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 www.suppversity.com, 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.

References:

• 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.

Science Round-Up Seconds: The Pro-Insulinogenic Effect of Artificial Sweeteners + Mechanisms & Consequences

Would having your coffee with splenda instead of sugar make this cookie even more hazardous for your glucose metabolism and what about your waistline?

If you've listened to yesterday's installment of the science Round-Up your are probably already in the know of the most important facts about the "pro-insulinogenic" effects of sucralose and how it is (a) neither sure what exactly is causing this increase in post-prandial insulin release, nor (b) whether this is the "bad thing" conventional wisdom would dictate it is.

If you've also read the corresponding press release from the Washington University in St. Louis, I've linked in yesterday's Facebook post on the matter, you will know that even the authors of the study are not yet sure about the real world implications of their results:

"The elevated insulin response could be a good thing, she pointed out, because it shows the person is able to make enough insulin to deal with spiking glucose levels. But it also might be bad because when people routinely secrete more insulin, they can become resistant to its effects, a path that leads to type 2 diabetes."

Before we are getting to those, let's briefly recap what exactly it was, the researchers did and what they observed: M. Yanina Pepino and her colleagues from the Washington University School of Medicine in St. Louis had recruited a group of people belonging to the rare species of obese subjects (BMI 42.3 ± 1.6 kg/m²) who (a) did not use non-nutritive sweeteners and were insulin sensitive. The subjects underwent  a 5-h modified oral glucose tolerance test on two separate occasions which was preceded by consuming either sucralose (experimental condition) or water (control condition) 10 min before the glucose load in a randomized crossover design in the course of which the researchers observed:

• 

  Figure 1: AUC (normalized for mean) and peak values of measured parameters of glucose metabolism (Pepino. 2013)

  20 ± 8% greater incremental increase in insulin area under the curve (AUC) (P < 0.03),
• 22 ± 7% greater peak insulin secretion rate (P < 0.02), 
• 7 ± 4% decrease in insulin clearance (P = 0.04), 
• 23 ± 20% decrease in the calculated insulin sensitivity

• all this occurred in the presence of a faster increase in blood glucose (remember this, it's going to be important)

• aside from the increase in the incremental area under the curve (AUC) for insulin, there were no statistical differences between the AUC (=totally produced) measured serum markers for any of the parameters in figure 2 (top)

Almost as interesting as the things, the researchers did observe were yet changes they didn't observe, namely differences between conditions in active glucagon-like peptide 1, glucose-dependent insulinotropic polypeptide, glucagon incremental AUC, or indices of the sensitivity of the β-cell response to glucose. Why this is important? Well, actually you would expect increased GLP-1 and GIP levels, lowered glucagon (the hormone that will have your liver produce glucose) and an increased sensitivity of the b-cells to glucose (why else would there be more insulin floating around), but none of these effects was observed.

So what's the mechanism here, then?

Just like the scientists themselves state: "Although we found that sucralose affects the glucose and insulin response to glucose ingestion, we don’t know the mechanism responsible." (Pepino in an interview with the press guy from the University) and we don't know if these effects of sucralose / splenda are obesity specific or will occur only transiently and disappear upon continuous exposure.

As I mentioned on the show, there are yet a couple of possible mechanisms, all of which are in some form or another related to the sweet taste receptors, which are activated by all natural and artificial sweeteners and are expressed on our tongues, in our intestines and on the pancreas:

• 

  Figure 2: Illustration of the signaling cascade that's initiated by the activation or the sweet taste receptor (based on Lindemann. 2001)

  in vitro studies have already shown a C-AMP (regular) dependent increase in insulin release from pancreatic cells by sucralose (Nagakava. 2009); this was yet not observed in previous human studies, where mostly lean subjects ingested pure sucralose
• the sweet taste receptor appears to have either a heterodimer structure or two distinct incarnations (as shown in the illustration to the right; see figure 2), of which sucralose could trigger only the 2nd pathway which may be insufficient to cause the depolarization of the pancreatic cells to trigger the consequent release of insulin, but it may well suffice to increase the depolarization and insulin release from the pancreas

From another artificial sweetener, namely Acesulfam-K we know that it can also increase the influx of glucose across the intestinal border by increasing GLUT-2 receptor expression (Zheng. 2013), so that this would a third - indirect effect on the insulin response that cannot be totally discarded.

In fact, the upregulation of intestinal glucose transport is the most likely explanation

If we take another look at the study outcomes, it is obvious that this increase in the transport of glucose across the intestinal border would in fact be the most likely mechanism to cause the (in this case appropriate) increase insulin response (more on that in the chapter on whether this is a good or bad thing). Previous studies in rodents also suggest that aside from the acute increase in GLUT-2 receptor expression, the chronic use of artificial sweetener has the ability to upregulate the expression of the "regular" Na-dependent glucose transporter and will thus have a persistent negative effect on what you could call the GI of everything you eat. Accordingly, the scientists speculate

"[...] that regular users of NNS [non-nutritive sweeteners] would have a higher glycemic response after an oral glucose tolerance test on the control day than irregular users and that the acute effects of sucralose intake would be blunted because differences between water and sucralose conditions would be smaller in regular than in irregular users of NNS." (Pepino. 2013)

In other words, chronic users won't be experiencing the effects that were observed in the study, but they will necessarily have a slightly increased insulin response to everything they eat (as long as they are healthy and not yet insulin resistance) irrespective of whether they consume it with or without non-nutritive (not just artificial) sweeteners.

Table 1: Sweetness, dose to stimulate the sweet taste receptor (EC50; based on Matsuda. 2011) and correlation of sweetness and EC-50 value.

In this context, it's certainly worth mentioning that it is unlikely that these effects are sucrolose specific. What is possible, though, is that different artificial sweeteners have more or less pronounced effects. From a 2011 study by Matsuda et al. we know that this is the case for their stimulatory effect on the sweet taste receptor and as my own juxtaposition + calulation of the correlation, which is missing a "minus" sign, in table 1 goes to show you, the "sweetness" measured in units of sucrose (normal sugar) is a relative reliable predictor of the degree to which the different artificial sweeteners activate the sweet taste receptor (not really surprising, is it?)

Being ~300x sweeter than sucrose stevia would by the way be somewhere between acesulfame K and saccharin Na and there is no reason to assume it would not have the same effects, only because it is "natural". I fact the observation Anton et al. made in a 2010 study, where the preingestion of stevia yielded a greater initial glucose spike and a correspondingly higher increase in 30min post-prandial insulin levels than aspartame (~37%) (Anton. 2010). These results clearly suggest that stevia is probably no exception to the rule (it could yet also be that aspartame is an exception to the rule, cf.  "Aspartame's Anti-Insulinogenic Effects During a Workout"; read more) - unfortunately the differences in the study design don't allow for a direct comparison of the Anton and the Pepino study.

And how bad is that?

If we don't really know what the mechanism is and who will be affected to which degree, do we at least know how bad the observed changes are? Unfortunately, the answer is "No", but the notion that any increase in insulin would be bad for you is clearly flawed.

As I hinted at in the show, one of the characteristic feature that renders Pima Indians susceptible to diabetes is the absence of an appropriate early spike in insulin (Lillioja. 1991). Corresponding evidence from other ethnicities (e.g. Kosaka.1996) confirms that the absence of this initial spike (early insulin response) is actually the first step people take on the "Royal Road to Diabesity", the underlying reasons are:

• a failure of immediate suppression of hepatic glucose production, when exogenous glucose is available
  

  "[...] the impact on suppression of hepatic glucose production was dramatic, with the liver releasing glucose at a higher rate despite the presence of hyperglycemia and hyperinsulinemia. The alteration was a direct consequence of the specific defect because restoration of first-phase insulin secretion was followed by complete normalization of hepatic glucose production." (Del Prato. 2001)

• the lack of the stimulatory effects of insulin on peripheral glucose uptake (Del Prato. 2003)

If you did not listen to the podcast yet, you are now probably asking yourselves: "Hold on, but does that not set you up to become obese?" The answer would certainly be yes, if you were insulin resistant, would not work out and would follow a hypercaloric diet with tons of carbs and fats.

Figure 3: Effects of insulin on glucose metabolism, glycogen storage (left) and fatty acid synthesis (right), time-resoled data (0, 2, 4, 8, 12h) on glycogen deposition in skeletal muscle in the inset b/w graph; the data (in mg per kg/min) was measured using an euglycemic clamp in the presence of high, but physiological insulin levels (Koopmans. 1998)

If that's not you, the actual effect of insulin on fatty acid synthesis and thus the amount of carbs that is stored as fat will be of a >20x lower magnitude than the effect insulin exerts on the storage of muscle glycogen - if you extrapolate the data from the first 20min of the euglycemic clamp data figure 3 is based on the ratio could be as high as 2,000x (in other words for each 1 unit of glucose being converted to fat, 2,000 units will be shuttled into the muscle).

"That's all bullocks? Insulin is bad *fullstop*"

If the above is what you still believe I may remind you that insulin is the natural solution to the "sugar problem", only when it seizes working trouble ensues. Moroever, I suppose some of you will be supplementing with pro-insulinogenic agents such as:

• 

  Figure 4: Data from 12 normal subjects using 5g or 10g of oral GABA (Cavagnini. 1982)

  arginine

• taurine

• GABA

• whey

• EAAs

• etc.

I guess it would be easy to extend the list of agents that will increase the insulin response and have still been shown to have beneficial effects on diabetes risk and body composition, but I am to lazy to do this now ;-)

"Where's my Splenda I want more Splenda!"

Before you order a 20kg batch of sucralose from China, now, I do yet still want to remind you of the fact that you can also find arguments in favor of the potential detrimental effects this hitherto non-understood +20% increase in insulin response during an OGGT could have:

• We don’t know about long-term consequences. Will the increase remain or will we “depend” on the artificial sweetener to get an adequate insulin spike in the future (remember the study participants were non-users before)? 
• In the same vein, we don't know what the consequences of the increased intestinal glucose absorption in response to chronic use  (if it is actually present in humans) will be.
• Moreover, although previously published studies don't support this, you could develop an even more pronounced sweet tooth and totally mess the self-regulatory mechanism for food intake that is skewed in the "average Westerner", anyways.
• Importantly, the effects are probably different in the obese + insulin intolerant for them the spike in insulin will have little benefits and tons of downsides (the beneficial effect cited above wrt to the glucose disposal in muscle are probably irrelevant), so that exactly those people who are targeted by artificially sweetened foods could see negative effects which may not be present in lean individuals.
• And lastly, the general beneficial effects of insulin on glycogen repletion depend on glycogen depletion! In other words, if you don’t work out you will not benefit to the same degree, simply because there is no place to put the glucose (it should be said that this is a general problem, which is not specific to dietary sweeteners, but "having room" for glycogen to be stored is a major determinant of whether insulin is rather good or rather bad) 

And if all that is not convincing enough, just remind yourself that we do not even know what exactly is going on here.

---

Bottom line: It does therefore not appear to be indicated to change whatever has been working for you in the past. I can guarantee that you are NOT stagnating because you use a sweetened whey protein or BCAA product. The evidence simply is not there or as Renwick et al. put it in their review, there is "no consistent evidence that low-energy sweeteners increase appetite or subsequent food intake, cause insulin release or affect blood pressure in normal subjects." (Renwick. 2010).

Finally, I guess, I don't have to mention this, but still: I will keep you posted on any future research.

References:

• Anton SD, Martin CK, Han H, Coulon S, Cefalu WT, Geiselman P, Williamson DA. Effects of stevia, aspartame, and sucrose on food intake, satiety, and postprandial glucose and insulin levels. Appetite. 2010 Aug;55(1):37-43.  
• Del Prato S, Tiengo A. The importance of first-phase insulin secretion: implications for the therapy of type 2 diabetes mellitus. Diabetes Metab Res Rev. 2001 May-Jun;17(3):164-74.  
• Del Prato S. Loss of early insulin secretion leads to postprandial hyperglycaemia. Diabetologia. 2003 Mar;46 Suppl 1:M2-8. 
• Koopmans SJ, Mandarino L, DeFronzo RA. Time course of insulin action on tissue-specific intracellular glucose metabolism in normal rats. Am J Physiol. 1998 Apr;274(4 Pt 1):E642-50.
• Kosaka K, Kuzuya T, Hagura R, Yoshinaga H. Insulin response to oral glucose load is consistently decreased in established non-insulin-dependent diabetes mellitus: the usefulness of decreased early insulin response as a predictor of non-insulin-dependent diabetes mellitus. Diabet Med. 1996 Sep;13(9 Suppl 6):S109-19. 
• Lillioja S, Nyomba BL, Saad MF, Ferraro R, Castillo C, Bennett PH, Bogardus C. Exaggerated early insulin release and insulin resistance in a diabetes-prone population: a metabolic comparison of Pima Indians and Caucasians. J Clin Endocrinol Metab. 1991 Oct;73(4):866-76. 
• Masuda K, Koizumi A, Nakajima K, Tanaka T, Abe K, Misaka T, Ishiguro M. Characterization of the modes of binding between human sweet taste receptor and low-molecular-weight sweet compounds. PLoS One.
• Nakagawa Y, Nagasawa M, Yamada S, Hara A, Mogami H, Nikolaev VO, Lohse MJ, Shigemura N, Ninomiya Y, Kojima I. Sweet taste receptor expressed in pancreatic beta-cells activates the calcium and cyclic AMP signaling systems and stimulates insulin secretion. PLoS One. 2009;4(4):e5106.
• Pepino MY, Tiemann CD, Patterson BW, Wice BM, Klein S. Sucralose Affects Glycemic and Hormonal Responses to an Oral Glucose Load. Diabetes Care. 2013 Apr 30.
• Renwick AG, Molinary SV. Sweet-taste receptors, low-energy sweeteners, glucose absorption and insulin release. Br J Nutr. 2010 Nov;104(10):1415-20.
• Zheng Y, Sarr MG. Effect of the artificial sweetener, acesulfame potassium, a sweet taste receptor agonist, on glucose uptake in small intestinal cell lines. J Gastrointest Surg. 2013 Jan;17(1):153-8.

Not All Artificial Sweeteners Are Created Equal: New Studies on Aspartame, Acesulfame-K & Combination of Saccharin + Neohesperidin Dihydrochalcone

It was about time for an artificial sweetener update, wasn't it?

Alright, I have to admit I am not following the artificial sweetener scene closely enough to have heard about SUCRAM, an artificial sweetener that is composed of saccharin (a classic) and neohepseridin dihydrochalcone, the new kid on the blog, which is yet not officially approved by either the FDA or it European equivalent o be used in the processed junk, most people call "food", these days. If we put some faith into the latest study investigating the effects of this agent, which is apparently already heavily used in animal feeds in Europe it does yet "dramatically reduce enteric disease" and "enhance growth performance in early-weaned piglets." (Daly. 2014)

Whether and to which extent these beneficial effects on gut health are mediated by changes in the gut microbiome is yet still uncertain; and since "uncertain" is a word scientists don't like, Kristian Daily and his colleagues from the University of Liverpool conducted a study to find out, whether the non-negligible health benefits would be brought about by AI <> gut interactions.

You can learn more about this topic at the SuppVersity

Food Gut Interactions

Macrobiotic MaPi2 What's That?

Sweet But not Innocent?

Sucralose is for Diabetics Not

Stevia: Much More Than Sweet

Sweeter Than Legal

To this ends, the scientists employed a DNA-based pyrosequencing technology to investigate the changes in the intestinal microbiota of piglets weaned to a diet supplemented with either a natural sugar, lactose or said artificial sweetener (SUCRAM)

Figure 1: Total and lactobacillus OTU4228 concentrations in piglets on hydrolzysate carbohydrate diet without sweeteners, with lactose or SUCRAM diets and corresponding concentration of lactic acid in the caecal contents (Daly. 2014)

As you can see in Figure 1, both, the addition of lactose and the saccharin/NHDC mix lead to dramatical increases in the caecal Lactobacillus population and could well explain the previously reported "pro gut health" effect of SUCRAM in piglets (Vente-Spreeuwenberg. 2004; Pierce. 2006)

But that's obviously not all that's news-worthy!

I did after all promise you news on products you may be using, as well - aspartame and acesulfame-k, to be precise. Now, while the former is a constant target of public (mostly broscientific) criticism, the latter has been a thorn in my side ever since I have started investigating artificial sweeteners.

Lean more about the "Gut Type Diet" - No Fad, Guaranteed!

And while previous studies only suggested that the effects of acesulfam-k on the pancreas could have pro-obesogenic consequences, a recent model experiment from the Louisiana State University appears to finally prove that acesulfam-k may actively promote the deposition of body fat in the presence of insulin resistance.

Ok, the results have been derived in a Caenorhabditis elegans, a "worm", but one that has long and actually surprisingly successfully been used as a "model for studying the basic biology of obesity" (Jones. 2009) - I know, I am not convinced either, but if the results do actually translate to humans, this would be major (bad) news for the food industry.

In view of the fact that most companies have been pulling acesulfame-k from their products over the past years, anyway, I would not discard the findings Jolene Zheng et al. present in their latest paper in Chemico-Biological Interactions as meaningless, not despite, but rather because a scientists from PepsiCo was part of the research team which observed these significant increases in intestinal fat (=visceral fat of the worm) when the critters were fed with acesulfam-k sweetened coke.

Cheating? Why would be using artificial sweeteners cheating? In spite of the fact that there is no credible evidence for a causal relationship between the consumption of artificially sweetened foods and obesity (there is a correlation that could well be the result of reverse causation), there is some concerning evidence that the extreme sweet taste and the way people appear to escalate the dosages reduce your bodies ability to control its energy balance by thwarting with its mostly sugar-based first-line energy intake sensor.

What I would not recommend either, though, is to (ab-)use aspartame-containing diet coke as a "weight loss beverage": It's certainly ok to sooth your sweet tooth, when you're dieting and I am not saying that you must not drink one or another Diet Coke or Pepsi on the weekend. What I am saying, though, that I don't believe that the consumption of copious amounts of this stuff will result in a similar body fat reduction (see Figure 2) in you, where compensatory mechanisms, your sweet tongue and a whole host of other things complicate weight and even more so fat loss compared to C. elegans.

That being said, I would be inclined to know, when and if SUCRAM is going to be available as a food additive for humans. It does after all sound quite nice to do your tummy a favor while you're "cheating", right? Although,... when I come to think about it, we actually don't need a "new" sweetener to mess up our gut microbiome. As I already hinted at in a related SuppVersity Classic Article Series with the telling title "Sucralose, Hazardous or Innocent?" (Part I, Part II, Part III), Payne et al.  (2012) have already identified fructose, mannitol and d-tagatose as promoters of lactobacillus growth and sucrose as their primary enemy (learn more about the interaction in Part II of the series).

References: 

• Payne, A. N., C. Chassard, and C. Lacroix. "Gut microbial adaptation to dietary consumption of fructose, artificial sweeteners and sugar alcohols: implications for host–microbe interactions contributing to obesity." Obesity Reviews 13.9 (2012): 799-809.
• Pierce, K. M., et al. "The effect of lactose and inulin on intestinal morphology, selected microbial populations and volatile fatty acid concentrations in the gastro-intestinal tract of the weanling pig." ANIMAL SCIENCE-GLASGOW THEN PENICUIK- 82.3 (2006): 311.
• Jones, Kevin T., and Kaveh Ashrafi. "Caenorhabditis elegans as an emerging model for studying the basic biology of obesity." Disease models & mechanisms 2.5-6 (2009): 224-229.
• Vente-Spreeuwenberg, M. A. M., et al. "Effect of dietary protein source on feed intake and small intestinal morphology in newly weaned piglets." Livestock Production Science 86.1 (2004): 169-177.

The Unsatiating Truth About Aspartame, Acesulfam K, Sucralose & Co: They Don't Induce Glucose or Insulin Spikes, But Do They Make You Hungry?

Image 1: If you plan to eat the stuff on the plate behind the coffee cup, I guess it does not really matter if you use sugar, fructose, Aspartame, Acesulfam K, Sucralose or everybody's  new darling, stevia to sweeten the coffee ;-)

If there was a yearly top 10 list of the furiously and most passionately debated topics, in the health & fitness community, the issue of "artificial sweeteners" (personally I would include high fructose corn syrup as "artificial", but I guess the FDA or rather their financiers think otherwise) would probably make it to the TOP 5 every year. All concerns about toxicity issues aside, the two main concerns people are worrying about are a direct negative effect on glucose metabolism and an indirect intake on subsequent / concurrent food intake. Both would obviously predispose consumers who buy respective products because they trust in the industry's promise that they would help the lose weight and/or ward off diabetes to the exact ailments they are intended to prevent.

Sweet taste receptors are all over the place!

My personal interest in this topic has always revolved around the issue of "sweet taste receptors" (i.e. cells that will recognize certain molecules as being sweet), the existence of which in / on all sorts of organs / tissues scientists had been overlooked for decades. I mean, isn't it revealing that the same "sensors" that are responsible for the sweet sensation you experience when you spooning your delicious full-chocolate ice cream are also present in your gut and even on your pancreas, where their activation sets the stage for the release of insulin into the bloodstream (Nakagawa. 2009)? This rather recent revelation could after all finally explain the early results of Blundell et al. who observed an increase in calorie consumption in subjects after consumption of foods containing the artificial sweeteners Aspartame and Saccharin (Coke light & Co), back in the fat-phobic 1980s (Blundell. 1986; 1989). Subsequent more sophisticated studies were yet unable to reproduce those early results (at least in humans).

Artificial sweeteners are obesogenic! Bitter truth or just another myth?

With the advent of a more sophisticated understanding of the complex physiological processes and integrated signaling systems which regulate appetite and satiety in mammals and humans in particular (I doubt we will ever be able to understand all the psychological factors that come into play with the latter), Robert E. Steinert and his colleagues from the Clinical Research Center at the University Hospital in Basel (Steinert. 2012), Switzerland, took another, more closer look at what actually happens, when we consume beverage which taste as if they contained tons of sugar, but are totally devoid of nutrients.

Figure 1: Intensity of sweetness, total amount per 250ml solution and energy equivalent of the five sweet test solutions (the sixth beverage was plain water); mind the logarithmic scale! (data adapted from Steinert. 2012)

To this ends, the Swiss scientists recruited 12 healthy, non-smoking volunteers (6 men, 6 women; mean age 23.3y; normalweight, BMI 23kg/m², min. 3 months of stable weight) to perform a randomised, placebo-controlled, double-blind, six-way cross-over trial. In each of the 6 trials, which were seperated by 3-5d the subjects reported to the lab at 8:00am after an 10h overnight fast (no alcohol, no exercise, no supplements or medication), where they received one (on each occasion) out of six 250ml test solutions containing either tap water (no problem to drink that, in Switzerland ;-), or freshly prepared solutions with concentrations of the different sweeteners, of which the scientists state that they "were comparable with the amounts found in commercially available beverages and soft drinks" (Steinert. 2012; cf. figure 1).

Note: I guess I should mention that the test beverages were administered via an intranasal feeding tube. I honestly have no clue, why the scientists chose this method over the natural route through the mouth. After all, this reduces the real world significance of their results. If, for example the sweet taste receptors in the oral cavity (which were obviously bypassed by the intranasal feeding tube) are hard-wired to the brain, while those in the gut are not, this would not only influence the "psychological" aspect of satiety, but could also induce hormonal, i.e. physiological effects... but hey, who am I to criticize the professionals? After all I am only a stray physicist in the realms of nutrition and exercise science ;-)

The intranasal feeding tube was removed immediately after the administration of the respective test beverages. Blood was drawn at regular time intervals at 5, 10, 15, 20, 30, 45, 60, 75, 90 and 120 min and the subjects were asked to rate their hunger, satiety and fullness on a visual analogue scale.

No insulin response, no glucose response to any artificial sweetener

Before we get to the significant findings, I want to address the often touted insulinogenic effect some of the artificial sweeteners are supposed to have... let me make it short and concise, so that everyone can understand it: There was NO insulin response to ANY of the ARTIFICIAL SWEETENERS!

Figure 2: Glucose and insulin response to glucose and fructose sweetened beverages; there were NO changes in either glucose or insulin in response to the artificially sweetened beverages (adapted from Steinert. 2012)

If you scrutinize figure 2 you will notice that I did not even bother to plot the "straight" lines for either Aspartam, Acesulfam K, or Succralose. The reasons for me to include the glucose and insulin responses, at all, were that...

1. there was a minimal yet statistically non-significant increase in both blood glucose as well as insulin levels in response to the fructose sweetened beverage, and
    
2. there was a huge +/- 20µU/ml (=20%!) standard deviation for the insulin response to glucose at the 20min mark.

While the former, i.e. the fructose induced increase in both blood glucose and insulin is probably a result of gluconeogensis in the liver, the latter, i.e. the huge inter-individual variation with respect to the amount of insulin that was released to a standardized beverage, which contained 50g of glucose, goes to show you how large the discrepancies wrt "insulin tolerance / resistance" actually are, even in otherwise healthy young individuals.

Sweetness alone is not satiating - neither "hormonally", ...

Apposite to the previously established non-insulinogenic effects of the three artificial sweeteners in the study, neither Aspartame, nor Acesulfam K or Sucralose led to increases in the glucagon-like peptide-1 (GLP-1, cf. figure 3), which is involved in the so-called "incretin effect". The latter is responsible for the more pronounced insulin response to an oral vs. an intravenous glucose load and is ascribed to the presence / release of GLP and GIP in the gut.

Figure 3: Area under the curve (AUC) and maximal value (Cmax) of GLP-1, PYY and Ghrelin in response to the administration of the six test beverages; values expressed relative to water = control (data calculated based on Steinert. 2012)

In a similar vein, the administration of the artificially sweetened beverages increased neither the "satiety hormone" peptide tyrosine tyrosine (PYY) nor the "hunger hormone" ghrelin over the levels the scientists observed for the control beverage which contained plain water, relative to which the values in figure3 are expressed. Glucose and fructose, on the other hand, led to large and small increases both the area under the curve (AUC, figure 3, left) and the maximal expression (Cmax, figure 3, right) of GLP-1 and PYY, as well as corresponding decreases in ghrelin. Accordingly, Steinert et al. conclude:

We infer from these obser- vations that sweetness per se is not sufficient to stimulate the secretion of these peptides in humans. Additional chemosensory mechanisms directed towards the structural integrity of the glucose molecule (as one of the major fuels for the body) must exist including active transport systems. Finally, potential energy-sensing mechanisms or energy thresholds might exist for the secretion of GLP-1 and PYY, although it is unlikely that the release is directly related to the energetic load in a dose–response manner.

And if we were all nothing but hormonally controlled machines, I guess this would be the end of today's blogpost, but since we are not, it is probably prudent to look at the subjective hunger, satiety and fullness ratings of the study participants before we settle this case.

... nor "psychologically", and in fact, it could even make some people hungrier!

If we had to make prediction based on the hormonal data Steiner et al. collected, what would you say, which group will feel the most satiated and the least hungry? What? The glucose group? Why? Because they consumed the largest amount of calories? But what about the insulin spike? Well, I guess, it is pointless to continue this feigned dialog... so, let's just take a look at the actual results:

Figure 3: Time (in min) until hunger, satiety and fullness after ingestion of the six test beverages returned to baseline; statistical averages, left; median, right (data adapted from Steinert. 2012)

I guess, the results won't please everyone out there, after all fructose, which has as of late been deemed responsible for whatever ailment our obesity ridden society is suffering from, induced the most profound (=long lasting) satiety effect. Fructose reduced the hunger longer than any other sweetener and the subjects felt full for a longer time period after the ingestion of the fructose-sweetened beverage than after any other sample.

A brief note: Maybe I can calm the followers of Dr. Lustig down, if I remind them of the way fructose is metabolized? Remember? Fructose is largely being processed into triglycerides by the liver. Now, the latter obviously are fats and I guess nobody will challenge the satiating effects of fat, these days, right?.

With the glucose beverage taking a close second and only non-significant (you know "statistically" ;-) differences to the artificial sweeteners, Steinert et al. thusly summarize their results as follows:

The appetite profile revealed that the (energy-containing) carbohydrate sugar loads induced the longest-lasting increase in fullness ratings above baseline, which was prolonged for fructose 108·4 (SEM 6·1) min and for glucose 90·5 (SEM 11·2) min. In contrast, water (74·0 ( SEM 13·4) min) and the AS [artificial sweeteners] acesulfame K (65·6 (SEM 15·8) min), aspartame (83·1 (SEM 15·9) min) and sucralose (65·3 ( SEM 14·1) min) induced shorter augmented fullness above initial ratings. However, due to the large data variability, these differences did not reach statistical significance. Satiety and hunger ratings showed similar trends, however, with generally smaller differences. Overall, the AS increased satiety and fullness and reduced hunger ratings to an amount that was intermediate between the carbohydrate sugars and the water control.

Now, the SuppVersity would not be the place to go to read about the latest studies, if I would content myself with someone else's analysis of data that has already undergone a selection process, in the process of which the individual responses got lost. If we do yet take a look at the difference in mean (i.e. the statistical average; figure 3, left) and median (which is the median value in an ordered list; figure 3, right) time it took for the hunger, satiety and fullness ratings to return to baseline, we have - yet again - enough evidence for the presence of a huge interpersonal variability.

Figure 4: Ratio of the statistical averages and the respective median time until the hunger, satiety and fullness ratings returned to baseline after ingestion of the six test beverages.

If we take the ratio of the average to the median as an obviously very unreliable marker of this inter-personal variability (I plotted the respective values for you in figure 4). It becomes obvious that Acesulfame K, which is the sweetener most companies who pride themselves of not using Aspartame put into their products, could in fact be a wolf in sheep's clothing. While the low median satiety scores in figure 3 (right) already suggested that it must have been significantly less satiating than plain water, let alone the other sweetened beverages, for some of the subjects, at least, the alternative representation of the data as the ratio of the average to the median in figure 4 reveals how pronounced this effect actually is.

"So, tell me: What's the unsatiating truth now?"

In spite of the fact, that I do believe that the concerns about potential insulin spikes from foods / beverages which are sweetened with artificial sweeteners only is unwarranted, the large intra-individual variation of the satiety effects of the Acesulfam K should raise your awareness of your individual response to artificial sweeteners, in general, and anything that contains Acesulfam K, in particular. If you feel that respective foods make it difficult for you to stick to your diet, just don't eat / drink them! If, on the other hand, the 1l of Coke light you consume during your fast (just an example ;-) does not make you hungrier than the same amount of water and you are not worried about the fact that rats develop cancer when you feed them with amounts of Aspartame that would equal the consumption of several truckloads of diet coke per day (and that over weeks or months), don't bother and stick to what works for you...

If you do however have trouble sticking to your diet, cannot lose weight or have existing blood sugar issues, don't use the results of this study as an excuse for your unwillingness to (at least try to) go without your beloved diet Coke for at least a month to see whether or not the latter is not part of the underlying physiological (and psychological) causes of your misery!