Can Stevia Help You Ward Off Type II Diabetes? A Review

Can Stevia Help You Ward Off Type II Diabetes? A Review

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Unfortunately, it is not even clear if you need the "white stuff", i.e. pure steviosides, whole leaves of leaf-extracts to maximize the anti-diabetic effects of stevia. What is clear, though, is that there's still a lot of research to be done.

"Can Stevia Help You Ward Off Type II Diabetes?" That's not just the title of today's SuppVersity article, it is also the research question of a recent paper by Esteves A.F. dos Santos from Farmácia Progresso (dos Santos. 2016). An interesting question with an obvious answer: if you replace sugar in your diet with stevia, it will help.

Now, you know that this would not be worth discussing in a SuppVersity article of its own. What is worth discussing, though, is that stevia contains "compounds and other substance obtained from stevioside hydrolyses" (dos Santos. 2016) such as isoteviol of which studies show that they can be used as 'active' diabetes treatments - meaning: they help, even if you take them on top of sugar / your regular diet.

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To understand how stevia may help you to ward off diabetes, you will first have to understand how the latter actually develops. In the previously references review, dos Santos writes about the consequences of life-style induced weight gain and concomitant increases in body fat and insulin resistance (IR):

Figure 1: Illustration of the etiology of type II diabetes from a secondary source (in dos Santos. 2016)

"After an initial increase of insulin production as a response to IR in peripheral tissue, pancreatic β cells no longer have the ability to control glucose homeostasis, leading to endocrine sys-tem imbalances. Under glucagon influ-ence, the liver contributes significantly in glucose homeostasis because liver makes the balance between capture / storage of glucose, via glycogenesis, and the release of glucose by glycogenolysis and gluconeogenesis. 

Constant, prolonged state of hypergly-cemia enables the formation of Advanced Glycation End-Products (AGEs). AGEs are responsible for the onset of diabetic complications, such as neurological and kidney complications (diabetic nephropathy), aging and cardiovascular complications: dyslipidemia, hyperten-sion, [etc.]" (dos Santos. 2016).

The previously referenced AGEs and the significant increase of reactive oxygen specimen (ROS), which leads to decreased levels of antioxidants enzymes, increase lipid peroxidation, will increase the risk for cardiovascular diseases and exacerbate the state of the disease, which has - at this point - started to self-propel its own progression.

If using stevia could break this vicious cycle, this would obviously be awesome!

Initial evidence that suggests that stevia could do what the subheading suggests, and decrease blood glucose levels comes from ... you guessed it: rodents. In a 4 week supplementation study, rats who were fed Stevia rebaudiana extract - combined with high-carbohydrate and high-fat diets - exhibited a sign. lower increase in glucose and worsening of their glucose tolerance in an oral glucose tolerance test (OGTT) - a result that was soon confirmed in human beings who ingested an infusion of 5 Stevia rebaudiana leaves for 3 days, every 6 hours (see Figure 2):

Figure 2: Effect of stevia leaf extract (5g) blood glucose of 16 healthy subjects on oral glucose tolerance test (Curi. 1986).

Similar results have been observed by Anton et al. (2010) who compared the effect of preloads of stevia with preloads of other sweeteners, such as aspartame or sucrose in obese and normal subjects. As the data in Figure 3 shows, these preloads, which were consumed by study participants 20 minutes before their test lunch and dinner meals, decreased postprandial insulin significantly.

Figure 3: Blood glucose response in man with preloads of either sucrose, aspartame or stevia (Anton. 2010)

Now, the obvious question we have to answer is: how did that work? There are different speculative and proven mechanisms that could contribute to the anti-diabetic effects of stevia:

• one study showed that Stevia rebaudiana will inhibit the pancreatic enzyme alpha-amylase and alpha-glucosidase and thus the breakdown of carbs in the intestine (Adisakwattana. 2010),

• 

  Figure 4: Effects of Stevia extracts on glucose transport activity compared to the effect of insulin. SH-SY5Y (a) and HL-60 (b) cells were treated with steviol glycosides (1 mg/mL), with 100 nM insulin (I), with steviol glycosides and insulin simultaneously, or 1 mM standard compounds (StReb, StStev | Rizzo. 2013).

  stevia rebaudiana extracts may also act similar to insulin and are equally effective in increasing glucose uptake,because the co-treatment with insulin and stevia extracts increase glucose uptake significantly higher than the increase due to insulin alone (Rizzo. 2013), , similar results were reported by Akbarzadeh et al. (2015) in STZ-induced diabetic rats
• various studies provide evidence for the anti-oxidant effects of stevia and respective extracts, which will - in view of the inflammatory nature of type II diabetes - obviously contribute to its anti-diabetic effects
• at least one study shows that isostevial, one of the stevia glycosides, appears to work part of its magic via activating the PPAR receptor alpha (Xu. 2012)

Whether there is one specific agent that is responsible for the previously listed effects is still debated. Among the "suspects" are primarily steviol glycosides for which anti-hyperglycemic effect has been observed in doses ranging from 5 mg / kg to 200mg/kg (González. 2014)

Is stevia even safe? You will be surprised to hear that, but the safety of the chronic consumption of stevia, the "natural sweetener", cannot be guaranteed (see possible ill effects on fertility). While studies in adult hypertensive patients show that it is "likely safe" when taken orally (250-500mg stevioside) thrice daily for up to two years, scientists argue that it could be "possibly unsafe, [...w]hen taken [by] children, or pregnant or lactating women or for periods longer than two years, due to insufficient available evidence" (Ulbricht. 2010). The same goes for its use by patients with hypotension, hypocalcemia, hypoglycemia, or impaired kidney function. In view of what we know about the possibility of allergy/hypersensitivity to other members the daisy family (Asteraceae/ Compositae), one may also suspect that allergic reactions, which have not been reported in the literature, yet, are not likely.

More specifically, these compounds have been observed to offset "the glucagon hypersecretion by pancreas α cells that's usually caused by prolonged exposure to fatty acids, and changed genes expression responsible for the metabolism of fatty acids" (dos Santos. 2016). They have also been shown to increase the glucose uptake of pancreatic cells, thus rendering them more sensitive to (small) changes in blood glucose levels; and Gonzalez et al. found them to be capable of increasing proinsulin mRNA concentration and insulin in pancreas INS-1 cells - with the result being a sign. increase the content of insulin in cells.

Figure 5: Glucose (left) and lipid (right) levels in rodents after 14 days on a high fat diet w/ different amounts of isosteviol in the diet - the effects are sign., but the effect size is small (Xu. 2012)

Of the various steviosides, dos Santos highlights isosteviol, a stevioside hydrolyzate, in particular, because it has been shown to have especially pronounced influence on glucose metabolism (Xu. 2012) in a 14-day rodent study in which the animals were fed high-fat chow and the oral administration of  isosteviol orally administrated at doses from 1 to 5 mg/kg/day led to a statistically significant decrease in insulin levels, accelerated glucose clearance and improved insulin sensitivity while simultaneously lowering total and LDL cholesterol and increasing HDL - not bad even if the effect size is relatively small, right?

"The mechanism underlying these effects may be related to the expression of PPARα, since this has changed in the treatment with isosteviol. Furthermore, the pretreatment with isoteviol improves antiapoptosis factor Bcl-2 expression and inhibits the NF-kB expression, and increases SOD and GSH-PX activity. Isosteviol has anti-inflammatory effects, which may possibly be related to hypoglycemic effect and the ability to change lipid profile" (dos Santos. 2016).

Unfortunately, the results Xu et al. presented 4 years ago still await confirmation in human studies. The same goes for the first stevia based anti-diabetes "drugs" which seek to increase the bioavailability (in serum) of steviosides by bioconjugating them on biodegradable Pluronic-F-68 copolymer based PLA nanoparticles by the means of nanoprecipitation (Barwal. 2013). These studies exist, like a recent study by Kassi et al. who introduced low glycemic load snacks based on Stevia to a low calorie diet in patients with metabolic syndrome and found this to be a safe and highly efficient means to "further reduc[e] BP [blood pressure], fasting glucose, ox[idized] LDL and leptin compared to a hypocaloric diet alone, decreasing, thus, further the risk of atherosclerosis and DMT2" (Kassi. 2016) - as part of a regular diet and in place of high sugar foods, stevia is thus the most effective.

Figure 6: One of the few long(er) term studies in (diabetic) humans found no effect of 1g rebaudioside on glycemia (Maki. 2008) - so, don't get too excited about stevia being the new metformin.

So what's the verdict then? Well, I guess you won't be happy if I say that more research is, as usually, necessary. Dos Santos is yet right that "Stevia rebaudiana is a good option to be included in the group of nutraceuticals", in view of its "action and its main compounds (stevioside and rebaudioside A) concerning glycaemia control, diabetes consequences, and early development of IR" (dos Sanots. 2016).

In as much as it can be considered a "medicinal herb," though, its safety of and necessity of higher dosages, as well as the exact mechanism of action require further investigation. Whether it makes sense to develop sustained released, high bioavailability 'stevia drugs' does yet appear questionable to me. - in particularly, because isosteviol "is not subject to intestinal hydrolysis and has shown results as therapeutic agent for type 2 diabetes and its consequences" (dos Santos. 2016), without being chemically / molecularly altered - using "regular" stevia and that to replace sugar does therefore still appear to be the best 'anti-diabetic' use for this sweetener which is up to 150 times sweeter than sugar, heat- and pH-stable, and not fermentable | Comment on Facebook!

References:

• Adisakwattana, Sirichai, et al. "Evaluation of α-glucosidase, α-amylase and protein glycation inhibitory activities of edible plants." International Journal of Food Sciences and Nutrition 61.3 (2010): 295-305.
• Akbarzadeh, Samad, et al. "The Effect of Stevia Rebaudiana on Serum Omentin and Visfatin Level in STZ-Induced Diabetic Rats." Journal of dietary supplements 12.1 (2015): 11-22.
• 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.
• Barwal, Indu, et al. "Development of stevioside Pluronic-F-68 copolymer based PLA-nanoparticles as an antidiabetic nanomedicine." Colloids and Surfaces B: Biointerfaces 101 (2013): 510-516.
• Curi, R., et al. "Effect Of Stev/A Reba Ud/Ana On Glucose Tolerance. In Normal Adult Humans." Braz. j. med. biol. res (1986).
• González, et al. "Stevia rebaudiana Bertoni: a potencial adjuvant in the treatment of diabetes mellitus." CyTa – Journal of Food 12.3 (2014): 218- 226.
• Kassi, Eva, et al. "Long-term effects of Stevia rebaduiana on glucose and lipid profile, adipocytokines, markers of inflammation and oxidation status in patients with metabolic syndrome." (2016).
• Maki, K. C., et al. "Chronic consumption of rebaudioside A, a steviol glycoside, in men and women with type 2 diabetes mellitus." Food and Chemical Toxicology 46.7 (2008): S47-S53.
• Rizzo, Benedetta, et al. "Steviol glycosides modulate glucose transport in different cell types." Oxidative medicine and cellular longevity 2013 (2013).
• Ulbricht, Catherine, et al. "An evidence-based systematic review of stevia by the Natural Standard Research Collaboration." Cardiovascular & Hematological Agents in Medicinal Chemistry (Formerly Current Medicinal Chemistry-Cardiovascular & Hematological Agents) 8.2 (2010): 113-127.

Want to Home-Brew Your Own 15x More Bioavailable Super-Curcumin? Buy Buttermilk and a Yogurt Starter Culture

Want to Home-Brew Your Own 15x More Bioavailable Super-Curcumin? Buy Buttermilk and a Yogurt Starter Culture

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No one says you cannot add other ingredients to the yogurt to make it more tasty if you add the curcumin before fermenting the buttermilk.

If you're a regular at the SuppVersity you will know that curcuminoids, the polyphenols found in turmeric roots (Curcuma longa), have health effects that are similar, in some cases even superior to several anti-inflammatory, anti-diabetic and lipid-lowering drugs. Yes, their consumption has even been linked to significant reductions in cancer risk. Unfortunately, there's a problem with these powerful polyphenols: they are hydrophopbic (Tønnesen. 2002) and prone to degradation in an aqueous environment at neutral and alkaline pH (Tønnesen. 1985; Wang. 1997) - two properties of which Gupta and others (2013) believe that they are responsible their poor oral bioavailability.

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Low bioavailability or not, Shishan Fu and rightly highlight in the introduction of their latest paper, even the hardly absorbed "regular" curcuminoids have been reported to offer many health-promoting properties (Gupta and others 2013), it is thus only logical that there's an "interest in the development of functional foods containing these compounds is increasing" (Fu. 2016).

Figure 1: Even dispersing them in buttermilk will increase the bioavailability by decreasing the breakdown of curcuminoids during digestion - that's at least what a 2014 study by Fu et al. shows. 

Hitherto scientists have (more or less successfully) tried to increase the solubility and stability of curcuminoids by dispersing them in matrices such as lipid-based emulsions (Ahmed. 2012; Yu and Huang. 2012), modified starch (Yu and Huang 2010), hydroxypropyl methyl cellulose (Chuah. 2014), milk proteins (Yazdi and Corredig. 2012), and buttermilk (Fu. 2014). As Fu et al. point out, ...

"[...t]he bioavailability may also be increased when formulated in appropriate delivery systems. For example, lecithin–piperine formulations containing curcuminoids and curcuminoids encapsulated in cellulose have been reported to have enhanced bioavailability after oral administration in humans (Antony and others 2008; Vitaglione and others 2012)" (Fu. 2014).

Based on their own previous study with regular buttermilk and evidence that yogurt can significantly increase the stability and bioavailability of bioactives, like green tea polyphenols (Lamothe and others 2014), Fu et al. speculated that dispersing curcuminoids in buttermilk prior to yogurt manufacture would exert even more powerful effects than simply mixing them with buttermilk (see Figure 1). To test this hypothesis, the scientists did something anyone of you can do at home (see Figure 2 for information on how the control samples were prepared, too):

Figure 2: Preparation of yogurts (Fu. 2016).

"A buttermilk dispersion (14% total solids, w/w) was prepared by reconstituting 142.3 g of buttermilk powder in MilliQ-water which was made up to 1000 g. The powder was dispersed in the water at 45 °C with stirring using an overhead stirrer (Heidolph RZR 2051 control, Germany) at 1000 rpm for 30 min. The dispersion was then stored at 4 °C overnight for more complete hydration. The chosen fortification level of curcuminoids in yogurt was 300 mg/ 100 g yogurt (0.3% w/w)

An ABT-5 culture was prepared by mixing 0.2 g of culture granules in 10 mL of buttermilk dispersion (14% total solids, w/w) and stirring for 15 min in an ice bath. This culture solution was prepared freshly prior to fermentation. The ABT-5 culture was added at a level of 0.2 g/L of yogurt buttermilk. The buttermilk was subsampled (50 mL) into separate plastic containers and incubated at 43 °C until pH reached 4.6. These set yogurts were put into the ice water bath for 30 min, stirred at 200 rpm for 20 s using a mixer (Heidolph RZR 2050, Germany) and then stirred manually (approximately 20 times) to obtain a uniform product. The stirred yogurts were stored in a cool room (4 °C) overnight. All analysis was completed within 2 d of yogurt manufacture. The total solids of the yogurts were estimated using a moisture analyser (Sartorius AG, Germany)." (Fu. 2016).

To be able to tightly control the experiment, the curcumin enhanced yogurt and the other samples were exposed to in vitro digestion. During this procedure, the sample (5 g) was mixed with 15 mL of simulated gastric fluid (SGF) containing 2 g NaCl and 7 mL 37% w/v HCl per liter (pH 1.23) and 3.2 mg/mL pepsin, and incubated in a water bath with 100 rpm at 37 °C for 2 h (United States Pharmacopeia Convention 2009).

"After exposure to SGF, the mixture was adjusted to pH 6.5 using 1 M NaOH and mixed with 9.6 mL of simulated intestinal fluid (SIF) containing 3 mL of 2 M NaCl, 0.3 mL of 0.075 M CaCl2, and 6.3 mL of 36.5 mg/mL bile extract in 5 mM phosphate buffer. The pH was adjusted to 6.8 and then 5.4 mL of 10 mg/mL pancreatin in phosphate buffered saline was added. Samples were incubated at 37 °C, 100 rpm for 3 h and then placed in an ice bath to arrest the enzyme activity. At the end of the in vitro digestion period curcuminoids were extracted from the whole digested mixture with acetone and quantified using HPLC-DAD" (Fu. 2016). 

The in-vitro digestion, which is described in a previous paper by Fu et al. (2015), provided the scientists with an estimate of the amount of undegraded curcuminoids - it is yet not a 100% reliable method to determine the real world biological effects in humans, which would have to be tested in future studies. In view of the fact that the scientists calculations show that the resistance of the curcuminoids to degradation after sequential exposure to SGF and SIF improved more than just statistically significantly (see Figure 3), it is logical to assume that benefits would be observed in vivo, too.

Figure 3: Bioaccessibility of curcuminoids after sequential exposure of samples to SGF and SIF (Fu. 2016).

The difference pre-processing, i.e. the prior dissolution in ethanol (which wouldn't make you drunk, anyway, because the total ethanol content of the yogurt would be marginal), the dissolution of curcuminoids in buttermilk and its fermentation to "curcumin enhanced" buttermilk yogurt with a standard ATB yogurt starter culture, made in terms of the bioavailability is after all huge.

In fact, the bioavailability of the curcuminoids increased to an extent that easily surpasses the hyped BCM-95®, a combination of curcumin and bioperin, which has been shown to exhibit a 6.93-fold higher bioavailability. In all fairness, we shouldn't forget, though, that, unlike the yogurt trick described here, Biocurcumax™ has already been studies in humans (Antony. 2008).

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The total bioavailability is still low, but... As, Fu et al. point out in the conclusion of their soon-to-be-published paper, "[t]he most important and practical finding from the bioaccessibility data is that the incorporation of powdered curcuminoids into buttermilk prior to yogurt manufacture results in a 15-fold increase in bioaccessibility of curcuminoids compared to that of neat curcuminoids dispersed in aqueous buffer" (Fu. 2016).

The scientists are yet also right to point out that even with the enhanced bioaccessibility of curcuminoids the total bioavailability was still low (approximately 6%) when they were delivered in yogurt.

In view of the fact that the polyphenols which are transferred into the colon are degraded by gut microflora and the degradation products contribute to the bioactivity of these compounds in the body, the real-world relevance of this astonishing increase in bioavailability will have to be tested in in vivo, before we can have a final say on the practical significance of these findings | Comment!

References:

• Ahmed, Kashif, et al. "Nanoemulsion-and emulsion-based delivery systems for curcumin: encapsulation and release properties." Food Chemistry 132.2 (2012): 799-807.
• Antony, B., et al. "A pilot cross-over study to evaluate human oral bioavailability of BCM-95® CG (Biocurcumax™), a novel bioenhanced preparation of curcumin." Indian journal of pharmaceutical sciences 70.4 (2008): 445.
• Chuah, Ai Mey, et al. "Enhanced bioavailability and bioefficacy of an amorphous solid dispersion of curcumin." Food chemistry 156 (2014): 227-233.
• Fu, Shishan, et al. "Bioaccessibility of curcuminoids in buttermilk in simulated gastrointestinal digestion models." Food chemistry 179 (2015): 52-59.
• Fu, Shishan, e al. "Enhanced Bioaccessibility of Curcuminoids in Buttermilk Yogurt in Comparison to Curcuminoids in Aqueous Dispersions." Journal of Food Science (2016): Ahead of print. doi: 10.1111/1750-3841.13235
• Yazdi, S. Rahimi, and M. Corredig. "Heating of milk alters the binding of curcumin to casein micelles. A fluorescence spectroscopy study." Food Chemistry 132.3 (2012): 1143-1149.
• Yu, Hailong, and Qingrong Huang. "Enhanced in vitro anti-cancer activity of curcumin encapsulated in hydrophobically modified starch." Food Chemistry 119.2 (2010): 669-674.
• Yu, Hailong, and Qingrong Huang. "Improving the oral bioavailability of curcumin using novel organogel-based nanoemulsions." Journal of agricultural and food chemistry 60.21 (2012): 5373-5379.

Cinnamon as Nutrient Partitioner and 1st-Line Treatment for Pre-Diabetes? 5% Decrease in Fasting Glucose per Month in Human Studies, Up to 24% in 40 Days W/ High(er) Doses

Cinnamon as Nutrient Partitioner and 1st-Line Treatment for Pre-Diabetes? 5% Decrease in Fasting Glucose per Month in Human Studies, Up to 24% in 40 Days W/ High(er) Doses

anti-diabetes cassia cinnamon cinnamon Coumarin diabesity diabetes fasting blood sugar glucose management HbA1c health insulin sensitivity lose fat

Yes, that's how real cinnamon look like. It does not grow as powder in plastic boxes on trees as I suspect the members of the generation McBurgerSubway believe ;-)

No, this is not absolutely new. In fact this is just "another" SuppVersity articles on the anti-diabetic effects of cinnamon, but I promise it's going to be the most comprehensive one. One that discusses the currently available evidence from human trials, as well as the things we know and believe to know about how cinnamon acts its anti-diabetic magic qualitatively and quantitatively.

Before I even go into further details, though, I would like to address one of the "cinnamon myths" that says that only the highly expensive Ceylon or Sri Lankan Cinnamon would do the trick, while the commonly sold Cinamon cassia would be useless or even dangerous due to its high (and in fact toxic) coumarin content.

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Interestingly, all human studies have been done with the "cheap toxic stuff from the supermarket". In view of what you are about to learn about its effects on blood glucose later in this article, the first take-home-message from today's article is thus: "Cheap cinnamon cassia will work just fine as a blood glucose management supplement!" Unfortunately, long-term studies the safety of "common cinnamon" with its highly variable coumarin content (0.31 g = harmless to 6.97 g = potentially dangerous per kg raw powder | Wang. 2013 | see Table 1) are non-existent.

Table 1: Content of Coumarin 1, Cinnamyl Alcohol 2, Cinnamaldehyde 3, Cinnamic Acid 4, Eugenol 5, Cinnamyl Acetate 6 in Cinnamomum Species and Commercial Samples (g/kg) | DUL = Detected under limits of quantitation; ND = not detected (Wang. 2013).

The only advise I can give you is thus to rely on supplements with standardized (low to non-detectable) amounts of this potentially carcinogenic substance (Wang. 2014) if you plan to take it regularly for years. Using the next best cinnamon powder from the supermarket next door on the other hand is probably not advisable even though some of the scientists who conducted the studies Arjuna B. Medagama reviewed for his (or her?) latest paper in Nutrition Journal (Medagama. 2015) probably did just that: Buy cinnamon powder from the supermarket next door to test its effects on blood glucose management in 40-days- to 4-months-studies in cinnamon-naive patients with (pre-)diabetes.

If you take a closer look at the data, though, it becomes obvious that some studies used plain cinnamon powder, while others used regular or commercial water-extracts (CinSulin. Anderson).

Effect of 6g of cinnamon on post-prandial blood glucose in healthy subjects (Hlebowicz. 2007). This hefty dose also slowed down gastric emptying and triggered non-significant increases in satiety in 14 healthy subjects after high CHO meals.

What's the optimal dosage? Even though the overview in Figure 1 suggests that "more helps more", Anand, et al. (2010) observed negative effects on the liver of rodents at dosages that would tantamount to ~40g of cinnamon per day. Ok, I assume you already apprehended that this is madness, but in the world of fitness maniacs and mad bodybuilders I thought it would be worth mentioning that even the coumarin free Ceylon cinnamon appears to have ill side effects when it is consumed in extremely high dosages. It would thus appear to be more reasonable to target an intake of 3-6 g of cinnamon with every major meal (it slows down gastric emptying and reduces postprandial blood glucose, therefore it makes sense to take it with a meal | Hlebowicz. 2007, see Figure to the left).

If you scrutinize the results I've plotted for you in Figure 1, you will notice that (a) the improvements in fasting blood glucose were significantly more pronounced than those of the long-term blood sugar maker HbA1c, that (b) the former appear to increase with the dosage that was used (Klan and Mang observed the highest reductions and used the highest amounts of cinnamon powder), and that (c) the reductions in HbA1c take time, i.e. several months and are not guaranteed, even if there are significant reductions in fasting blood glucose (cf. Belvins).

Figure 1: Relative changes in fasting blood glucose and HbA1c levels of pre-diabetic subjects (Medagama. 2015)

On average, the fasting blood glucose levels of the study participants in all studies decreased by 4.7% in four weeks; the HbA1c, on the other hand, by only 1%. Since part of the effects on blood glucose are merely a results of the reduced gastric emptying and will thus affect the peak values, yet not the overall glycemia, it appears logical that the HbA1c reacts slowly to the intervention. As Medagama points out, the effects of cinnamon are yet more far-reaching, so that more pronounced effects on the slow-reacting HbA1c levels can be expected to be seen in the hitherto non-existent long-term (= 1-2 year) studies, because cinnamon will also have ...

• 

  Figure 2: Molecular mechanisms of Cinnamon by which it exerts hypoglycaemic activity. (Medagama. 2015).

  direct effects on the insulin receptor have been observed for Cinnamtannin B1, a proanthocyanidin isolated from the stem bark of Ceylon cinnamon that activates the phosphorylation of the insulin receptor β-subunit on adipocytes as well as other insulin receptors,
• indirect effects on glucose management that are mediated by increased GLP-1 levels, a satiety hormone that decreases the amount of insulin that is necessary to clear glucose from your blood - as Medagama points out, probably by improving glucose transport,
• direct effects on the GLUT-4 glucose uptake receptor, the expression of which is increased by 42.8 % to 73.1 % in brown adipose tissue and muscle by cinnamon in a dose dependent manner,
• indirect effects on insulin sensitivity that are mediated by the effects of cinnamon on the expression of PPAR (α) and PPAR (γ), the increase of which is linked to increased glucose uptake - unfortunately, also in fat cells,
• direct effects on carbohydrate availability that are mediated by the inhibition of the amylase enzyme that is responsible for breaking down complex carbs into simple sugars,
• indirect effects on the endogenous production of glucose in the liver that is inhibited by cinnamon (glucogenesis, i.e. the storage of sugar in the liver, on the other hand, is promoted), and
• indirect effects that are brought about by the reduced rate of gastric emptying that will naturally slow down the absorption of glucose after a meal.

If that was too much for you to remember, I guess the graphical overview Medagama created may serve as a memory aid, when you come back to this article to refresh your knowledge about cinnamon and pre-diabetes. Speaking of which...

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So, what's the verdict about cinnamon and pre-diabetes? As Medagama points out in the conclusion to the previously referenced recently published review, "[b]oth true cinnamon and cassia cinnamon has the potential to lower blood glucose in animal models and humans" (Medagama. 2015). The problem is yet that we do not have reliable long-term safety studies for both, the problematic, potentially coumarin-laden regular cinnamon, as well as the expensive 99% coumarin-free Ceylon cinnamon, which has actually never been tested in human studies (rodent studies suggest that it works at least as well, though).

Addendum: As previously hinted at, there is no evidence from human studies that the "healthier", "true cinnamon" aka Ceylon cinnamon even works. Well, I just noticed that there's a single, rarely cited study in healthy individuals from the Lund University in Sweden that says that Ceylon cinammon has no effect whatsoever on glycemia and thus concludes "The Federal Institute for Risk Assessment in Europe has suggested the replacement of C. cassia by C. zeylanicum or the use of aqueous extracts of C. cassia to lower coumarin exposure. However, the positive effects seen with C. cassia in subjects w/ poor glycaemic control would then be lost." (Wickenberg. 2012)

To recommend regular cinnamon as a standard-supplement, you'd take everyday for years, on the other hand cannot really be recommended - not for pre-diabetics and by no means for healthy, active individuals who have no reason to take supplements with non-muscle specific glucose partitioning effects, anyways. If you want to improve your glucose management folks, work out - a glycogen-depleting strength or HIIT workout, that's the only scientifically proven muscle specific glucose repartitioner | Comment on Facebook!

References:

• Akilen, R., et al. "Glycated haemoglobin and blood pressure‐lowering effect of cinnamon in multi‐ethnic Type 2 diabetic patients in the UK: a randomized, placebo‐controlled, double‐blind clinical trial." Diabetic Medicine 27.10 (2010): 1159-1167.
• Anand, Prachi, et al. "Insulinotropic effect of cinnamaldehyde on transcriptional regulation of pyruvate kinase, phosphoenolpyruvate carboxykinase, and GLUT4 translocation in experimental diabetic rats." Chemico-biological interactions 186.1 (2010): 72-81.
• Anderson, Richard A., et al. "Cinnamon extract lowers glucose, insulin and cholesterol in people with elevated serum glucose." Journal of Traditional and Complementary Medicine (2015).
• Blevins, Steve M., et al. "Effect of cinnamon on glucose and lipid levels in Non–insulin-dependent type 2 diabetes." Diabetes care 30.9 (2007): 2236-2237.
• Crawford, Paul. "Effectiveness of cinnamon for lowering hemoglobin A1C in patients with type 2 diabetes: a randomized, controlled trial." The Journal of the American Board of Family Medicine 22.5 (2009): 507-512.
• Hlebowicz, Joanna, et al. "Effect of cinnamon on postprandial blood glucose, gastric emptying, and satiety in healthy subjects." The American journal of clinical nutrition 85.6 (2007): 1552-1556.
• Khan, Alam, et al. "Cinnamon improves glucose and lipids of people with type 2 diabetes." Diabetes care 26.12 (2003): 3215-3218.
• Mang, B., et al. "Effects of a cinnamon extract on plasma glucose, HbA1c, and serum lipids in diabetes mellitus type 2." European journal of clinical investigation 36.5 (2006): 340-344.
• Suppapitiporn, Suchat, and Nuttapol Kanpaksi. "The effect of cinnamon cassia powder in type 2 diabetes mellitus." Journal of the Medical Association of Thailand= Chotmaihet thangphaet 89 (2006): S200-5.
• Vanschoonbeek, Kristof, et al. "Cinnamon supplementation does not improve glycemic control in postmenopausal type 2 diabetes patients." The Journal of nutrition 136.4 (2006): 977-980.
• Wang, Yan-Hong, et al. "Cassia cinnamon as a source of coumarin in cinnamon-flavored food and food supplements in the United States." Journal of agricultural and food chemistry 61.18 (2013): 4470-4476.
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GABA Supplementation Improves Glucose Management - Even in Healthy Subjects | Significant Reduction in Glycated Albumin Levels After Only 7 Days on 3x2g GABA per Day

GABA Supplementation Improves Glucose Management - Even in Healthy Subjects | Significant Reduction in Glycated Albumin Levels After Only 7 Days on 3x2g GABA per Day

anti-diabetes beta cells blood glucose diabetes gaba gamma aminobutyric acid glucagon glucose management health insulin lose fat

No acute changes in blood glucose, but extreme changes in insulin levels. How can this trigger a reduction in glycated albumin - How's that possible? 

You've read about gamma aminobutyric acid (GABA) at the SuppVersity before. While most people think of it mainly as a calming agent, though, SuppVersity readers know that it has the remarkable ability to heal the insulin producing β-cell in rodents by stimulating their replication, protecting them against apoptosis, and attenuating insulitis (Soltani. 2011; Tian. 2013; Prud'homme. 2014; Purwana. 2014). And while these favorable effects were first observed in mice, researchers are quite sure that they are valid in humans, too- that's also because said effects have been confirmed only recently by Tian et al. (2014) and Purwana et al. (2014) in vitro as well as in xenotransplanted human islets.

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If you know that, the observations researchers from the Fudan University in Shanghai report in their latest study probably won't come as a surprise. In their investigation into the  pharmacokinetics and pharmacodynamics of GABA in healthy volunteers, the researchers found that the chronic provision of 2g of GABA three times per day triggers a highly significant decrease in glycated albumin (GA) levels, the intermediate measure of blood glucose control (in-between acute blood glucose measurements and HbA1c | Roohk. 2008), within only 7 days.

Figure 1: Acute glucose (top) and insulin (bottom) response after single and repeated administration of 2g of GABA (left). Chronic effects of repeated dose-administration of GABA on glycated albumin (right | Li. 2015).

If you scrutinize the data in Figure 1, though, there are a few questions we still need to find answers to. Obviously, the acute administration of GABA (Figure 1, left) lead to significant increases in insulin - both, under either fasting (1.6-fold, single dose; 2.0-fold, repeated dose; p < 0.01) or fed conditions (1.4-fold, single dose; 1.6-fold, repeated dose; p < 0.01).

Glucose, insulin and glucagon: Let's briefly recap how the three are related. To lower your glucose levels, your body produces insulin which will then tell your cells suck the glucose from the bloodstream. If the glucose levels are getting lower and lower, your body produces glucagon which will then trigger a cascade of events to increase your blood glucose levels. This can be done by mobilizing stored glycogen (mostly from the liver) or producing new glucose via gluconeogensis - a process that relies heavily on amino acids, first and foremost alanine and glutamine.

Usually, this 1.4-fold or 1.6-fold increase in insulin should trigger a significant (at least transient) decrease in blood glucose. Since the latter wasn't the case in either the fasted or the fed tests the scientists conducted on the twelve subjects, who participated in the open-labeled, three-period trial, it appears more than counter-intuitive that the chronic administration of GABA which does not accumulate in the body and was found to be almost completely absorbed in 60 minutes and to have a half-life of 5h still lead to an GA decrease of approximately 11-12%.

Now this obviously confirms that GABA, due to its ability to increase islet hormonal secretion, has potential therapeutic benefits for diabetes, what the study does not tell us, though, is whether the lack of immediate effects on blood glucose levels can, as the scientists suspect, "in part be attributed to GABA-induced counter regulatory mechanisms, especially elevated glucagon" (Li. 2015) which rose so that the insulin-to-glucagon ratio remained unchanged. Yet while the latter could explain why the subjects did not become hypoglycemic in the face of increased insulin levels, the lack of certainty with respect to the underlying mechanisms makes the study results difficult to interpret.

As a loyal SuppVersity reader you will know that I talked about the potential need to re-balance glucose levels and its paradoxically agitating effects in a 2013 episode of SHR, already.

So what's the verdict, then? Whether and for whom GABA can be useful tool to improve his or her blood glucose management is virtually impossible to tell based on the study at hand. In spite of the fact that the scientists observed only minor adverse events such as transient dizziness and a sore throat, a further reduction of glycated albumin levels is not necessary an advantage that's worth having elevated insulin and glucagon levels. The latter would after all promote the use of proteins or rather amino acids as substrate for gluconeogenesis, the process of which the scientists believe that it is responsible for the non-existent instantaneous glucose response in the study at hand, while the former, i.e. the increase in insulin levels, is well-known for its negative effects on fatty acid oxidation.

Overall, "the verdict" is thus that we need additional research in both, healthy and diabetic individuals to be able to tell for whom the benefits of chronic high(er) dose (3x2g per day) GABA supplementation outweigh potential side effects. If you asked me for an educated guess, though, I would say (pre-)diabetics benefit while the average individual sees either no relevant benefits or detrimental effects due to the repeated need to re-stabilize the blood sugar levels... a phenomenon of which I have by the way previously said and written that it may explain the paradoxically agitating effects the ingestion of GABA has on some individuals - most likely those with already low(ish) blood glucose levels | Comment on Facebook!

References:

• Li, Junfeng, et al. "Study of GABA in Healthy Volunteers: Pharmacokinetics and Pharmacodynamics." Frontiers in Pharmacology 6 (2015): 260.
• Prud’homme, Gérald J., et al. "GABA protects human islet cells against the deleterious effects of immunosuppressive drugs and exerts immunoinhibitory effects alone." Transplantation 96.7 (2013): 616-623.
• Prud’homme, Gérald J., et al. "GABA protects pancreatic beta cells against apoptosis by increasing SIRT1 expression and activity." Biochemical and biophysical research communications 452.3 (2014): 649-654.
• Purwana, Indri, et al. "GABA promotes human β-cell proliferation and modulates glucose homeostasis." Diabetes 63.12 (2014): 4197-4205.
• Roohk, H. Vernon, and Asad R. Zaidi. "A review of glycated albumin as an intermediate glycation index for controlling diabetes." Journal of diabetes science and technology 2.6 (2008): 1114-1121.
• Soltani, Nepton, et al. "GABA exerts protective and regenerative effects on islet beta cells and reverses diabetes." Proceedings of the National Academy of Sciences 108.28 (2011): 11692-11697.
• Tian, Jide, et al. "γ-Aminobutyric acid inhibits T cell autoimmunity and the development of inflammatory responses in a mouse type 1 diabetes model." The Journal of Immunology 173.8 (2004): 5298-5304.
• Tian, Jide, et al. "Oral GABA treatment downregulates inflammatory responses in a mouse model of rheumatoid arthritis." Autoimmunity 44.6 (2011): 465-470.
• Tian, Jide, et al. "γ-Aminobutyric acid regulates both the survival and replication of human β-cells." diabetes 62.11 (2013): 3760-3765.
• Tian, Jide, et al. "Combined Therapy With GABA and Proinsulin/Alum Acts Synergistically to Restore Long-term Normoglycemia by Modulating T-Cell Autoimmunity and Promoting β-Cell Replication in Newly Diabetic NOD Mice." Diabetes 63.9 (2014): 3128-3134.