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.

You can learn more about sweeteners at the SuppVersity

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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.

Baking Bread With ~100g Extra-Fat Reduces the Glycemic Response: Coconut Oil Beats Butter, Grapeseed & Olive Oil

Baking Bread With ~100g Extra-Fat Reduces the Glycemic Response: Coconut Oil Beats Butter, Grapeseed & Olive Oil

bread diabetes glucose management glycemia health high fat insulin resistance lose fat

No, adding fat to your bread's dough won't make you lose fat magically.

While fat no longer has the bad rep it still had a decade ago, the notion that baking bread with extra fat could have anti-diabetic effects, because it reduces the glucose peaks and the 2h area under the curve (AUC) is unconventional, to say the least; and thus SuppVersity news-worthy, because it is not broscience, but the result of a recent study.

In said study, the scientists tested (a) the effect of different types of fat / oil on the formation of amylose–lipid complexes (ALC) and, more importantly, (b) the effect of the ALCs on the glycemic response to a standardized amount of bread that was baked with the same amount of different fats / oils.

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The study was an acute, randomised, controlled, single-blinded trial that consisted of five types of bread, each tested on one occasion in a randomised order on separate days, with at least 3 washout days between test visits.

"Participants were recruited through advertisements and personal communications. Inclusion criteria were as follows: (1) males aged between 21 and 50 years, (2) BMI values between 18·0 and 24·9 kg/m2, (3) blood pressure≤120/80 mg/dl and (4) fasting blood glucose≤6·0 mmol/l. People who had metabolic diseases, were on prescribed medication, were smokers, took part in sports at competitive levels or were concurrently participating in other clinical trials were excluded from the study. Females were excluded from the study to prevent differences in menstrual cycles from affecting carbohydrate metabolism" (Lau. 2016).

On the day before a test session, no drinks, caffeine or physical activity were allowed. In addition, a standardised dinner was provided the evening before to reduce potential variations in GR that may arise because of the second meal effect. On the day after, participants had to report to the centre after a 10–12 h fast between 08.00 and 09.00 hours. There, they rested for at least 15 min before starting the test session, before the test meal was consumed "at a comfortable pace within 15 min" (Lau. 2016). Following consumption of test bread, participants were asked to rate their liking of the bread on a 100-mm liking scale. Blood samples (both venous and capillary) were collected at 15, 30, 45, 60, 90, 120, 150 and 180 min after test bread consumption. The same protocol was repeated until the completion of all the five test sessions.

Serving size, energy content and macronutrient composition of the test breads (per serving | Lau. 2016)

How was the bread prepared? This is what the scientists report: "The five types of bread used were as follows: control bread without any added fats (CTR) and breads baked with butter (BTR), coconut oil (COC), grapeseed oil (GRP) or olive oil (OLV). The ingredients used for test breads were as follows: 250 g bread flour (Prima), 125 g potable water, 10 g baker’s yeast (SAF), 40 g sugar (Fairprice) and 6 g salt (Fairprice). These ingredients were mixed at speed 1 for 8 min (Kitchenaid) to form base dough, of which 320 g was weighed and then fat/oil was added.

The fats/oils added were 96 g butter that contained predominantly SFA (Anchor), 87 g coconut oil that was rich in medium-chain TAG (Titi Ecofarm), 80 g grapeseed oil containing predominantly PUFA (Borges) and 76 g olive oil containing predominantly MUFA (Naturel). The amount of fats/oils added was calculated based on the percentage fat as stated on the nutritional panel on the packaging, and was added at 20 %, w/w of dough. Oil was not added into the control bread. The dough mixture was kneaded for a further 12 min, and was then allowed to rest at room temperature for 10 min. Following this, the dough was moulded into serving portions and proofed in the oven (EOB98000; Electrolux) at 40±1°C for 30 min in a fan-assisted mode. Baking was carried out in the same oven at 200°C for 18 min, and bread was allowed to stand for 10 min before being served warm" (Lau. 2016).

The results of the scientists' analysis of the ALC formation in the bread showed that the coconut (COC) and olive oil (OLV) had significantly higher amylose–lipid complex forming ability [reported wrong in the result section of the FT, but correct in the discussion] as compared with butter (BTR) and grapeseed oil (GRP | P<0·05).

Figure 1: Complexing index results for different types of bread. Values are means (n 6), with standard errors represented by vertical bars. a,b Mean values with unlike letters were significantly different (P < 0·05; one-way ANOVA with post hoc Tukey’s test). BTR = butter; COC = coconut oil; GRP = grapeseed oil; OLV = olive oil (Lau. 2016).

Interestingly, the increased ALC levels in the olive oil bread did not produce the same beneficial effects on the glucose response the scientists observed when the subjects consumed the bread that was baked with coconut oil.

Figure 2: (a) Postprandial response curves for change in blood glucose and (b) plasma insulin levels after consumption of 50 g available carbohydrate portion of test bread. Values are means (n 15), with standard errors represented by vertical bars. For glucose response, there were significant time (P < 0·001), bread (P < 0·001) and bread×time interaction effects (P=0·002) when analysed by two-way, repeated-measures ANOVA. For insulin response, two-way, repeated-measures ANOVA showed a significant time effect (P < 0·001) and bread×time interaction effect at near significant levels (P=0·074), but no effect of bread was seen (P=0·195). open circle, Control bread without oil; filled circle, bread with butter; open triangle, bread with coconut oil; filled triangle, bread with grapeseed oil; open square, bread with olive oil (Lau. 2016).

As you can see in Figure 2, all fat-enhanced breads improved the glycemia, but only the grapeseed (closed triangle) and coconut (open triangle) oils also rduced the insulin levels.

Can't I just add the coconut oil on top of the bread? No, you can't, because it has to be in the dough during baking - otherwise the amylose–lipid complexes won't form. What will happen though is that your insulin levels will rise sign. longer (see previous SV article). Edit: Elizabeth Alcott just posted this cool suggestion on Facebook: "Bake low carb coconut flour bread with coconut oil. Reduced calories and glycemic response at the same time." Not a bad idea, for sure.

What is interesting to see, though, is that the glucose AUC, i.e. the total amount of glucose that is released into the blood was still the lowest in those oils / fats with the highest ALC levels: coconut oil and olive oil.

Figure 3: Postprandial glycaemic and insulinaemic responses (AUCs for 180min) after consumption of test bread (Mean values with their standard errors for fifteen healthy young men | Lau. 2016)

As the authors point out in the discussion of the results of their study, their regression analysis "further confirmed that CI [=indicator of ALC formation] was a significant predictor of GR [glucose response], although it only accounted for 13·3 % of the observed variability" (Lau. 2016). Furthermore, the scientists highlight that ...

"[w]hen examined as IAUC, COC showed the greatest attenuation of GR [glucose response] in baked bread. A similar study by Clegg et al. (2012) showed that high-fat pancakes containing MCT had the slowest gastric emptying rate as compared with other fats/oils over a 4-h period. The low GR [glucose response] of COC in this study could be due to a combination of factors. These include delay in gastric emptying rates to MCT having a higher osmolarity (Clegg. 2012) and formation of ALC resulting in resistant starch (Kaur. 2000)" (Lau. 2016).

To assess the physiological significance of these observations, Lau et al. also investigated the surrogate measures of postprandial β-cell function (IGI30 and IGR) and the insulin response which did - in contrast to the glucose response (see Figure 3), not correlate with the ALC content of the breads. Instead, it appeared to be "partially due to rate of appearance of glucose as a result of carbohydrate digestibility" (Lau. 2016).

Will the additional butter on top of the potatoes reduce the insulin response? You can find the answer to this and the other questions in today's episode of "True or False?" | learn more!

So, what's the verdict? Well, adding ~25g of fat to bread increases its energy content significantly. Therefore, it is not clear how advantageous the improvements in glycaemia observed in the study at hand will actually be - after all, calories still count!

With that being said, the scientists' conclusion that "[t]he incorporation of fats during bread baking reduces GR, with the greatest attenuation seen in COC," is a significant result. One that can be partly explained by the reduction in carbohydrate digestibility via ALC formation, but not by any effects on the insulin response to the meal (if you fear insulin, adding fat is thus not going to cut it | learn more).

That the 'coconut advantage' is due to lauric acid and myristic acid in coconut oil is likely, but warrants further investigation; the same goes for the scientists' concluding remark that "[t]he use of simple dietary interventions (addition of functional lipids during cooking of carbohydrate-rich staple foods) may be an effective and practical strategy for improving glycaemic control, and may help in the prevention and management of [...T2DM] and CVD" (Lau. 2016) | Comment!.

References:

• Clegg, Miriam E., et al. "Addition of different fats to a carbohydrate food: Impact on gastric emptying, glycaemic and satiety responses and comparison with in vitro digestion." Food Research International 48.1 (2012): 91-97.
• Kaur, Kulwinder, and Narpinder Singh. "Amylose-lipid complex formation during cooking of rice flour." Food Chemistry 71.4 (2000): 511-517.
• Lau, et al. "Effect of fat type in baked bread on amylose–lipid complex formation and glycaemic response." British Journal of Nutrition, Published online: 22 April 2016.