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.

Cure! Diabetes With 8 + 24 Week Diet Intervention: 40% Stay Normo-Glycemic After Switching from VLCD to Normal Diet

Cure! Diabetes With 8 + 24 Week Diet Intervention: 40% Stay Normo-Glycemic After Switching from VLCD to Normal Diet

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If gaining body fat triggers T2DM, is is not surprising that losing it, cures it.

From the SuppVersity Facebook News you will remember that studies have shown that type II diabetes can be send into remission with "nothing" but a very low energy diet (Steven. 2015). The question scientists still had to answer, though, was whether the astonishing improvements in glycemia and overall health could be maintained on an energy-sufficient diet. In a newstudy from the Newcastle University scientists did now try to confirm just that by combining an 8-week dieting phase with a stepped return to isocaloric diet based on a structured, individualized (isocaloric) program of weight maintenance.

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Glucose control, insulin sensitivity, insulin secretion, and hepatic and pancreas fat content were quantified at baseline, after return to isocaloric diet, and after 6 months to permit the primary comparison of change between post–weight loss and 6 months in responders.

Table 1: Fasting anthropometric and metabolic data in responders and nonresponders at baseline, after VLCD and return to isocaloric eating, and after the 6-month weight maintenance period (Steven. 2016).

To qualify as "responder" and thus patient who successfully reversed his diabetes, the subjects, thirty individuals with T2DM who had been suffering from T2DM for either either short- (<4 years) or long (<8 years)-duration, had to achieve a fasting blood glucose <7 mmol/L - and that not just after the initial 6 weeks, but after return to isocaloric diet.

Figure 1: The weight loss speaks in favor of the efficacy of the diet intervention in both groups; filled responders, open circles non-responders (Steven. 2016).

What did the diet look like? The VLCD consisted of a liquid diet formula (43% carbohydrate, 34% protein, and 19.5% fat; 2.6 MJ/day [624 kcal/day]; OPTIFAST; Nestle Nutrition, Croydon, U.K.) taken as three shakes per day. In addition, up to 240 g of nonstarchy vegetables was consumed, making total energy intake 624–700 kcal/day. Participants were encouraged to drink at least 2 L of calorie-free beverages per day and to maintain their habitual level of physical activity. To maximize adherence, one-to-one support was provided weekly by telephone, e-mail, text message, or face-to-face contact (S.S.).

During stepped food reintroduction, shakes were gradually replaced by solid food over 7 days; with one meal replacing a shake every 3 days. Isocaloric intake was determined from resting energy expenditure measured by indirect calorimetry using an open circuit calorimeter (Quark RMR; COSMED, Rome, Italy) and a canopy hood and ended up ~1/3 below their previous obesogenic food intake - no wonder that they got diabetic before at an energy intake that was ~30% above what they'd needed to stay in a healthy body fat range. Physical activity was encouraged, but food behaviors were the priority.

As the average weight loss in Figure 1 tells you, all but one subject that was excluded after the initial 8-week VLCD phase, achieved a highly significant weight loss. What not all subjects achieved, however, was the desired diabetes remission. To be more precise, only 40% of the participants (12 of 30) achieved the targeted fasting glucose <7.0 mmol/L levels (responders) after return to isocaloric eating (to put that in perspective | even RYGB weight loss surgery achieves only 9% remission rates; albeit measured over 14 vs. 4 months | Wood. 2015). Since that's in spite of similar weight loss, the question is: What is it that made the difference between responders and non-responders? The answer is complex and consists of many factors:

• The responders (n = 12 [8 males, 4 females]) had a shorter diabetes duration (3.8 +/- 1.0 vs. 9.8 +/- 1.6 years, P = 0.007) 
• The responders were also younger (52.0 +/- 2.9 vs. 59.9 +/- 2.1 years, P = 0.032) than nonresponders (n = 17 [7 males, 10 females]). 
• Responders were more likely to suffer from diabetes for a short(er) duration (9 of 15 of the short-duration and 3 of 14 of the long-duration groups).
• At baseline, responders had lower fasting glucose(8.9 +/- 0.7 vs. 13.2 6 0.6 mmol/L, P < 0.001) and HbA1c (7.1 +/- 0.3 vs. 8.4 6 0.3% [55 +/- 4 vs. 68 +/- 3 mmol/mol], P = 0.01). 

In addition, the responders had a lower total fat mass than the nonresponders at baseline (P = 0.04) (see Table 1) and didn't try as many (failed) treatment options, such as diet control (five vs. two); metformin only (six vs. four); metformin and sulfo nylurea (one vs. seven); metformin, sulfonylurea, and insulin (zero vs. two); metformin, sulfonylurea, and thiazolidi nedione (zero vs. one); and insulin only (zero vs. one), as the nonresponders did before participating in the study at hand.

Diabetes can be cured by dieting down below your personal fat threshold! A previous study led by Professor Roy Taylor from 2011, who commented on the study at hand in press release stating that "[t]he study also answered the question that people often ask me - if I lose the weight and keep the weight off, will I stay free of diabetes?" and answering his own question as follows: "The simple answer is yes!" In the same press release from the Newcastle University, Taylor highlights that the results of the study at hand "supports our theory of a Personal Fat Threshold. If a person gains more weight than they personally can tolerate, then diabetes is triggered, but if they then lose that amount of weight then they go back to normal" and adds "[t]he bottom line is that if a person really wants to get rid of their Type 2 diabetes, they can lose weight, keep it off and return to normal."

It is important to point out that the study at hand is part of a growing body of evidence showing that people with Type 2 diabetes who successfully lose weight can reverse their condition (Lim. 211; Steven. 2015)- probably because the fat loss correlates with a reduced fat deposition and increased function in / of the pancreas.

Figure 2: While there were no sign. differences in weight loss, there were other antropometric and related differences between the two groups: BMI, body fat %, triglycrides and the insulin resistance of the liver (Stevens. 2016).

And with a larger trial involving 280 free-living patients is already underway, it may only a question of time before people can no longer ignore that type II diabetes, which is triggered by bad lifestyle choices, can be reversed by healthy ones. This can be "tough" as Allan Tutty, 57, from Sunderland, who transformed his health by taking part in the study and is now

"eat[ing] normal foods though [...] less than [he] used to, and enjoy[ing] takeaways and chocolate but not on a regular basis so [he has] maintained my lower weight [and] changed [his life]completely thanks to this research" (Tutty in press release),

says; and still, I am pretty sure that, just like Tutty who says that, "with [his] diabetes in remission, I haven't looked back", those who are able and willing to follow Tutty's example won't look back either.

The elevated liver enzymes observed in the study point, once again, to the liver - Learn how to help your liver manage your glucose metabolism in this SuppVersity Classic.

Dieting is a diabetes cure, but one that does not work for everyone - yet? While it is not clear whether a longer weight-loss phase that would have brought the non-responders to similarly low bodyfat percentages as the responders wouldn't have changed the results, we have to be honest:  losing weight is easy, but eating 30% less than before, because that's all you need w/ your now normal weight is difficult... too difficult for many, probably.

With that being said, it should be obvious that further research is necessary to determine the factors that distinguish responders from non-responders and whether the latter simply failed to pass their "personal fat threshold" as Professor Taylor's remarks suggest | Comment!

References:

• Lim, Ee Lin, et al. "Reversal of type 2 diabetes: normalisation of beta cell function in association with decreased pancreas and liver triacylglycerol." Diabetologia 54.10 (2011): 2506-2514.
• Steven, S., and R. Taylor. "Restoring normoglycaemia by use of a very low calorie diet in long‐and short‐duration Type 2 diabetes." Diabetic Medicine 32.9 (2015): 1149-1155.
• Steven, et al. "Very-Low-Calorie Diet and 6 Months of Weight Stability in Type 2 Diabetes: Pathophysiologic Changes in Responders and Nonresponders." Diabetes Care (2016) Accepted Article.
• Wood, G. Craig, et al. "Preoperative use of incretins is associated with increased diabetes remission after RYGB surgery among patients taking insulin: A retrospective cohort analysis." Annals of surgery 261.1 (2015): 125-128.