Sucralose, Carcinogen or Sweet Relief? Part III: DNA Breaks + Drug & Hormone Interactions | Sucralose, White Death?

Fearmongering fake, or true biohazard. This is the life-or-death- question this last installment of the sucralose trilogy will have to answer.

It's time for the third and last installment of the SuppVersity sucralose review trilogy. Looking back at the list of issues in the first installment of this series, it appears as if the one thing that was still left to discuss are the mutagenic, pro-carcinogenic and tissue damaging effects of sucralose and its potentially endocrine disrupting metabolic / thermic byproducts. It goes without saying that the previously discussed and largely rebutted effects on blood glucose management, body weight gain and even the balance of your gut microbiome would be hardly significant, if today's analysis confirms that the use of Splenda© & Co was linked to direct mutagenic, carcinogenic or general toxic effects.

Put your hazard suits on, folks!

It's obvious that I got carried away by my imagination, when I wrote this subheading, but if the same wasn't true for the author of the repeatedly cited press release, many of us are about to suffer the consequences of the potential unsafety of the hitherto unknown sucralose metabolites in our guts, pretty soon.

This is part III 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?

In fact, you don't even have to go searching the databases for hours to find evidence that would support the claim that some of these metabolits that supposedly arise, while sucralose passes through our digestive tract (hitherto we have only highly debated evidence from rodent studies that there are any metabolits at all, by the way) could be pretty nasty bastards. In their 2008 paper, Abou-Donia et al. (2008), whose rodent study is still the only one to support the claim that the consumption of sucralose (HED 42mg/day or more over 3 months) will lead to a "reduction in the number and balance of beneficial bacteria in the gastrointestinal tract" (quote from press release; learn more), cite a study, for example, in which Sasaki et al. (2002) confirmed that sucralose exerts genotoxic effects. This does not mean that the DNA breaks / changes the researchers observed lead to the development of cancer, but the in vivo comet essay the researchers used, is generally considered a very reliable indicator of the genotoxicity of the tested compound in a particular body part (Brendler-Schwaab. 2005).

Believe it or not, but aspartame is one out of three sweeteners Sasaki et al. tested that are not genotoxic | more about aspartame

It's not just sucralose: I guess it's only fair, if I point out that Sasaki's study showed that sodium cyclamate, saccharin, sodium saccharin, likewise artificial sweeteners, caused DNA damage to various organs, as well. The dosage that was necessary to trigger these effects was yet unrealistically high: 2000mg/kg for sucralose and sodium cyclamate, 1000mg/kg for saccharin and sodium saccharin - for humans that would be 26g and 13g of pure sweetener every day! Ah, before I forget to mention that: Acesulfame-K, aspartame and stevia were also tested and found to be benign.

The absence of direct evidence of real-world negative effects, the insignificance of the long-demonstrated weak muatgenicity in the mouse lymphoma mutation assay, both, the WHO and the FDA have confirm ed in independent reports (WHO, 1989; U.S. FDA, 1998), is thus probably the reason the compound has still been approved as a food additive in 1991 - initially in Canada and Australia, then in the rest of the federally regulated world (Canada & Australia, 1993; New Zealand, 1996; US, 1998; EU, 2004). Today, the sales in sucralose alone account for 27.9% of the $1.146 billion global highpotency sweetener market (Leatherhead Food Research, 2011). No wonder, after all, sucralose is utilized in thousands of food, beverage, and pharmaceutical products in North America, Latin America, Europe, the Middle East, and the Asia-Pacific region (Schiffman. 2013).

So what does the (almost) "real-world" evidence say?

It's unquestionably debatable whether this was a good idea or a tragic mistake, but without corresponding "real-world" assays from longer-term rodent studies, the damage that occurs in response to the DNA breaks that have been observed in in-vitro studies may well be so small that the DNA repair machinery that operates in our bodies 24/7 can fix it easily. In this case, our coroners would probably find a similar increase in non-neoplastic findings (=non-cancerous, often minimal tissue growth, where it does not belong), as they were reported by Mann et al. (see list below the red box) in a combined chronic toxicity/carcinogenicity study of sucralose in Sprague–Dawley rats and a carcinogenicity study of sucralose in mice (Mann. 2000a, 2000b). Direct evidence for the development of cancer and/or the potential epigenetic changes is yet, as Schiffman & Rother have to concede, simply not available.

Don't bake your arginine-containing anti-diabetes cookies with sucralose

Sucralose + heat - a potentially hazardous combination: Contrary to often cited claims by Barnd & Jackson (1990) or Miller, et al. (1999), there is more recent evidence that suggest sucralose is not heat stable (Jahn & Yaylayan. 2010; Schiffman. 2012; Schiffman and Abou-Donia. 2012). According to these more recent papers ther are a whole host of thermal degradation products in cookies. Whether these byproducts pose a health risk is however not know for most of them. Only the chloropropanols that form when the reaction occurs in the presence of gylcerol (Rahn. 2010), are well-known genotoxic, carcinogenic, and tumorigenic compounds (Biles. 1983; Cho. 2008; Tritscher. 2004; SCF. 2001; WHO, 2002).

Quite the contrary, if you look at the literature as a whole, there is plenty of data that would support the decision of the Australian, US and EU to approve sucralose as a food additive, e.g.:

• No toxic effects even with 3% of total dietary intake in Sprague–Dawley rats; all non-neoplastic findings that occurred were of no toxicological significance and are part of the regular aging process of this strain of rats (Mann. 2000a)
• No positive results in in vivo chromosome aberration test in rats and two separate micronucleus tests in mice with doses of up to 2,000mg/kg for 5 days (Brusick. 2010)
• No effect on organ and general development, when fed to pregnant rats and rabbits in HEDs of up to 26g (rats) and 9g, respectively (Kille. 2000)

I don't want to discard the existing evidence Schiffman et al. cite in favor of their "sucralose is the devil" hypothesis, but results of the vast majority of these studies can hardly be considered relevant with respect to the question whether the comparatively small amount of sucralose that may be present in your foods, supplements or whatever you may be sweetening with sucralose is going to harm you or your DNA:

• The death of one out of 10 mice in a study by Finn and Lord that occured in response to the ingestion of the human equivalent of 1g/day of sucralse can hardly be considered conclusive evidence in favor of the "sucralose is poison hypothesis (Finn. 2000).
• The effects Mann et al. describe in a study where 3%-5% of the chow was pure sucralose is devoid of any relevance for our question (Mann. 2000a; Goldsmith. 2000). The same goes for the numerous studies where the lab animals received sucralose in amounts of >500mg/kg body weight (e.g. Finn. 2000; Kille. 2000). For a human being that would be more than 6.5g/day - and that's only if the lab animal was a rodent. For larger animals it would be even more.

Now, you can always argue that the negative studies just weren't long enough to elicit similar effects at lower dosages or, if you prefer that, work yourself up into a lather about the fact that (conspiracy-)theoretical, all the benficial studies could have been openly funded or secretly supported by people / companies with a vested monetary interest in positive safety data. In fact, the existence of a review of the safety of Splenda the lead author of which works for McNeil Nutritionals, LLC, who market Splenda for Johnson & Johnson (Grotz. 2009), or a "expert panel" review you will read about later in this article actually support that this may be the case, the same can unfortunately be said of almost every food additive - including stevia, by the way.

Let's get on to potential endocrine effects

In view of the fact that it is pointless to speculate about the validity of the data from the positive studies in the foregoing list, I want to turn to another, the final and as we are going to see not necessarily more "productive" topic of this third and last installment of my sucralose review trilogy: The endocrine effects.

Due to sucralose not just vegans (more) may be at risk of low B12

Sucralose + Vitamin B12: This is not exactly an endocrine effect, but in the end it could become one, when large enough quantities of cobalamine, aka "vitamin B12" react with sucralose in the liver, vitamin B12 deficiency could be a potential side effect. Aside from the in-vitro evidence Motwani et al. present in their 2011 paper in Food and Chemical Toxicology, there is yet no evidence that would suggest that this is actually happening, let alone to an extent that would leave you B12 deficient like a vegan ;-)

In that, I am using the word "endocrine" in its most general sense, which denotes anything that is produced or directly triggered by an organ and has influence on other organs / tissues or the whole body. The sucralose induced changes in the expression of enzymes from the P450 cytochrome cascade that are responsible for the interconversion / metabolism of all sorts of molecules, including hormones and medications would be one example for such effects.

To this ends we have to go back to the previously cited study by Abou-Donia et al. (2008), of which I did not tell you in the last installment of this series that it has (obviously) been under heavy attack by toxicology experts who do not necessarily doubt the validity of the study data Abou-Donia et al. present, but claim that their interpretation was irresponsible.

A brief note on the criticism of the Abou-Donia study: As you'd expect it's no coincidence that  the corresponding paper carries the phrase "expert panel" in it's title. It was after all written and published on request of McNeil Nutritionals, a marketer of retail products that contain the non-nutritive sweetener, sucralose, who paid the "panel of experts" to do a "independent and rigorous review of the 2008 study by Abou-Donia et al." (Brusick. 2009)

I won't discuss all the objections the "expert panel" proffers. Not because I think that their general objections against hasty conclusions with respect to unwanted negative health effects weren't justified, but rather because I want to get back to Schiffner's & Rother's review, where you'll find the following comment about the CYP-modifiying effects Abou-Donia et al. observed and Brusick et al.'s criticism:

"The results in Table 1 [identical copy on the right] indicate that the magnitude of elevation for both CYP3A and CYP2D expression increased in a linear, dose-dependent manner as the dosage of sucralose increased from 3.3 to 5.5 to 11 mg/kg/d.

This finding of significant and parallel increases in expression of two different CYP enzymes does not support the claim made by Brusick et al. (2009) that increases in CYP from sucralose ingestion were only normal biological variations."(Schiffman. 2013)

In other words: Coincidental increases in CYP activity would not 'coincidentally' be dose-dependent, as well. If we also remind ourselves of the fact that the human equivalent doses of said 3.3, 5.5 and 11mg/kg sucralose would be (only) 43mg, 71mg and 143mg it is self-evident that we cannot simply ignore the acute and persistent increases in intestinal P-gp, CYP3A, and CYP2D (in humans this is CYP2D6; cf. Laurenzana. 1995) in the jejunum and ileum of About-Donia's hairy subjects.

The obvious question, now, is: Does this even matter?

I mean, changes in the expression of some cryptic enzymes in the gut - who cares? After taking a look a the list of substrates that are enzymatically processed by CYP3A, alone, even the small 44% increase that occured in response to the rodent equivalent of 43mg appears relevant.

Figure 1: Important supplement drug interactions | learn more

On this list are some immunosuppressants, many chemotherapeutics including tamoxifen and anastrazole, which are popular with athletes who use PEDs. There are SSRIs, like citalopram, norfluoxetine, sertraline, other anti-depressants like mirtazapine, or buspirone, the whole list of anti-psychotics, opoids and many analgesics, benzodiazepines, statins like atorvastatin, lovostatin and simvastatin, calcium channel blockers, anti-histamins and even viagra and Co (PDE-5 inhibitors). And even our good old caffeine is on the list of CYP3A4 substrates, on which you'll also find estrogen, testosterone, progesterone, finasteride and torimifene. It's thus not just that your chemotherapy may fail, your depression may return, you may run havoc, hurt all over, increase your cholesterol levels, get high blood pressure, have life-threatening allergic reactions, because your meds are not working properly no (!), even worse caffeine may stop working ;-)

Unlike the increase in CYP2D6 that simply adds to the sucralose ↔ drug interactions, the corresponding increase in P-gp activity and thus the transport of chemicals from gut cells (enterocytes), back into the intestinal lumen could affect the absorption of an even wider range of both wanted and unwanted chemicals / xenobiotics with a hydrophobic and amphiphilic structure.

The net result of the increases in CYP and pGP activity is thus a significant decrease in the concentration of a xenobiotic compound on its way from the gastro-intestinal tract to the liver. Whether this amplified "first pass effect" would actually have physiologically relevant consequences in human beings is yet something we cannot tell without somebody paying for the costly research.

To complicate things, we must not ignore the possibility that "[...t]he rise in CYP expression reported by Abou-Donia et al. (2008) may result from 'autoinduction', by which sucralose enhances it own metabolism." It would thus be a second St. John’s wort, which will also increase its own metabolism by the activation of P-gp and CYP. For Hypericum perforatum extracts, which are often used as mild anti-depressants, we do already know that it affects the metabolism of an endless list of drugs and herbal supplements, and can reduce the levels of 5-alpha reduced androgens like DHT (estrogen and testosterone appear not to be influenced, though; cf. Donovan. 2005).

So what about toxicity and endocrine disruption? If we discard the potential interference with drugs and consequent "St. John's Wort"-esque side effects, I would say that the dosages that are necessary to actively induce more or less insignificant DNA damage in rodent studies, as well as the absence of any evidence of toxic effects from one of the historical single-dose or short-term sucralose studies in humans (Mezitis. 1996; Baird. 2000) make it appear very improbable that the habitual, but reasonable use of sucralose could have toxic or carcinogenic effects.

Remember the Science Round-Up from March? The safety of  stevia, is not beyond doubt either | more

The "benefit of the doubt" is yet no acquittal, it is only my assessment of the reasoning Schiffman & Rother provide in their paper, the relevant parts of which are all based on mere hypothesis, e.g. the "IBD ↔ sucralose"-hypothesis by Qin et al. (2011, 2012), or the "there may arise different more toxic sucralose metabolites in the human vs. rat digestion tract"-hypothesis by Goldsmith (2000) and Mann (2000a) and/or rely on data from the highly disputed Abou-Donia study, the most significant result of which are (imho) still the pronounced changes in the gut microbiome (read more in the last episode of this three part series).

At the moment, it does yet still look as if you were on the "safer" side if you prefer stevia sweetened products, although I honestly have my doubts that we wouldn't observe similar effects in mice, rats and all sorts lab critters, if 5%+ of their diet was pure stevia. The dosage makes the poison, you better remember that.

References:

• Abou-Donia, M. B., El-Masry, E. M., Abdel-Rahman, A. A., McLendon, R. E., & Schiffman, S. S. (2008). Splenda alters gut microflora and increases intestinal p-glycoprotein and cytochrome p-450 in male rats. Journal of Toxicology and Environmental Health, Part A, 71(21), 1415-1429.
• Brendler-Schwaab, S., Hartmann, A., Pfuhler, S., & Speit, G. (2005). The in vivo comet assay: use and status in genotoxicity testing. Mutagenesis, 20(4), 245-254.
• Brusick, D., Grotz, V. L., Slesinski, R., Kruger, C. L., & Hayes, A. W. (2010). The absence of genotoxicity of sucralose. Food and Chemical Toxicology, 48(11), 3067-3072. 
• Brusick, D., Borzelleca, J. F., Gallo, M., Williams, G., Kille, J., Wallace Hayes, A., ... & Burks, W. (2009). Expert panel report on a study of Splenda in male rats. Regulatory Toxicology and Pharmacology, 55(1), 6-12.
• Biles, R. W., & Piper, C. E. (1983). Mutagenicity of chloropropanol in a genetic screening battery. Fundamental and Applied Toxicology, 3(1), 27-33.
• Cho, W. S., Han, B. S., Lee, H., Kim, C., Nam, K. T., Park, K., ... & Jang, D. D. (2008). Subchronic toxicity study of 3-monochloropropane-1, 2-diol administered by drinking water to B6C3F1 mice. Food and Chemical Toxicology, 46(5), 1666-1673.
• Finn, J. P., & Lord, G. H. (2000). Neurotoxicity studies on sucralose and its hydrolysis products with special reference to histopathologic and ultrastructural changes. Food and chemical toxicology, 38, 7-17.
• Goldsmith, L. A. (2000). Acute and subchronic toxicity of sucralose. Food and chemical toxicology, 38, 53-69.
• Grotz, V. L., & Munro, I. C. (2009). An overview of the safety of sucralose. Regulatory toxicology and pharmacology, 55(1), 1-5.
• Motwani, H. V., Qiu, S., Golding, B. T., Kylin, H., & Törnqvist, M. (2011). Cob (I) alamin reacts with sucralose to afford an alkylcobalamin: Relevance to in vivo cobalamin and sucralose interaction. Food and Chemical Toxicology, 49(4), 750-757.
• Kille, J. W., Tesh, J. M., McAnulty, P. A., Ross, F. W., Willoughby, C. R., Bailey, G. P., ... & Tesh, S. A. (2000). Sucralose: assessment of teratogenic potential in the rat and the rabbit. Food and chemical toxicology, 38, 43-52.
• Laurenzana, E. M., Sorrels, S. L., & Owens, S. M. (1995). Antipeptide antibodies targeted against specific regions of rat CYP2D1 and human CYP2D6. Drug metabolism and disposition, 23(2), 271-278.
• Leatherhead Food Research. (2011). The global food additives market, 5th ed., September.
  Leatherhead, Surrey, UK: Leatherhead.
• Mann, S. W., Yuschak, M. M., Amyes, S. J. G., Aughton, P., & Finn, J. P. (2000a). A combined chronic toxicity/carcinogenicity study of sucralose in Sprague–Dawley rats. Food and chemical toxicology, 38, 71-89.
• Mann, S. W., Yuschak, M. M., Amyes, S. J. G., Aughton, P., & Finn, J. P. (2000b). A carcinogenicity study of sucralose in the CD-1 mouse. Food and chemical toxicology, 38, 91-97.
• Rahn, A., & Yaylayan, V. A. (2010). Thermal degradation of sucralose and its potential in generating chloropropanols in the presence of glycerol. Food Chemistry, 118(1), 56-61.
• Sasaki, Y. F., Kawaguchi, S., Kamaya, A., Ohshita, M., Kabasawa, K., Iwama, K., ... & Tsuda, S. (2002). The comet assay with 8 mouse organs: results with 39 currently used food additives. Mutation Research/Genetic Toxicology and Environmental Mutagenesis, 519(1), 103-119. 
• Scientific Committee on Food. (2001). Opinion of the Scientific Committee on Food
  on 3-monochloro-propane-1,2-diol (3-MCPD). European Commission, Health and
  Consumer Protection Directorate-General. http://ec.europa.eu/food/fs/sc/scf/out91_en.
  pdf (accessed December 14, 2013)
• Tritscher, A. M. (2004). Human health risk assessment of processing-related compounds in food. Toxicology letters, 149(1), 177-186.
• World Health Organization. (2002). 3-Chloro-1,2-propanediol. In Safety evaluation of certain food additives and contaminants. WHO Food Additives Series 48. http:// www.inchem.org/documents/jecfa/jecmono/ v48je18.htm (accessed December 14, 2013).

Sucralose, Hazardous or Innocent? Part II: Appetite, Gut Health & Food Reward | Sucralose, Gluttony & Adiposity?

Plain mineral water is still the best thing to quench your thirst.

Today we are going to continue our thorough, educated reading of the recently published overview over the biological issues with sucrolase, a "popular" artificial sweetener most of you will probably know by its brand name Splenda. The focus of part I of this series was on the potential pro-diabetic effects of this agent that belongs to a class of molecules that has originally been hailed as a solution to the diabetes problem (it goes without saying that I am talking about artificial sweeteners here, right?). In a way we are thus only continuing the discussion, when we are trying to verify Schiffman's & Rother's argument that the consumption of sucralose is associated with an increase in obesity risk... or, put more simply that using sucralose is going to make you fat, not lean.

The good old "energy in" vs. "energy out" argument

As SuppVersity readers you are well aware that the oversimplified concept of an "energy balance" is fundamentally flawed. My recent post "Anorexia study suggests: Your body can easily reduce its resting metabolic rate by 10%" in the SuppVersity Facebook News is only one out of thousands of scientific papers you could quote to point out that replacing 420kcal of energy from pure sugar, i.e. three cans of regular coke, with its diet variety is not going to produce a net weight, let alone fat loss of 420g per week (suggested read: "Busting the 3,500kcal = 1lbs Weight Loss Myth!" | learn more).

This is part II 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?

Thus being "in the know", you can only shake your head, when you read how Schiffman and Rother (ab-)use a recent study by Ruyter et al. (2012) to support the non-significant, not sufficiently differentiated data from epidemiological studies which inform us that obese people are more likely to consume artificial sweetened products than lean ones, to subliminally imply that artificial sweeteners would not help, in some cases even hinder weight loss.

"In an 18-mo trial with children, participants were randomly assigned to receive an 8-oz can per day of either a noncalorically sweetened or a sugarsweetened beverage that provided 104 kcal (de Ruyter et al., 2012). [...] The calorie consumption from these beverages was 46,627 kcal greater for children in the sugar-sweetened group than in the sucralose-sweetened group (5.8 × 77.3 × 104). In spite of this highly significant difference in calories consumed from the beverages, the total weight gain over this 18-mo study was only 1 kg greater for children in the sugar-sweetened group compared to sucralose group. No explanation was provided to account for the small difference in weight gain given the large difference in caloric consumption from the beverages." (Schiffman. 2013)

Despite the fact that Schiffman & Rother acknowledge that the scientists would not have been able to detect, if the children who consumed the sugar-sweetened beverages compensated by reducing their food intake, the reviewers fail to point out that neither this, nor the second "evidence" they cite, a 2-year study by Ebbeling et al. (2012), where Schiffman & Rother simply ignore the fact that the mere provision of diet sodas to the families of the adolescent subjects did reduce the weight gain in the active intervention period (1st year, see Figure 1, below), would confirm a negative real-world effect on body weight.

Figure 1: Change in body fat percentage (vs. basleline) of adolescents during the intervention & follow up period in the Ebbeling study (2012), of which the reviewers only cite the results of the follow up.

Let's be honest: If you actually take a look at the results from the Ebbeling study (Figure 1), you will have to concede that this study refutes the claim that artificial sweeteners make you fat. During the active treatment period, in the course of which the adolescent participants were...

• 

  "What Really Happens, When Nutrition Science Meets Real Life" | more

  ... supplied with noncaloric beverages (e.g., bottled water and “diet” beverages for the whole family) every 2 weeks, getting monthly motivational telephone calls with parents (30 minutes per call), 
• ... having three check-in visits with participants (20 minutes per visit), and 
• ... receiving written intervention messages with instructions to drink the delivered beverages and not to buy or drink sugar-sweetened beverages, were mailed to participants

...they do exactly what we originally expected them to do: They ameliorate the body fat gain in the adolescent subjects. In other words: As long as respective products are available, and dietary adherence is encourages, replacing regular sugar sweetened with artificial sweetened or unsweetened beverages can have a significant ameliorative effect on the body fat gains of adolescents - irrespective of the fact that they were obviously free to compensate with chocolate, cookies, etc..

Contemporary evidence from RCTs suggest either no, or beneficial effects

If you follow Schiffman's and Rother's lead and discard potential differences between sucrose and other sweeteners, acknowledge the fact that the results from previous rodent experiments have repeatedly failed to translate to human beings and take into account that this data is "inconsistent and conflicting" (Schiffman. 2013), anyways, you will be hard pressed to find arguments to support the claim that artificial sweeteners could hinder weight loss.

"No-Carb Foods, Artificial Sweeteners & The Cravings" | more

Potential mechanisms for the obesogenic effects: In a very detailed review Mattes & Popkin list a whole host of hypothesis ranging from the disproven stimulation of insulin and differences in the GLP-1 response, over osmotic effects and increase food palatability, up to the "Zero sugar, great, I'll have 10 instead of one of those cookies!" effect and the development of an extremely sweet tooth. What's important, though, is that none of this mechanisms is "supported by the available evidence, although some warrant further consideration" (Mattes. 2009).

In fact, the vast majority of RCTs clearly supports the assumption that non-nutritive sweeteners (NNS), artificial or not, promote weight loss and blunt weight (re-)gain (De la Hunty. 2006; Bellisle. 2007). The argument that these effects do satisfy the calories in vs. calories out hypothesis is pathetic, to say the least. Even a 100% controlled diet won't comply to an equation that is about as accurate as "1+2=343". We can thus register that:

1. There is ample evidence to support the beneficial effects of artificial sweeteners (including sucralose) as a tool during controlled dietary interventions.
2. There is insufficient evidence to support the claim that their regular consumption has a negative effect on body weight.

With respect to (2) we would even have to say that the limited amount of useful* evidence we have would rather suggest beneficial than detrimental effects (*a 'useful' study is not a study that tells me that obese individuals are more likely to consume artificially sweetened products than lean ones like the often cited epidemiological data). This is particularly true, for controlled interventions where sugar-sweetened beverages were replaced by their artificially sweetened counterparts.

The great unknown: Hunger, appetite and food reward

If data on the real-world effects of sucralose consumption on body weight gain is "scarce", consistent, experimentally verified hypotheses that would explain the potential underlying mechanism are quasi non-existent... or, I should clarify: They are still in their infancy. Against that background it's quite astonishing that more and more people appear to take it for granted that the consumption of artificially sweetened foods will mess with both, (a) your ability to control your energy intake and (b) the hedonistic response you derive from foods.

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

It goes without saying that there is no sucralose-specifc data out there, but the decrease in hypothalamic sweet taste receptor density I mentioned in the first installment of this series is something I'd expect to see in response to all artificial sweeteners that make it across the blood brain barrier (Note: Even Schiffman & Rother acknowledge that we do not know if they even do that!) - probably "sweetness" dependent,  by the way.  This would imply that sucralose would be the worst, cyclamate the least offender among the common artificial sweeteners in Table 1. With a sweetness that's 300x higher than that of sucrose, stevia would end up being the "(un?)happy medium".

Despite the fact that Schiffman & Rother don't really address this issue in their paper, I still want want to address the practical and thus relevant aspect of the various proposed theories for potential sweetener-induced increases in energy consumption.

Figure 2: Mean effective change in energy intake (%) in RCTs investigating the degree of energy compensation in response to the provision of artificial sweetened products (De la Hunty. 2006)

As the data from De La Hunty's 2006 meta-analysis of 32 study outcomes in Figure 2 clearly demonstrates, there is a statistically highly significant (p < 0.001) trend towards reduced energy consumption in the RCT [randomized controlled trial]. In that, the degree of compensation for the sudden energy reduction due to ingestion of calorically less dense, since artificially sweetened product ranged from statistically non-significant 18% to statistically highly significant 86% in trials such as Porikos et al. (1982), where 6 men lost and gained 0.8kg of body weight within 2x12 days in a metabolic ward on artificially sweetened and sucrose sweetened ad-libitum diets, respectively.

Non-nutritive sweetener (NNS) intake 1965-2004 (Mattes. 2009)

So, sweeteners can't ever make you hungry? I would not necessary subscribe to this idea. While the consumption of artificial sweetened foods as part of your regular diet, e.g. diet coke with your dinner, does not seem to be a problem, Mattes & Popkin (2009) rightly point out that "non-energy-yielding products may heighten appetite", when they are not "ingested in conjunction with other energy sources". So, if you are guzzling diet coke all day, this may very well trigger binge eating. With an ever increasing consumption of sweeteners from partially / totally artificially sweetened beverages (see table to the left), this could thus well be part of our obesity problem.

Just like the previously discussed (relatively short term) effects on insulin, GLP-1 and co, the #2 on the list of most frequently heard objections against the use of artificial sweeteners, i.e. dietary overcompensation, does thus appear to have little basis in fact. What we do not know, though, is whether the results will be identical for all types of sweeteners, or whether sucralose may be the toxic (this aspect will be covered in the next installment) or gut microbiome disrupting exception to the rule.

Sucralose induces changes in the gut microbiome

The last issue I want to address in this second installment of the "Sucralose, Hazardous or Innocent Trilogy" will thus revolve around the question, whether a modulatory effect of sucralose on the microbial composition of your gut could induce potential negative long-term effects that would not show up in the hitherto discussed RCTs.

Under the headline "Effect of Sucralose on the Number and Relative Proportions of Different Intestinal Bacterial Types", Schiffman & Rother argue that it has long been known that bacteria from the oral cavity and soil cannot use sucralose as a growth substrate. If the same was true for the bacteria in our guts the replacement of regular sugar with sucralose would thus starve our (beneficial) subtenants.

Table 2: Differences (%) in bacterial counts in feces of rodents on diets containing what in human terms would be ~14mg, 43mg, 71mg and 156mg of sucralose per day after 12 weeks treatment and 12 weeks into "recovery" (Abou-Donia. 2008)

Based on the fecal bacterial count of rodents on diets that would be equivalent to 14mg, 43mg, 71mg and 156mg of sucralose per day in human beings (see Table 2), Schiffman & Rother argue that chronic (12-week) ingestion of relatively low amounts of sucralose (a single can of Diet Crush Cream Soda, for example, has 42mg of sucralose) lead to highly significant reductions in the numbers of total anaerobes, bifidobacteria, lactobacilli, Bacteroides, clostridia, and total aerobic bacteria.

In view of the fact that Abou-Donia et al. (2008) observed the most significant losses in bifido- and lactobacillus strains, i.e. those strains that have repeatedly been implicated as the driving forces of the beneficial health effects of probiotic supplementation, this and not the previously discussed pro-diabesity effects should be the point where people start to freak out.

Table 4: Other sweeteners are preferred food for certain bacteria and may also alter the gut microbiome (Payne. 2012).

This is particularly true if you take into account that at least part of the beneficial effects of lactobacilli may be related to their ability to keep the number of enterobacteria, a large family of Gram-negative bacteria that includes both harmless symbionts, as well as a whole host of familiar pathogens, such as Salmonella, Escherichia coli, Yersinia pestis, Klebsiella and Shigella, Proteus, Enterobacter, Serratia, and Citrobacter in check (Liévin-Le Moal. 2006) - exactly those bacteria, which produce the nasty lipo polysaccharides (LPS) that have been associated with inflammation and its downstream metabolic effects, such as obesity, diabetes, heart disease, gastrointestinal cancer etc. and, as the data in Table 2 tells you. Now, unfortunately, the these villains are all part only type of bacteria that was not significantly decimated by the sucralose challenge.

As Schiffman et al. point out these reductions are not, as Brusick et al. (2009) suggest simply a result of "normal variation". In fact, the probability to see a similar random reduction in bifidobacterial count occur "naturally"within 12 weeks would be 1/5000. It is thus more than just unlikely that the71.9%, 76%, and 77.7% reductions in bifidobacteria counts Abou-Donia et al. observed at dosages of 3.3, 5.5, and 11 mg/kg/d were coincidental.

Prebiotics, anyone? In view of the alleged neg. effects on your gut microbiome, you may feel inclined to increase your prebiotic intake. If that's the case, this top 10 list of food items with prebiotic fiber contents of up to 65% of total weight may help:

1. Chicory root - 65%
2. Jerusalem artichoke - 32%
3. Dandelion greens - 24%
4. Garlic - 18%
5. Leek - 12%
6. Onion - 9% 
7. Cooked Onion - 5% 
8. Asparagus - 5% 
9. Wheat bran - 5% 
10. Banana - 1% 

Remember: These are the "richest" not necessary the "best" sources ;-)

If there is reason to be concerned it's about your gut health and its downstream metabolic effects: In view of the important role of bacteroides for the health of the intestinal eco-system (Lee. 2013) and their persistent reduction even after the 12-week recovery period, the selective antibiotic activity of sucralose is as of now the by far most disconcerting negative health effect discussed in this series.

If the changes Abou-Donia et al. observed in their rodent studies were to be confirmed in human studies, where the subjects consumed a balanced whole foods diet with a high prebiotic content. The profound changes the researchers from the Duke University Medical Center report in their paper from September 2008 would be reason enough to revise my previous conclusions about a potential contribution of sucrose to the diabesity (=obesity + diabetes) epidemic.

In fact, a revision of the potential long(er) term downstream effects of sucralose on your metabolic health could be all the more indicated, if it turns out that the alleged toxic and endocrine-disrupting effects I will discuss in the next installment of this series turn out to be substantiated, as well.

Reference:

• Abou-Donia, M. B., El-Masry, E. M., Abdel-Rahman, A. A., McLendon, R. E., & Schiffman, S. S. (2008). Splenda alters gut microflora and increases intestinal p-glycoprotein and cytochrome p-450 in male rats. Journal of Toxicology and Environmental Health, Part A, 71(21), 1415-1429.
• Bellisle, F., & Drewnowski, A. (2007). Intense sweeteners, energy intake and the control of body weight. European Journal of Clinical Nutrition, 61(6), 691-700.
• De la Hunty, A., Gibson, S., & Ashwell, M. (2006). A review of the effectiveness of aspartame in helping with weight control. Nutrition Bulletin, 31(2), 115-128.
• de Ruyter, J. C., Olthof, M. R., Seidell, J. C., & Katan, M. B. (2012). A trial of sugar-free or sugar-sweetened beverages and body weight in children. New England Journal of Medicine, 367(15), 1397-1406.
• Ebbeling, C. B., Feldman, H. A., Chomitz, V. R., Antonelli, T. A., Gortmaker, S. L., Osganian, S. K., & Ludwig, D. S. (2012). A randomized trial of sugar-sweetened beverages and adolescent body weight. New England Journal of Medicine, 367(15), 1407-1416.
• Liévin-Le Moal, V., & Servin, A. L. (2006). The front line of enteric host defense against unwelcome intrusion of harmful microorganisms: mucins, antimicrobial peptides, and microbiota. Clinical Microbiology Reviews, 19(2), 315-337.
• Mattes, R. D. (1996). Dietary compensation by humans for supplemental energy provided as ethanol or carbohydrate in fluids. Physiology & Behavior, 59(1), 179-187.
• Mattes, R. D., & Popkin, B. M. (2009). Nonnutritive sweetener consumption in humans: effects on appetite and food intake and their putative mechanisms. The American journal of clinical nutrition, 89(1), 1-14.
• Payne, A. N., Chassard, C., & Lacroix, C. (2012). 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), 799-809.
• Porikos, K. P., Hesser, M. F., & Van Itallie, T. B. (1982). Caloric regulation in normal-weight men maintained on a palatable diet of concentional foods. Physiology & behavior, 29(2), 293-300.
• 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. 

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.

Sucralose is for Diabetics Not, Scientists say. But How Significant is the Cholesterol Increase They Observed?

This way of consuming Splenda is quite certainly going to increase your cholesterol levels ;-)

I guess, all of you will still remember the show Carl and I did on the "Pro-Insulinogenic Effects of Artificial Sweeteners" (read more), right? The one where I tried to point out that even if there was a meager change in the insulin response, this would only be a problem if there was any truth to  narrow-minded condemnation of insulin as the deadly obesity hormone, so that, in the end, the whole hoopla turned out to be way less daunting than some scare-mongers would have it.

Yet while something deep inside of me is telling me that the latter is probably going to be the same with the recently published study that's at the focus of today's SuppVersity article, cannot refute that the data from that very rodent study that was published in the Journal of Nutrition Sciences does clearly suggest that...

...sucralose increases cholesterols!

That certainly doesn't sound so scary to you, as it does to someone who still adheres to the "cholesterol is the root cause of all evil" paradigm, yet still. The fact that the administration of  11 mg/kg body weight of SPLENDA® over the course of 6 weeks to "intensifie[d the already existing] hypercholesterolemia in STZ-induced diabetic rats" (Saada. 2013) does sound as if there must be something to the rumors about sucralose being one of the main ingredients of devil's excrements.

Would having your coffee with Splenda instead of sugar make this cookie even more hazardous to your glucose levels and what about your waistline? Read more about the effects of artificial sweeteners on glucose-management, insulin and obesity in a previous article.

Now 130-150mg of sucralose per day is unquestionably a whoppy dose of artificial sweeteners. After all, this stuff is approximately 600x sweeter than sugar. Sounds like a total overkill, but if you do the math, i.e. 150mg x 600 = 90,000 mg, you will realize that this is not more than the non-caloric sweetness equivalent of ~1.5 Snickers bars. And if the figures a Scivation rep mentions in a post on the most popular bodybuilding website on the planet are correct this would be exactly 10 servings of their highly popular BCAA formula. Considering the fact that for most people Xtend is probably not the only dietary source of sucralose in the diet it is thus not a totally unrealistic dose (especially for those diabetic or non-diabetic sugar addicts, who are using splenda as a means to sweeten their tea, coffee and whetever else, as well).

Good you've made it past the introduction

That being said the message that sucralose "intensifie[d the already existing] hypercholesterolemia in STZ-induced diabetic rats" (Saada. 2013) appears to be even more scary.

Fortunately (or unfortunately for the "sweeteners are devil's excrements"-faction out there), this is not your average "Pubmed-Warrior blog", where the authors read a headline copy and paste the conclusion of the abstract and try to sell it as "science news" and I do not leave you hanging with the inappropriately overgeneralizing conclusion of the author's that

"[...] diabetic people consuming high amount of sucralose must check their lipid profile to avoid diabetic complications" (Saada. 2013)

Now, it is obviously right that diabetics should "check their lipid profile" on a regular basis, but if you look at the actual study outcomes, it is hard to argue that this would be particularly important for those of them who use SPLENDA® on a regular basis.

Figure 1: Changes in blood glucose, insulin, triglyceride and total (TC), HDL, and LDL cholesterol, as well as the TC/HDL levels after 6 weeks on 150mg/day sucralose (Saada. 2013)

After all, the "dangerous" increase in cholesterol the scientists observed in their lab animals (remember: we are not even 100% sure the same is going to happen in human beings) is not just accompanied by highly desirable desirable reduction in glucose (-22%) and triglycerides (-22%), it also leaves the CVD-relevant ratio of total to HDL cholesterol literally unchanged (+2%, n.s.).

Moreover, if you look at the way statins help managing cholesterol, but increase diabetes risk, you could even speculate that there is a yin and yang connecting the two metabolic pathways, where a lower strain on the one side will precipitate a higher strain on the other. Within this paradigm, the increase in cholesterol, which is by the way something many people who are "going paleo" will see, as well, could be a totally normal part of a "balancing" process that has nothing to do with the pathological overprodcution (always remember this is not about eating too much cholesterol) of highly oxidizable small and very small density lipoproteins people fear like the plague.

---

In addition to reductions in blood glucose and triglyceride compared to cornflakes & co, the regular consumption of whole eggs increases HDL's ability to carry lipids out of the macrophages. If these accumulate, they will turn the macrophage into pro-atherogenic foam cells (learn more).

Bottom line: At least in my humble opinion, the results of this study don't imply that diabetics should stay away from sucralose. In the end, the benefits of lower glucose & triglyceride levels will outweigh the "downsides". This is all the more true, in view of the fact that we (a) the total-cholesterol-to-HDL-ratio remained essentially the same and (b) don't have data on the changes in lipoprotein particle profile. After all, improved glycemia and reduced triglyceride levels often go hand in hand with heat-healthy changes in the particle size distribution that is still totally ignored by way too many researchers.

That being said, the reduction in 10% reduction in TBARs, a marker of oxidative damage, clearly indicates that the rats with "increased" cholesterol levels were less inflamed than their sugar guzzling peers.

Needless to say that the same applies for the healthy rodents, where the changes in blood glucose, triglycerides and total, HDL and LDL cholesterol were much less pronounced, but the tendencies identical.

References:

• Saada H, Mekky N, Eldawy H, Abdelaal A. Biological Effect of Sucralose in Diabetic Rats. Food and Nutrition Sciences. 2013; 4(7a):82-89.

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.