Stevia Kills Good Gut Bacteria - One Study Enough to Stop Using the Natural Sweetener? Probably Not in View of its Anti-Diabetes, Anti-LDL, Anti-Viral & Anti-Cancer Effects

Study indicates stevia kills healthy gut bacteria. So, how bad is it? Are the effects significant, will they have an impact on your overall health and does this mean you must not use stevia any longer?

A recent study from the Institute of Microbiology and Biotechnology at the University of Latvia in Riga shows the impossible: Stevia, the "natural" sweetener that's everybody's darling, could mess up your gut microbiome by killing large numbers of the beneficial Lactobacillus Reuteri bacteria in your tummy - exactly those bacteria of which several studies have shown that supplementing will help cure acute diarrhea in young children (Shornikova. 1997), is capable of reducing frequency and intensity of antibiotic-associated side-effects during eradication therapy for H. pylori. (Lionetti. 2006), confers broad-spectrum protection against disease in humans and animals (Casas. 2000), has cholesterol lowering effects (Jones. 2012) and much much more.

You can learn more about the gut & your health at the SuppVersity

Bugs Dictate What You Crave

Sweeteners & Your Gut

Foods, Not Ma- cros for the Gut

Lactulose For Gut & Health

Probiotics Don't Cut Body Fat

The Macrobiotic MaPi2.0 Diet

In view of the fact that it would appear as id Lactobacillus reuteri was clearly one of the "good guys" it seems that the results I. Denin a, P. Semjonovs, A. Fomina, R. Treimane and R. Linde report on their latest study in Letters in Applied Microbiology (Denin. 2014) were really bad news:

Figure 1: Influence of stevioside (a) and rebaudioside A (b) on biomass formation in Lactobacillus reuteri strains (24 h | Denin. 2014).

"In samples supplemented with stevia glycosides, the growth of all Lact. reuteri strains was slightly inhibited – however, a statistically significant concentration-dependent inhibitory effect was not observed for all strains (Fig. 1).

Comparing both the glycosides, the inhibitory effect of stevioside was more pronounced for strains 44 and 16, while the effect of rebaudioside A was more pronounced for strains 16 and 19. Statistically significant concentration-dependent inhib itory effect was observed for lactic acid and acetic acid synthesis. The decrease in lactic acid and acetic acid production was observed for both stevioside and rebaudioside A. [...] Although the inhibitory effect of stevioside on pH was observed at different stevioside concentrations, the effect was evident for all strains. Rebaudioside A had a more pronounced inhibitory effect on pH values of certain strains including Lact. reuteri 12, 16, 43 and 44" (Denin. 2014 | my emphasis).

The good news, however, is in the details: The inhibitory effect was "slight" (see quotation above) and the design of the study leaves it open, whether similar effects would occur in vivo and thus outside of a glycoside, stevioside and rebaudioside laden Petri dish.

Previous studies seem to refute significant effects of stevia on the human microbiome! In 2003, Gardana et al. found no effect of stevia on the make-up of human fecal cultures when they were incubated with either stevioside or rebaudioside A. Only the fact that bacteroides, i.e. the "enemies" of lactobacilli, were the most efficient in hydrolyzing Stevia sweeteners to steviol would suggest that there may be an overall effect on the human microbiome form stevia (ab-)use.

And while we have little in vivo evidence that stevia is bad for you, a brief review of the contemporary scientific literature on Stevia yields the following "proven" (mostly only in a handful, if not just a single study) benefits:

• Stevia has been implicated in diabetes and hyperlipidemia treatment and its effects on blood glucose levels are not a mere result of the corresponding reduction in sugar intake.

  

  Figure 2: Effects of stevia vs. diabetes drug Glibenclamide on blood glucose and lipid levels in diabetic rodents; data expressed relative to healthy control (Singh. 2014)

  In a recent rodent study that compared the effects of stevia against those of the often-prescribed diabetes-drug Glibenclamide, the natural sweetener outperformed the drug in many in its ability to reduce LDL and blood sugar and was not far off of what the Glibencamide did for the diabetic lab animals in terms of its effects on HDL and VLDL (see Figure 2).
  
  Previous human studies indicate that stevia extracts will also increase the increased 16 healthy human volunteers whose plasma glucose levels during an oral glucose tolerance tests were significantly lower after having consumed 5 grams of aqueous leave extract at regular 6-h intervals for 3 days (Curi. 1985).

  

  Figure 3: Effects of stevia and aspartame replacement of sucrose in test meals that were fed to obese and normal-weight volunteers on postprandial blood glucose levels (Anton. 2010)

  Moreover, in a more recent study by Anton et al. where stevia was compared to aspartame, it had the same beneficial effects on total energy intake and let to statistically significant reductions in postprandial glucose levels of both obese and lean study subjects (see Figure 3) that did not reach significance when the sucrose content of the test meal was replaced by aspartame.
• In-vitro stevia appears to have anti-cancer effects, as well. That's at least what studies by  Jayaraman et al. (2008) observed with stevia extracts. An effect that may be related to both it's anti-microbial, as well as its potent anti-oxidant activity (Tadhani. 2007) of the whole leaves and leave extracts of which Tahani et al. found that they contain significant effects of folic acid (52.18 mg/100 g) and vitamin C, as well as 130.76 μg catechin and 15.64 μg quercetin for leaves and 43.99 μg catechin and 1.57 μg quercetin for cellus at mg of water extracts, respectively.
  
  Furthermore, Tadhani et al.'s results showed that the leaf extracts contained higher amounts of free radicals, hydroxyl radicals and superoxide anion radical scavenging activities than those of the callus extracts or the anti-mutagenic effects Cariño-Cortés et al. report in their 2007 study. Whether anything similar can be observed with the white "stevia" powder that is used by most people to sweeten their foods is yet questionable - it's after all pure steviosid and thus devoid of all of the previously mentioned compounds.

  

  Figure 1: Several natural constituents of the stevia plant, including steviosides, which are the naturally sweet agents in stevia have potent anti-viral activity against Epstein-Barr virus; values in brackets
  represent % of untreated control dish (Konoshima. 2002)

  Another possible anti-cancer mechanism may be related to stevia's ability to kill viruses like the Epstein-Barr virus that has been implicated in the pathogenesis of Burkitt’s lymphoma, Hodgkin’s disease, non-Hodgkin’s lymphoma, nasopharyngeal carcinoma, and lymphomas, as well as leiomyosarcomas arising in immunocompromised individuals.in humans (Thompson. 2014).

Against that background it seems questionable that the new evidence of negative effects on allegedly healthy gut bacteria (just want to remind everyone that we have no clue what the optimal gut microbiome would look like) is significant enough to have us all reconsider our use of tiny amounts of stevia as a sweetener in our foods.

Read more about the effects artificial sweeteners have on the microbiome in a prevoius article | go ahead!

Interim conclusion: While I am not all too scared that stevia will mess with my gut microbiome in a way that makes me sick, fat and what not, I truly believe that the effects of artificial sweeteners on the make-up and density of the human gut microbiome is still massively under-researched - and that in spite of the fact that it could have a significant effect on the health of us all.

As s SuppVersity reader you will also be aware that this is not a stevia-specific effects. Only recently I have written about similar effects for a bunch of artificial sweeteners - an article I can only recommend to anyone who hasn't read it yet | Comment on Facebook.

References:

• Anton, Stephen D., et al. "Effects of stevia, aspartame, and sucrose on food intake, satiety, and postprandial glucose and insulin levels." Appetite 55.1 (2010): 37-43.
• Casas, Ivan A., and Walter J. Dobrogosz. "Validation of the probiotic concept: Lactobacillus reuteri confers broad-spectrum protection against disease in humans and animals." Microbial ecology in health and disease 12.4 (2000): 247-285. 
• Curi, R., et al. "Effect of Stevia rebaudiana on glucose tolerance in normal adult humans." Brazilian journal of medical and biological research= Revista brasileira de pesquisas médicas e biológicas/Sociedade Brasileira de Biofísica 19.6 (1985): 771-774.
• Deniņa, Ilze, et al. "The influence of stevia glycosides on the growth of Lactobacillus reuteri strains." Letters in applied microbiology 58.3 (2014): 278-284. 
• Gardana, Claudio, et al. "Metabolism of stevioside and rebaudioside A from Stevia rebaudiana extracts by human microflora." Journal of agricultural and food chemistry 51.22 (2003): 6618-6622. 
• Jayaraman, Sathishkumar, Muthu Saravanan Manoharan, and Seethalakshmi Illanchezian. "In-vitro antimicrobial and antitumor activities of Stevia rebaudiana (Asteraceae) leaf extracts." Tropical Journal of Pharmaceutical Research 7.4 (2008): 1143-1149.
• Jones, M. L., C. J. Martoni, and S. Prakash. "Cholesterol lowering and inhibition of sterol absorption by Lactobacillus reuteri NCIMB 30242: a randomized controlled trial." European journal of clinical nutrition 66.11 (2012): 1234-1241.
• Konoshima, Takao, and Midori Takasaki. "Cancer-chemopreventive effects of natural sweeteners and related compounds." Pure and applied chemistry 74.7 (2002): 1309-1316.
• Lionetti, E., et al. "Lactobacillus reuteri therapy to reduce side‐effects during anti‐Helicobacter pylori treatment in children: a randomized placebo controlled trial." Alimentary pharmacology & therapeutics 24.10 (2006): 1461-1468.
• Shornikova, Aino-Vieno, et al. "Lactobacillus reuteri as a therapeutic agent in acute diarrhea in young children." Journal of pediatric gastroenterology and nutrition 24.4 (1997): 399-404.
• Singh, Sunanda. "Antidiabetic, Antidyslipidymic and Antioxidative potential of methanolic root extract of Stevia rebaudiana (Bertoni) on Alloxan induced Diabetic Mice Sunanda Singh and Veena Garg Department of Bioscience and Biotechnology, Banasthali Vidyapeeth, Banasthali, Rajasthan, India." (2014). 
• Tadhani, M. B., V. H. Patel, and Rema Subhash. "In vitro antioxidant activities of Stevia rebaudiana leaves and callus." Journal of Food Composition and Analysis 20.3 (2007): 323-329. 
• Thompson, Matthew P., and Razelle Kurzrock. "Epstein-Barr virus and cancer." Clinical Cancer Research 10.3 (2004): 803-821.

Stevia - So Much More Than Just a Natural Sweetener: Combination "Therapy" With Stevia and Fenugreek as Effective as Common Diabetes Drug!

Image 1: Nature vs. Pharma. Leavs and seeds vs. chemicals - guess who will win!

I have been wondering for quite some time now, why I, as a resident of the European Union, do still have to use my hair-care products to sweeten my tea, my yogurt, or whatever else, if I do want to avoid artificial sweeteners or the good, or I should say, "bad" old table sugar... for those of you who are now wondering how hair-care products relate to my sweet tooth - here in Europe, Stevia rebaudiana Bertoni has still not been approved as a food additive, so that the myriad of health-food shops carrying respective products simply relabel them as "hair-care" or "cosmetic products, not intended for internal application"... and as a obedient citizen I would, of course, never even remotely consider ingesting a product such as stevia that is so utterly natural and genetically unmodified that it must be harmful ;-)

A pros pos harmful: As it turns out, stevia could in fact be pretty harmful - yet not for my or your physiological health, but certainly for the financial health of the big pharma companies. After all, scientists from the Departments of Pharmacology at the Bangladesh Agricultural University and the Faculty of Medicine at the Kagawa University in Japan have recently been able to show that Stevia rebaudiana Bertoni, in combination with Fenugreek aka Methi (Trigonella foenum-graecum), exhibits similarly potent hypoglycemic effects in Streptozotocin treated rats (the reference model for type II diabetes) as Amaryl(R), a commonly used diabetes drug based on the active ingredient Glimepiride (Rafiq. 2011). It thusly stands to reason that big pharma has a vested interest in delaying or even preventing the admission of stevia as an allowable food additive. Think about it: Who would buy all the Amaryls, Metformins & Co if Coca Cola decided to put stevia instead of aspartame into their soft-drinks and - all of a sudden - all those pre-diabetic soft-drink junkies would not develop full-blown type II diabetes, anymore? Ah... I am digressing again. Let's get back to the facts.

For their study Kazi Rafiq and his (I hope that "Kazi" is a male first name ;-) colleagues had collected fresh stevia and methi (=fenugreek) leaves and seeds and prepared them according to the following procedure:

Fresh Stevia leaves that were collected from the garden were oven dried first and then dried leaves were grinded with Grinder machine. Then 1g dried leaves samples were mixed with 10ml distilled water and were allowed to stay for whole night. Everyday fresh extract were prepared by using these techniques. Water extract of methi was made from 100g fresh seed sample by grinding with Grinder machine, and mixed with 2000 ml distilled water. Then the water extract was lyophilized in Central Laboratory, BAU. Finally the herbal drug was collected as powder form by Freeze drying in Central Laboratory, BAU.

The scientists then injected their 30 of their 36 Long Evans rats with Streptozotocin (STZ) to induce insulin resistance (again, STZ-treaded rodents are the most commonly used model of type II diabetes). After two weeks of STZ injection the (then) diabetic rats were divided into 5 groups:

• Group-B: diabetic control (STZ).
• Group-C: STZ + aqueous extract of stevia leaves @ 100 mg/kg,
• Group-D: STZ + aqueous extract of methi leaves @ 500 mg/kg,
• Group-E: STZ + combination of aqueous extract of stevia and methi leaves @ 500 mg/kg
• Group-F: Amaryl @ 800µg/kg

The plant extracts and the drug were administered orally once daily for 60 days. Blood glucose levels were monitored during the treatment period and an oral glucose tolerance test was conducted at the end of the 60-day experiment (results cf. figure 1).

Figure 1: Blood glucose levels (in mg/dl) in response to oral glucose tolerance test in normal and diabetic (STZ) rats after 6 weeks on a combination of stevia and fengreek extracts or the anti-diabetes drug Amaryl - left; change in area under the respective curve (AUC) relative to normal control - right (data adapted from Rafiq. 2011)

As you can see Amaryl and the combination therapy with stevia and fenugreek extracts at 500mg/kg per day (equivalent to 81mg/kg for a human being; or ~6.5g of each for someone weighing about 80kg) were equally effective in ameliorating the blood glucose response (within the statistical margin the AUC was identical).

Figure 2: Elevations in blood sugar levels (compared to healthy control) after STZ treatment and consecutive administration of stevia, fenugreek, a combination of both or Amaryl (data calculated based on Rafiq. 2011)

Moreover, the combination of stevia and fenugreek ameliorated the negative effect the Streptozotocin treatment had on blood glucose concentrations to a similar extend as Amaryl (cf. figure 2), which led the scientists to conclude that...

these findingslend pharmacological support to the suggested folkloric and ethnomedical user of these plants in managing and /or controlling of diabetes mellitus in rural communities of Bangladesh.

While the use of small amounts of stevia to sweeten your beverages and / or food will probably not have the same profound effects on your blood glucose levels as the combination of what would amount to a ~6g equivalent of leaf and seed extracts from stevia and fenugreek used in this study, I would assume that those dubious"hair-care products" still constitutes the most healthy sugar-alternative on the European market - so do your pancreas, ahh.. I mean hair, a favor and get yourself some stevia ;-)

Stevia - More Than Super Sweet: More Scientific Evidence, More Potential Implications for Weight Loss & -Maintenance, Anti-Diabetic & -Autoimmune and Even Pro-Anabolic Effects

Image 1: Stevia is sweeter than sugar, healthier than sugar and could even help reverse some of the damage sugar may already have done to your pancreas.

I know that a few of you were almost furious, when I had the audacity to mention the case-report on the pro-cortisol effects of stevia in the On Short Notice post on Saturday, August 18, 2012; and though I did emphasize that this was most likely something like an allergic reaction and/or an issue with solvents, heavy metals (click here for data on heavy metals in stevia leaves; based on Das. 2012), or whatever else may have been in the specific stevia product the lady used; I suspect that you will like today's blogpost which is basically an update on the beneficial effects stevia could have on your overall and metabolic health, much better.

So what's the latest about stevia, then?

Previous studies have already hinted at the fact that the benefits of the use of stevia go well beyond a mere reduction in energy intake and the overall glucose load the average sweet tooth is exposing her- / himself to. Against that background, the results of a recent publication from the School of Pharmacy in Madhya  Pradesh in India are actually not really surprising.

Figure 1: Blood glucose response (mg/ml) to oral glucose load (left) and superoxide dismutase (SOD) levels in mice treated with 250mg/kg (HED: 20mg/kg; ~1.4-2.0g) stevia extract/day (right; data based on Sharma. 2012)

With most previous studies being conducted on isolated pancreatic islet cells in the petri dish, this is however one of the few studies, which in which the scientists were able to observe a robust in-vivo effect from the administration of no more than 250mg/kg of stevia extract (Herbocal) to alloxan-diabetic (this is a model of type II diabetes that is induced by the injection of the drug Alloxan aka 2,4,5,6-pyrimidinetetrone, an oxygenated pyrimidine derivative) and healthy rodents for 28days - with benefits for both, the sick (normalization of blood glucose and restoration of endogenous antioxidants) and the healthy animals (no drop of blood glucose to hypoglycemic levels and increases in SOD above baseline!)

Could stevia not just ameliorate, but actually "heal" diabetes?

Figure 2: It takes it's time but stevia appears to (fully?) restore pancreatic function!

What's also intriguing are the time-course and general trend of the beneficial effects on blood glucose levels in the diabetic group. If you take a closer look at the data in figure 2 you could even speculate that another four weeks later the blood glucose levels would have totally normalized! And if that were the case, this would mean that the steviosides and rebaudiosides, the active molecules in stevia extracts, could actually have the ability to restore or repair the pancreatic beta cells that have been destroyed by either years of high blood glucose (normal type II diabetics) or the assault of the toxic sugar equivalent alloxan (in the study at hand). and protect healthy individuals against future damage by increasing the endogenous antioxidant system (as can be seen by the allegedly non-significant, but probably still physiologically relevant increase in SOD in figure 1, right)

"But this won't work in humans, will it?"

The above is certainly a good question, but in view of the fact that the short term benefits (e.g. +40% increase in insulin response in type II diabetic with -18% reduced postprandial glucose AUV with 1g of stevia in Gregersen et al. 2004), of which the Hermansen group at the Aarhus University Hospital in Aarhus, Denmark, argues that they are based on the interaction of rebaudioside A (cf. table 1) with the ATP-sensitive K-channels of the pancreatic cells in healthy and its glucagon (and thus gluconeogenesis) inihibiting effects in diabetic individual (Abdula 2004 & 2008; Jeppesen. 2007), have already been reproduced in human trials, I would say that it is more than likely that we will see similar effects in humans, as well, once the correct dosing has been established

Note: especially if you use those combination products of stevia + sugar alcohol you are very unlikely to get sufficient amounts of stevia to elicit those restorative effects; this does not mean that this is a better alternative than aspartame or cyclamate, but in those tiny amounts stevia is a sweetener, not a substance with almost drug-like effects.

Table 1: What's in stevia leaves?
(based on Yadav. 2012)

The latter is by the way all the more likely in view of the fact that Maryam Mohammadi-Sichani and her colleagues from the Falavarjan Branch-Islamic Azad University and the Esfahan University of Medical Sciences in Iran found that stevia extracts will also kill S. mutans, a common bacteria in your mouth that has its share in the development of dental caries and shows, irrespective of generally lower caries rates in type I diabetics, a hitherto not fully explained correlation with (poorly controlled) type I diabetes (Siudikiene. 2006).

Your gut starts in your mouth: The stevia - bacteria connection

These observations stand in line with previous results, of a whole host of peer-reviewed studies Yadav & Guleria summarize in a 2012 review that's about to be published in the November edition of Critical Revision of Food Science, as follows :

Image 2 (20th Century Fox): You better feed your gut bacteria right, otherwise they will disbehave just like the Alien in Ellen Ripley in Alien 3  - read more about the "Gut Type Diet" and how what you eat influences the bacterial composition of your gut on the SuppVersity

"[...] Different extracts showed differential inhibitory activity against various microbes. This experimentation confirmed the antibacterial as well as antifungal potential of Stevia leaf extract and documented that Stevia might be a source of new non-antibiotic antibacterial and antifungal agent. Its antifungal activity was estimated to be higher than the standard fungicide usually used against plant pathogens. Such extraordinary antimicrobial activity of Stevia has presented it as a potent non-antibiotic pharmaceutical and an efficient food preservative. Stevioside alone has been observed to significantly reduce the amount of inflammation mediators and activate cytotoxic cells of the host. These activities suggested that stevioside might play a synergistic role with the innate immunity of the host. Thus stevioside is antibacterial, antifungal, anti-inflammatory, anti-tumorous, and safe for use. While at the same time rebaudioside A has been reported to be clinically insignificant." (Yadav. 2012; my emphases)

In other words, stevia could exert part of it's beneficial effects via the immune-modulatory effects it exerts due to it's impact on the human gut microbiome, the contribution of which to the etiology of both diet-induced type II, but also auto-immune type I diabetes is getting more and more attention among researchers, as of late:

"[...] the autoimmune microbiome for T1D may be distinctly different from that found in healthy children. These data also suggest bacterial markers for the early diagnosis of T1D. In addition, bacteria that negatively correlated with the autoimmune state may prove to be useful in the prevention of autoimmunity development in high-risk children." (Giongo. 2011; my emphases)

And even if the whole "bacteria theory" of autoimmune disease and inflammation turns out to be yet another sidetrack - you will always have the

• beneficial effects on skeletal muscle insulin sensitivity and glucose uptake that has been established by Lailerd et al. in insulin sensitive and resistant mice and the 
• hopefully physiologically relevant increase in satellite cell activity, Bunprajun et al. observed earlier this year in response to lower NF kappa-beta activity (=modulation of inflammation) in an in-vitro model (Lailerd. 2004; Bunprajun. 2012) 

as additional* arguments to satisfy your sweet tooth with stevia instead of sugar or artificial alternatives (*in addition to being able to avoid the "alternatives").

And as long as you keep an eye on the overall amount of food you consume, instead of simply stuffing yourself until you feel like there was no tomorrow, the previously discussed effects any sweetener - natural, artificial, or whatever else the future may hold - could have on your ability to sense the energy density of your foods should not be all too much of a problem problem (cf. "Sweeter Than Your Tongue Allows").

References:

• Abudula R, Jeppesen PB, Rolfsen SE, Xiao J, Hermansen K. Rebaudioside A potently stimulates insulin secretion from isolated mouse islets: studies on the dose-, glucose-, and calcium-dependency. Metabolism. 2004 Oct;53(10):1378-81.
• Abudula R, Matchkov VV, Jeppesen PB, Nilsson H, Aalkjaer C, Hermansen K. Rebaudioside A directly stimulates insulin secretion from pancreatic beta cells: a glucose-dependent action via inhibition of ATP-sensitive K-channels. Diabetes Obes Metab. 2008 Nov;10(11):1074-85. Epub 2008 Apr 22.
• Das, K., R. Dang, L. Hegde and A.S. Tripathi. Assessment of heavy metals in dried stevia leaves by Atomic Absorption Spectrophotometer grown under various soil conditions. Middle–East J. Sci. Res. 2011; 8: 107-113.
• Giongo A, Gano KA, Crabb DB, Mukherjee N, Novelo LL, Casella G, Drew JC, Ilonen J, Knip M, Hyöty H, Veijola R, Simell T, Simell O, Neu J, Wasserfall CH, Schatz D, Atkinson MA, Triplett EW. Toward defining the autoimmune microbiome for type 1 diabetes. ISME J. 2011 Jan;5(1):82-91.
• Gregersen S, Jeppesen PB, Holst JJ, Hermansen K. Antihyperglycemic effects of stevioside in type 2 diabetic subjects. Metabolism. 2004 Jan;53(1):73-6.
• Jeppesen PB, Dyrskog SE, Agger A, Gregersen S, Colombo M, Xiao J, Hermansen K. Can stevioside in combination with a soy-based dietary supplement be a new useful treatment of type 2 diabetes? An in vivo study in the diabetic goto-kakizaki rat. Rev Diabet Stud. 2006 Winter;3(4):189-99. Epub 2007 Feb 10.
• Sharma R, Yadav R, Manivannan E. Study of effect of Stevia rebaudiana bertoni on oxidative stress in type-2 diabetic rat models Biomedicine & Aging Pathology. 2012 August 28.
• Siudikiene J, Machiulskiene V, Nyvad B, Tenovuo J, Nedzelskiene I. Dental caries and salivary status in children with type 1 diabetes mellitus, related to the metabolic control of the disease. Eur J Oral Sci. 2006 Feb;114(1):8-14.
• Yadav SK, Guleria P. Steviol Glycosides from Stevia: Biosynthesis Pathway Review and their Application in Foods and Medicine. Crit Rev Food Sci Nutr. 2012 Nov;52(11):988-98. 

Stevia - Natural Sweetener With Anti-Diabetes + Anti-Obesity Effects? A Brief Research Update: GLP-1, Insulin, Glucose Transport and Uptake, Inflammation, Bitterness & Safety

Stevia is certainly one of the best choices to use as a sweetening agent. It is yet important to point out that this has nothing to do with the fact that it is "natural" - as "natural" as the white stevioside powder ism anyway.

You may remember from the Facebook News that Ripken et al. reported in a recent paper in the  Journal of Agricultural and Food Chemistry (2014) that Stevia will stimulate the release of the satiety (and pro-metabolic) hormones GLP-1 and PYY in the stomach of our (digestion- & nutrition-wise) next relatives, the pigs.

The results Ripken et al. presented about 3 weeks ago are yet only the tip of a whole heap of studies of which Nabilatul Hani Mohd-Radzman and colleagues believe that it is sufficient to postulate that the Stevia rebaudiana Bertoni plant "could benefit the community medicinally through several different pathways, all eventually leading to its antihyperglycemic qualities." (Mohd-Radzman. 2014)

You can learn more about sweeteners at the SuppVersity

Unsatiating Truth About Sweeteners?

Will Artificial Sweeteners Spike Insulin?

Sweeteners & the Gut Microbiome Each is Diff.

Sweeter Than Your Tongue Allows!

Stevia, Much More Than Sweet?

Artif. Sweetened Foods Help Weight Loss!

But is there really convincing  evidence that the beneficial effects of the consumption / use of stevia and its main sweetening agent stevioside go beyond the mere reduction in sugar consumption? Yes, there is; and here is a brief overview of what we've learned so far:

• Anti-inflammatory effects -- Some scientists believe that Stevia’s utility in diabetes protection is due to its antioxidant properties; a hypothesis that is supported by analysis of the phenols that may be extracted from the plant.
  
  Stevia has a large overall proportion of phenols, up to 91 mg/g; it is proposed that these constituents extracted from the leaves are the major agents contributing towards the anti- hyperglycemic activities exerted by the plant (Shivanna. 2013). This is further supported by the fact that the leaves have a greater ability to scavenge free radicals and prevent lipid peroxidation than controls such as butylated hydroxytoluene, butylated hydroxyanisole, and tertiary butyl hydroxyquinone.
  

  

  Figure 1: Effect of Stevia on lipid peroxidation in liver in STZ treated rats (n = 8; Shivanna. 2013).

  The mere presence of anti-oxidants does not ensure anti-diabetic effects, though. Against that background it's important that corresponding experimental evidence from streptozotocin-induced diabetic rats, in which phenolic compounds prevented several diabetic complications is already available. In addition, Shivanna et al. (2013) observed a significant decrease (about 30%) in peroxidation in the livers of Stevia-pre-fed rats, compared to those of their control groups. In view of the previously discussed involvement of the liver in the etiology of the metabolic syndrome, this is a good indicator of reduction in the progression of diabetic complications.
  
  The same goes for the levels of the pro-inflammatory cytokine NF-kappaB and TNF-alpha of which researchers from the Shanghai Institute of Endocrine and Metabolic Diseases report that it was significantly downregulated in a study on a C57BL6J mouse model of insulin-resistance, when the rodents received stevioside supplemented chow (Wang. 2012).
• Direct beneficial effects on blood glucose levels --  Whether the beneficial effects of stevia on blood glucose management are mediated solely via its anti-inflammatory effects is not yet certain. The initially mentioned effects on GLP-1, for example, could (and probably will) also contribute to the significant decrease in blood-glucose levels Susuki et al. observed in a study from 1977 that was published in the Japanese science journal Nippon Nogei Kagaku Kaishi (Susuki. 1977).  The Japanese researchers fed rats a stevia enriched high carbohydrate + high fat diet and observed "a significant reduction in glycemia" after four weeks on the otherwise highly prodiabetic rodent equivalent of the Western diet. 

You cannot stand the bitter taste of stevia? Unlucky you! You've simply got the wrong genes. As scientists from the Laboratory of Molecular Anthropology and Centre for Genome Biology at the University of Bologna observed in a very recent study, men and women with the TAS2R4 gene polymorphism rs2234001 and /or the TAS2R14 (TAS = taste receptor) gene polymorphism rs3741843 will never understand how the rest of us can ignore the obnoxious bitterness of steviosides - I know, that's bitter ;-)

• That these benefits are not rodent specific and don't arise in response to an interaction with certain components in the rodent chow was demonstrated 27 years later by Gregersen, et al.  (2004). In their paper in the January issue of Metabolism, the scientists report that they observed a similar, highly significant reduction (an average of 18%) in postprandial glucose levels in Type II diabetic patients given test meals supplemented with stevioside..
  
  A 2010 study by Anton et al. confirmed this (Anton. 2010) this; postprandial glucose levels were significantly lowered in patients supplemented with Stevia, compared to those
  given aspartame (a type of synthetic sweetener) or sucrose (normal table sugar). In that, the slightly increased insulin levels in the stevia vs. aspartame group provides further support for the involvement of GLP-1, which is likewise involved in health insulin function (Kjems. 2003)
  

  

  Figure 2: Total energy intake of type II diabetics in kcal/day on days with aspartame, setvia or sucrose sweetened foods (left); corresponding plasma insulin levels (Anton. 2010)

  In addition, patient satiety as an aftereffect of the different sweeteners was also tested; it was found that subjects given lower-calorie sweeteners (Stevia or aspartame) did not compensate by eating more than those given sucrose. Any potential increase in insulin did thus have the proven, but largely ignored satiety effect insulin is supposed to have (Vanderweele. 1994). 
• Possible interactions with the gut & its microbiome -- The research on the interactions of stevia with the microbes in our gut is still in its infancy.
  

  

  Table 1: Effects of non-nutritive sweeteners on gut hormones and glucose absorption:in vivo effects on animals (Brown. 2014)

  Nevertheless, the repeatedly mentioned effects on GLP-1, as well as evidence from animal studies which show a decrease in glucose uptake, when carbohydrates are fed in the presence of stevia (Brown. 2012) clearly indicate that there is more to the anti-diabetic & -obesity effects of stevia (and maybe other non-nutritive sweeteners) than direct antioxidant effects (Payne,. 2012).

Is stevia even safe? At "sane" intake levels toxic effects appear unlikely (Aze. 1990); studies show no detrimental effects on female reproduction, when consumed in amounts equivalent to those you would use in food products (Yodyingyuad. 1991; Saenphetet. 2006); there are minimal negative effects on seminal vesicle weight in high dose study with male rodents (Oliveira-Filho. 1989); studies show no genotoxic effects or DNA interactions (Brusick. 2008); stevia even appears to have a limited anti-viral activity (Takahashi 2000 & 2001)

"Natural and good", not "good since natural": As the previous elaborations have shown stevia really appears to be one of the best sugar replacements to chose. This is yet not due to the "naturalness" of stevia, but due to the specific molecular structure of the the glycosides the food industry extracts from the leaves of a plant.

Accordingly, the white substance we wrongfully call "stevia", when it's eventually only an extract of the sweet(est) tasting steviosides wouldn't be less effective or unhealtier if it was synthesized in the laboratories of Monsanto or extracted from the poop of genetically modified bacteria. And you know what? I guess, when the market keeps growing the way it does, this is soon going to be the white-washed sterile environment of a laboratory is probably soon going to be where 90% of the stevia is going to come from.

Reference:

• Anton, Stephen D., et al. "Effects of stevia, aspartame, and sucrose on food intake, satiety, and postprandial glucose and insulin levels." Appetite 55.1 (2010): 37-43. 
• Aze, Y., et al. "Subchronic oral toxicity study of stevioside in F344 rats." Eisei Shikenjo hokoku. Bulletin of National Institute of Hygienic Sciences 109 (1990): 48-54.
• Brown, Rebecca J., and Kristina I. Rother. "Non-nutritive sweeteners and their role in the gastrointestinal tract." The Journal of Clinical Endocrinology & Metabolism 97.8 (2012): 2597-2605. 
• Brusick, D. J. "A critical review of the genetic toxicity of steviol and steviol glycosides." Food and Chemical Toxicology 46.7 (2008): S83-S91.
• Gregersen, Søren, et al. "Antihyperglycemic effects of stevioside in type 2 diabetic subjects." Metabolism 53.1 (2004): 73-76.
• Kjems, Lise L., et al. "The Influence of GLP-1 on Glucose-Stimulated Insulin Secretion Effects on β-Cell Sensitivity in Type 2 and Nondiabetic Subjects." Diabetes 52.2 (2003): 380-386.
• Oliveira-Filho, Ricardo M., et al. "Chronic administration of aqueous extract of< i> Stevia rebaudiana</i>(Bert.) Bertoni in rats: Endocrine effects." General Pharmacology: The Vascular System 20.2 (1989): 187-191.
• 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.
• Ripken, Dina, et al. "Stevia Glycoside Rebaudioside A Induces GLP-1 and PYY Release in a Porcine Ex Vivo Intestinal Model." Journal of agricultural and food chemistry (2014).
• Shivanna, Naveen, et al. "Antioxidant, anti-diabetic and renal protective properties of  Stevia rebaudiana." Journal of Diabetes and its Complications 27.2 (2013): 103-113.
• Suzuki, H., et al. "Influence of oral administration of stevioside on levels of blood glucose and liver glycogen of intact rats." Journal of the Agricultural Chemical Society of Japan (1977).
• Takahashi, K., et al. "Extracts from Stevia rebaudiana is a potent anti-rotavirus inhibitor in vitro and in vivo." Antiviral Research. Vol. 46. No. 1. PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS: ELSEVIER SCIENCE BV, 2000.
• Takahashi, Kazuo, et al. "Analysis of anti-rotavirus activity of extract from< i> Stevia rebaudiana</i>." Antiviral research 49.1 (2001): 15-24.
• Vanderweele, Dennis A. "Insulin is a prandial satiety hormone." Physiology & behavior 56.3 (1994): 619-622.
• Wang, Zhiquan, et al. "Stevioside ameliorates high-fat diet-induced insulin resistance and adipose tissue inflammation by downregulating the NF-kappaB pathway." Biochemical and biophysical research communications 417.4 (2012): 1280-1285.
• Yodyingyuad, Vithaya, and Supranee Bunyawong. "Effect of stevioside on growth and reproduction." Human Reproduction 6.1 (1991): 158-165.

Stevia, the Anti-Diabetic Sweetener: Extract from the Leaves of Stevia rebaudiana Exhibit Anti-Diabetic Effects in Animal Model

Image 1: Stevia rebaudiana foliage
(photo by Ethel Aardvark)

The health-conscious consumer, you, as a SuppVersity reader, are, you will probably have heard of the natural sweetener stevia, which -despite its various advantages over its artificial counterparts- still has not made it to the mass market. While higher costs, certainly are the main culprit here, another factor could be the unfamiliar, for some commercially available products metallic taste. But hey, didn't people initially complain about the taste of aspartame and natrium-cyclamate, as well? And now, the very same people drink one bottle of diet coke after the other?

Well, if not being as toxic as it's artificial counter parts didn't convince people, yet, maybe the findings of a recent study from India will.

On a side note: don't you think it is kind of telling that studies on "alternative" treatments for diabetes never appear to come from the home countries and continents of Big Pharma?

Misra et al. (Misra. 2011) investigated the effect of two different dosages of a medium-polar (polarity determines solubility, with identical polarity of solvent = high solubility) leaf extract of S. rebaudiana at 200 and 400 mg/kg respectively on diabetic (alloxan induced) rats and found:

Medium-polar leaf extract of S. rebaudiana (200 and 400 mg/kg) produced a delayed but significant (P < 0.01) decrease in the blood glucose level, without producing condition of hypoglycemia after treatment, together with lesser loss in the body weight as compared with standard positive control drug glibenclamide.

Sweet and healthy, but not marketable? Well, the real problem is that the lack of financial interest the big beverage and food producers have to replace tried and proven artificial sweeteners, their customers got used (and sometimes addicted) to, with a sugar substitute, the taste of which could potentially harm their sales. Add to that the reluctance of the central organs of the European Union to finally approve "sweetleaves", as stevia is sometimes referred to, as well, for human consumption. Over here in Europe producers and vendors try to circumvent this problem by labeling their stevia products as "cosmetics" and selling them "solely for topical application". Coca Cola, on the other hand, would certainly have a hard time selling a new stevia-based Coca Cola Light as a cosmetic or heaven forbid bath water, which renders the development of a respective product simply unprofitable (let alone the possibility that costumers won't like its taste).

This being said, it is not even sure, whether the same product that would render your future "Stevi-Coke" (I should patent that name ;-) sweet and tasty will also induce the afore-mentioned revitalizing effects on your pancreatic beta-cells. In the end, consumer taste will probably require the extracts to be processed in order to get rid of any annoying flavors (and associated substances) and whether or not what "remains" will still be superior to sulfonylurea drugs such as glibenclamide in ameliorating hyperglycemia is certainly questionable.

Stevia Increases Satellite Cell Recruitment and Ameliorates Insulin Resistance by Reducing NF-KappaB Mediated Inflammatory Response to Muscle Damage & High Fat Diet

Image 1: If you take a look at the number of studies on production and processing techniques related to stevia and stevia products, it becomes evident that the production of the traditional South American "sweet leaf" has already been seized by the usual subjects from the "food industry"

"Rats would buy Stevia rebaudiana!" I don't know about you, but personally, I would not advertise my product with this slogan, but if I did, I would at least have valid scientific data to support this claim... well, sort of, because I am not 100% sure where or even that rats even buy any sweeteners. Be that as it may, although Sclafani et al. were able to show that the preference their lab animals showed for stevia over saccharine was related to the activation of the sweet taste receptors (Sclafani. 2010), you could also make a point that the rodents might have "tasted" that there is more to Stevia rebaudiana than its insanely sweet taste (personally, I have been using stevia for ~6months, now, and had to get used to the taste initially), if you take a closer look at some of the more recent data on the potential health benefits of (allegedly large amounts of) steviosids, the major steviol glycosides from the leaves of the stevia plant.

Steviosids work via NF-kappaB by reducing inflammation

Assuming that you have followed the Intermittent Thoughts on Building Muscle series, you will be familiar with the notion that the recruitment of so-called satellite-cells, i.e. muscle-specific stem-cells, is an essential part of the repair process after exercise (or otherwise) induced muscle damage. You will also be aware that inflammation plays an important, albeit hitherto not fully elucidated role in this process and that it is after the initial inflammation is abating, when the macrophages start the actual (re-)construction process (cf. "Inflammation & Hypertrophy"). You will thusly maybe even less surprised than a group of Malayan scientists from the Mahidol University in Bangkok (Bunprajun. 2012), when they found that 10mg/kg of pure steviosids, of which previous studies had already shown that they are able to ameliorate stress-induced NF-kappaB (which is believed to be one of the master regulators of inflammatory responses) expression, did not only lead to the expected amelioration in NF-kappaB expression in cardiotoxin injected tibialis muscles of male rodents, but also increased the post-recovery increase in myo-D positive, i.e. newly recruited satellite cells.

Figure 1: Inflammatory response (left) and satellite cell recruitment (right) after cardiotoxin injection in tibialis muscle in rodents after pre treatment (7 days) and concomitant (7 days after the injury) treatment with vehicle (control) or 10mg/kg steviosids (data adapted from Bunprajun. 2012)

The initial NF-kappaB response, three days after the injection of a cardiotoxin into the tibialis muscles of the rodents was identical (cf. figure 1). After seven days, however, the NF-kappaB levels in the steviosid group, who received their daily dose of stevia 7 days before and in the 7 days after the injury, are significantly lower than in their vehicle (control) treated peers and correspond well with the profoundly increased number of myoD positive (fresh) nuclei in the stained tissue samples of the treatment group.

The same effects on NF-kappaB also help ameliorate diet-induced insulin resistance

With the increased recruitment of satellite cells being only part of a very complex repair process, and given the fact that the scientists did not find any significant difference in tibialis anterior mass, myofibrillar protein content, the number of central located nuclei, it is actually not surprising that the contractile function of the injured legs was still identical 7 days after this profound injury. For an athlete or any active individual this would probably mean a few weeks away from the gym, the court, the green, or the stadium and this in turn could precipitate weight gain, which brings up another nice "side effect" of the NF-kappaB suppressing effects of high dose stevia supplementation that has been recently established by Wang et al. (Wang. 2012).

Figure 2: Body weight gain, fasting blood glucose and insulin levels and glucose infusion response in rats after 4 months on regular or high fat diet (49%fat / 36%carbs / 15% protein) with or without 2x10mg/kg steviosids per day (data calculated  based on Wang. 2012)

As the data in figure 2 goes to show, the oral administration of stevisoids as 2x10mg/kg was able to ameliorate the negative effects 4 months of "high fat" feeding (49% fat / 36% carbs / 15% protein) exerted on body weight and glucose metabolism of previously healthy rats. With a +36% increase in serum insulin and a -19% reduced glucose infusion response (GIR) the rats in the HFD+stevia group were yet still significantly more insulin resistant than their peers on the regular diet - and the results also show that an increase in insulin sensitivity does not translate into a decrease in weight gain. As we are going to see in the course of the current Intermittent Thoughts series on insulin sensitivity, "ideally" the exact opposite should be the case.

Pounding stevia to stay healthy and gain muscle? Probably not the best good idea.

If we get back to my introductory remarks and the not really advertisable slogan "rats would buy stevia rebaudiana", the question that has to be answered now is: Would you buy stevia? I already told you that I do, but certainly not because of the aforementioned effects. I guess, I would probably die from over-sweetening (if there was such a thing), if I took the corresponding one to two "servings" of 1.6mg/kg (human equivalent of 10mg/kg for a rat) of pure steviosids on a daily basis... but all jokes aside, if you are looking for a healthy sweetener, there probably is no better option than stevia.

If you want to ward off insulin resistance, on the other hand, a "clean" diet with a reasonable amounts of carbs (unless you are diabetic ~100g, which as Beth /thx/ rightly pointed out would be way less than 30% of your total energy intake, is something everyone should be able to handle - and what's more, can help you perform better, keep energy levels and metabolism up and contrary to the contemporary anti-carb paradigm, eventually improve weight- and fat-loss), fats and protein in it should be your main concern. This is particularly important, because a combination of the latter with a reasonable workout routine, sufficient time to recover and a decent amount of quality sleep, will also make the use of stevia as a means to increase muscle repair obsolete,... at least as long as you are not attacked by mad Malayan scientist with a syringes full of myotoxins ;-)