I am talking about it ;-)
This is part I of a multi-part series:

Sucralose, insulin, glucose, GLP-1

Appetite, Obesity & Gut Health

Cancer, Drug & Hormone Interact.
I know that Mark Sisson likes to says this, but this website is not written by a machine, but by a man who has the same "short" 24h days you have... basically, what I am trying to say is that I had to split this review of the review into a "trilogy" - and be honest, you wouldn't want an article thrice as long as this one, would you?
Next on the list is some information about the "extensive review" and the hint that it was authored by Susan S. Schiffman, PhD, "an internationally known sweetener researcher" and Kristina I. Rother, MD, MHSc, "of the National Institutes of Health (NIH)". So, now it stands out of question that what's in this review is the truth and nothing but the truth. I mean, what else would it be if these experts, one working for the almighty and benevolent NIH "summarize[d] the biological properties of sucralose based on hundreds of archival, peer-reviewed scientific journal publications" (my emphasis).

Based on hundreds of [...] publications?

While it is true that the review has 476 references, not all of them deal with sucralose and only few of them provide data that would by any means be relevant to the most important question of all: "Can sucralose consumption harm us". The statement "based on hundreds of [...] publications" is thus misleading, because when it's used in conjunction with the word "review" people will interpret it as the number of relevant papers - or, even worse, of studies the data of which has been used in a systematic review. The paper at hand is yet everything but a systematic review - it's a narrative one.

Next on the list of our "review with your critical thinking cap on the head" list are the following claims about the health / environmental effects of sucralose:
  • Please note: I will address all the issues within this trilogy, but for today I will focus on the one with the asterisk (*). As you can see from the headlines in my preliminary outline above, the rest of the issues are going to follow, asap.
    The best thing you can do if you want to make sure you're not going to miss a single article is to register for the SuppVersity Newsletter at the bottom of the page or - even better - like the SuppVersity Facebook Page and you'll always be in the know.
    alterations in insulin, blood glucose, and glucagon-like peptide 1 (GLP-1) levels,
  • metabolism of sucralose in the gastrointestinal tract to metabolites whose identity and safety profile are unknown,
  • induction of cyctochrome P450 and P-glycoprotein in the gastrointestinal tract to levels that may limit the bioavailability of therapeutic drugs,
  • reduction in the number and balance of beneficial bacteria in the gastrointestinal tract,
  • histopathological findings in gastrointestinal tract including lymphocytic infiltrates into epithelium, epithelial scarring, mild depletion of goblet cells and glandular disorganization in the,
  • decomposition and generation of chloropropanols (a potentially toxic class of compounds) during baking, and
  • mutagenic alterations using several types of biological assays
What I am going to do now, is to track each and every of them back to the review and take a brief look at the research that's out there to make sure that we are actually dealing with "the truth", here ;-)

Claim I: Sucralose messes w/ blood glucose management

I have to admit I was very curious to see the evidence on which Schiffman & Rother base this claim and was pretty disappointed, when I saw an extensive list of rodent and cell model studies, like those by Jang et al. and Margolskee et al., in which human NCI-H716 cells (Jang. 2007) and mouse enteroendocrine cells (GLUTag; Margolskee. 2007) were used to support the claim that sucralose would lead to an increase in GLP-1 - which is, by the way you usually won't hear as an argument against artificial sweeter use ... anyways, we are going to see why later, for now it should suffice to say that this intrigued me.

In view of the physiological role of GLP-1 it's by no means clear whether the mentioned increase is actually something to be afraid of (see "Eat More, Burn More and Lose Fat Like on Crack with GLP-1!? Roux-en-y Bypass Study Sheds a Whole New Light on Satiety(Hormone)-Induced Weight Loss" | learn more)
After taking a closer look at the two studies and realizing that I had no way to tell whether it's realistic to assume that our cells are exposed to 1nM or 5nM of sucralose, which is what Jang et al. observed was the dosage they needed to elicit the desired increase in GLP-1 (Jang. 2007). And even if it would - would increases in GLP-1 actually be such a bad thing? I mean, you've read about the use of GLP-1 and its synthetic analogues to treat diabetes I & II (Pettus. 2013; Schwartz. 2013), protect you from NAFLD (Panjwani. 2013), reduce the oxidative damage to the heart during hypoglycemic episodes in type I diabetics (Ceriello. 2013), etc. both right here at, as well as over on the SuppVersity Facebook Wall.

The thing we'd have to fear is thus not the release of GLP-1 (for a large majority of the increasingly overweight population this could actually be beneficial), but a "dysregulation" GLP-1, GIP, C-peptide, insulin, glucose, and so on and so forth....

I don't say that it's impossible that this is going to happen, but by no we have no convincing evidence that it will and in view of the fact that a scarcity of glucose is not exactly something to be afraid of in this day and age, an increase in GLP-1 could actually be an advantage for the majority of SAD-dieters. Unfortunately, the real-world (=non-petri dish) evidence from a 2009 study by Ma et al. tells us that this is not going to happen in humans.
Figure 1: GLP 1 (left) + insulin (right) response in healthy individuals to sucrose, saline (control) or 80mg and 800mg sucralose (theoretically this would be as sweet as 48g and 480g of pure sugar; Ma. 2009).
In face of the data in Figure 1, which leaves little doubt that only sugar (sucrose), but neither 80mg, nor 800mg of sucrose will have any effect on the critical hormones / peptides GLP-1, GIP, and insulin, Schiffman & Rother's argumentation breaks down. And if you take into account that the corresponding (theoretical) sweetness equivalents of 80mg and 800mg of sucralose are 48g and 480g of pure sugar, I seriously doubt that we'd have to test higher dosages to make sure that nobody "intoxicates" himself ;-)

Granted: Even the authors cite evidence against the GLP-1 hyothesis

I know, not everyone is willing to briefly type "GLP1 subjects sucralose" into a search engine, wait for the results to pop up and follow the link to the previously cited study by Ma et al. I understand that, but if that was you, you would actually just have to scroll down to the bottom of sensationalist press release, I cited on Facebook and click on the link (or enter the doi) to the (free) full-text, to find the following line on page 402:
"Oral consumption of sucralose without co-administration of glucose (Brown et al.,
2011) produced no significant effect on blood glucose levels. Sucralose delivered by intraduodenal infusion in combination with glucose also exerted no marked effect on blood glucose or plasma GLP-1 (Ma et al., 2010)."
In other words, contrary to the author(s) of the press release, Schiffman and Rother are well aware that their evidence is far from being conclusive. What I am not so certain about, though, is whether they are also aware that their reference to a study by Brown et al. from 2009, where the coningestion of sucralose with acesulfame-K in 240 ml of caffeine-free diet soda (Diet Rite cola) produced an increase in the GLP-1, but not insulin or glucose (see figure 2), could actually be interpreted as a highly beneficial result.
Figure 2: Glucose, insulin and GLP1 response to oral glucose tolerance test conducted 10min after the ingestion of 240 ml of caffeine-free diet soda (Diet Rite cola; boxes) or carbonated water (circles; Brown. 2009)
If glucose is around, an increased GLP-1 response is after all not necessarily a bad thing. In 2002, for example, Zander et al. reported in The Lancet that 6 weeks "on GLP-1" ...
  • The WM-HDP ↔ GLP-1 ↔ fatty oxidation connection | reread "Waxy Maize Reloaded" read more
    reduced the fasting and 8h post-meal free fatty acid levels of type II diabetics by -25% and 30%,
  • improved the 8h blood glucose levels,
  • decreased the HbA1c value from 9.2% to 7.9%,
  • normalized the levels of cell-toxic fructosamine, 
  • slowed down gastric emptying 
  • decreased their ravenous appetite,
  • improved insulin sensitivity and β-cell function, and
  • induced a -3% reduction in total body fat.
Not much of a surprise, if you are familiar wit the effects of GLP-1 I discussed in the "Waxy Maize Reloaded" article (learn more), right? As far as the physiologically measurable mechanisms for derangements of the blood glucose management go, this leaves us with a potentially centrally mediated dysregulation of glucose sensing for which we do as of yet only have in-vitro "evidence" from a 2009 study by Ren et al. The researchers observed (obviously in the petri dish) that the normal expression of one out of three hypothalamic sweet taste receptors (Tas1R2) in cells from the hypothalamus is reduced in the presence of 0.5mM of sucralose. Up to now we do yet neither know if orally ingested sucrose can actually make it into the brain, whether the corresponding changes in Tas1R2 expression would be physiologically relevant, or what its consequences would be.
"Science Round-Up Seconds: The Pro-Insulinogenic Effect of Artificial Sweeteners + Mechanisms & Consequences" | more
Preliminary bottom line: As far as a potential dysregulation of the glucose metabolism is concerned, I still believe that there is currently not enough evidence to support the claims from the press release or implications of the biased listing of "significant findings" in the conclusion of the full text, where the authors discard all previously cited counter-evidence from human studies and focus on a study by Pepino et al., the questionable implications of which I already discussed in the Science Round-Up on May 21, 2013 (more). In the absence of controlled long term human studies this bottom line must however not be misunderstood as a full acquittal. In other words, the only thing this study demonstrates is how little we actually now.

As far as centrally mediated effects are concerned, the upcoming installments of what began as a comment and became a series of articles on sucralose may provide at least some insights into potential long(er) term effects on blood glucose management. Derangements that occur in response to changes in the gut microbiome, endocrine system or toxic effects of sucralose or its byproducts would after all only become visible after weeks or months of chronic (high dose?) ingestion of this globally approved artificial sweetener.
  • Brown, R. J., Walter, M., & Rother, K. I. (2009). Ingestion of diet soda before a glucose load augments glucagon-like peptide-1 secretion. Diabetes Care, 32(12), 2184-2186.
  • Ceriello, A., Novials, A., Ortega, E., Canivell, S., La Sala, L., Pujadas, G., ... & Genovese, S. (2013). Vitamin C Further Improves the Protective Effect of Glucagon-Like Peptide-1 on Acute Hypoglycemia-Induced Oxidative Stress, Inflammation, and Endothelial Dysfunction in Type 1 Diabetes. Diabetes care, 36(12), 4104-4108. 
  • Fujita, Y., Wideman, R. D., Speck, M., Asadi, A., King, D. S., Webber, T. D., ... & Kieffer, T. J. (2009). Incretin release from gut is acutely enhanced by sugar but not by sweeteners in vivo. American Journal of Physiology-Endocrinology and Metabolism, 296(3), E473-E479.
  • Jang, H. J., Kokrashvili, Z., Theodorakis, M. J., Carlson, O. D., Kim, B. J., Zhou, J., ... & Egan, J. M. (2007). Gut-expressed gustducin and taste receptors regulate secretion of glucagon-like peptide-1. Proceedings of the National Academy of Sciences, 104(38), 15069-15074. 
  • Ma, J., Bellon, M., Wishart, J. M., Young, R., Blackshaw, L. A., Jones, K. L., ... & Rayner, C. K. (2009). Effect of the artificial sweetener, sucralose, on gastric emptying and incretin hormone release in healthy subjects. American Journal of Physiology-Gastrointestinal and Liver Physiology, 296(4), G735-G739.
  • Margolskee, R. F., Dyer, J., Kokrashvili, Z., Salmon, K. S., Ilegems, E., Daly, K., ... & Shirazi-Beechey, S. P. (2007). T1R3 and gustducin in gut sense sugars to regulate expression of Na+-glucose cotransporter 1. Proceedings of the National Academy of Sciences, 104(38), 15075-15080.
  • Panjwani, N., Mulvihill, E. E., Longuet, C., Yusta, B., Campbell, J. E., Brown, T. J., ... & Drucker, D. J. (2013). GLP-1 receptor activation indirectly reduces hepatic lipid accumulation but does not attenuate development of atherosclerosis in diabetic male ApoE−/− mice. Endocrinology, 154(1), 127-139.
  • Pettus, J., Hirsch, I., & Edelman, S. (2013). GLP-1 Agonists in Type 1 Diabetes. Clinical Immunology. 
  • Ren, X., Zhou, L., Terwilliger, R., Newton, S. S., & De Araujo, I. E. (2009). Sweet taste signaling functions as a hypothalamic glucose sensor. Frontiers in integrative neuroscience, 3. 
  • Schiffman, S. S., & Rother, K. I. (2013). Sucralose, A Synthetic Organochlorine Sweetener: Overview Of Biological Issues. Journal of Toxicology and Environmental Health, Part B, 16(7), 399-451.
  • Schwartz, S., & DeFronzo, R. A. (2013). Is Incretin-Based Therapy Ready for the Care of Hospitalized Patients With Type 2 Diabetes? The time has come for GLP-1 receptor agonists!. Diabetes care, 36(7), 2107-2111.