Resistant Starch (RS4) for Fat Loss & Exercise Performance

Resistant Starch (RS4) for Fat Loss & Exercise Performance

cycling lose fat performance resistant starch RS RS4

RS4 is still relatively difficult to come by. Options I know of are ActiStar® from Cargill and Fibersym® fom MGP. RS2 and RS3 alternatives are raw potato starch and, as previously discussed, banana starch or reheated starches. They'll have (presumably) very similar effects, but come directly from food.

You will probably remember the good old "Waxy Maize Reloaded" article from 4 years ago that caused quite a stir!? Well, I guess four years is a long time - more than enough to revisit the idea of designer resistant starches and their effect on your physique and performance. To do so, I've picked two recent studies from the South Dakota State University (Upadhyaya. 2016) and the Florida State University (Baur. 2016) that have one thing in common: they add to the hitherto still inadequate number of studies on resistant starch type 4 (RS4), one out of five forms of "resistant", i.e. (partly) undigestible, starches with significantly different chemical properties and corresponding functional differences such as their fermentability or their influence on the microbiota in the gut and their applicability as ergogenics in sports drinks and/or functional foods.

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To elucidate the effects on the gut microbiome and the production of health-relevant short-chain fatty acid (SCFA) production, of which the previously cited article about WM-HDP from 2012 explains how they affect GLP-1, glycemia and metabolism (read it), Upadhyaya et al. conducted an experiment with twenty individuals with signs of, but not fullly established metabolic syndrome (MetS).

Table 1: Overview of the study design (Upadhyaya. 2016).

With a total duration of 26 weeks that included two 12-week interventions periods, with one each for RS4 (30%, v/v in flour that is currently not available in supermarkets) and control flour (CF), and a two-week washout in between the interventions, the randomized cross-over study is one of the longest dietary interventions with any form of resistance starch I have read and thus also the one with the highest potential of yielding relevant insights into the long-term effects of RS-4 consumption. As previously pointed out, ...

"[...] all twenty participants who had signs of metabolic syndrome at baseline and submitted adequate stool samples at four data collection time points were included in the current investigation, which allowed for comparison of the gut microbial and SCFA profiles before and after the interventions and also between the endpoints of the RS4 and CF (control) interventions" (Upadhyaya. 2016). 

In view of the fact that adverse gastrointestinal side effects from the interventions were not evaluated in this cohort, we have to simply follow the scientists' reasoning that no bloating, belching or other unwanted sides would occur - an assumption that appears to be at least reasonable in view of the observations the scientists made in a previous study w/ similar design (Nichenametla. 2014).

The visible performance decrements in the low HMS group was sign. correlated with gastrointestinal distress (Baur. 2016).

What about performance? Those were evaluated by Daniel A. Baur in a study which investigated the metabolic and gastrointestinal effects of a hydrothermally-modified starch supplement (HMS) before and during cycling for ~3 h (1 h at 50% Wmax, 8 x 2-min intervals at 80% W max, and 10 maximal sprints) in 10 in male cyclists who underwent three nutritional interventions (crossover design): (1) a commercially available sucrose/glucose supplement (G) 30 min before (60 g carbohydrate) and every 15 min during exercise (60 g/h); (2) HMS consumed at the same time points before and during exercise in isocaloric amounts to G (Iso-HMS); and (3) HMS 30 min before (60 g carbohydrate) and every 60 min during exercise (30 g/h; Low HMS).

Interestingly enough, the supplement had no effects on sprint performance with Iso HMS vs. G, being identical and G and Iso HMS resultin in nothing but a "likely", yet small performance enhancement of 5.0% compared to the "low carb" = Low HMS trial.

What may  be considered a success, though, is the sign. increase in fat oxidation (31.6%+/-20.1%; very likely (Iso); 20.9%+/.16.1%; likely (Low)) and corresponding reduction in carbohydrate oxidation (19.2%+/-7.6%; most likely; 22.1%+/-12.9%; very likely) during exercise relative to the plain glucose trial (G). That the latter was dearly bought by increased during repeated sprints with ingestion of Iso HMS (17 scale units +/-18; likely) and Low HMS (18 +/-14; likely) that also explained the decreased performance with Low HMS vs. G (likely), future studies will have to either find ways to make HMS more gut friendly or test whether the repeated administration of HMS solves the issue by the means of intestinal adaptation - a corresponding study could also yield insights into whether the increased fatty oxidation would also trigger long-term mitochondrial growth that goes beyond what you'd see with regular Gatorade aka a sugar-containing workout beverage.

I know that you will probably me most interested in the effects on the subject's body composition. Therefore I plotted those in Figure 1 and postponed the presentation and discussion of the authors' actual research interest, the microbial composition of their subjects guts on a later paragraph.

Figure 1: Effects of control and RS4 diet on body composition and lipid variables (Updahyaya. 2016).

As you can see, the consumption of the RS4 diet had significant (beneficial) effects on the subjects' waist lines (~2% or 2 cm vs. baseline and control). In conjunctions with the beneficial effects on HDL (p = 0.001) and total cholesterol (p = 0.01), which were 10% higher and lower, respectively, after the RS4 vs. control diets, and a significant increase in adiponectin (p < 0.01), and none-significant improvements in fasting blood glucose (+5% and -4% vs. baseline in control and RS4, respectively) and HbA1c (-1% and -2% vs. baseline in control and RS4, respectively), there appears to be little doubt that the significant improvement in the firmicute to bacteriode ratio, which is frequently perceived as an indicator of a leaner phenotype (although the previously reported results are not always consistent | Fernandes. 2014) in the RS4 weeks, as well as specific results, such as ...

• the previously observed increase of species from Clostridial cluster XIVa, but not cluster IV, that was triggered by RS4 supplementation of the diet; at the species level, RS4 consumption increased the abundance of Bifidobacterium adolescentis (90.5 fold, q= 0.087) and Parabacteroides distasonis (1180.2 fold, q< 0.001) but not Ruminococcus bromii (−3.2 fold, q > 0.05), Faecalibacterium prausnutzii (−1.2 fold, q > 0.05), or Dorea formicigenerans (1.1 fold, q> 0.05)

• 

  Timing Matters if You Want to Turn Regular into Resistant Starch | more

  a not previously observed RS4-induced increase in Christensenella minuta abundance (119.7 fold, q= 0.038, 97% query coverage, 88% identity and E< 0.001 in NCBI-BLAST) as well as in several OTUs in the family Ruminococcaceae and genus Bacteroides; at the species level, Bacteroides ovatus (37.6 fold, q= 0.087), Ruminococcus lactaris (2866.7 fold, q< 0.001), Eubacterium oxidoreducens (3.3× 105 fold, q< 0.001), Bacteroides xylanisolvens (47.8 fold, q= 0.037), and Bacteroides acidifaciens (92.4 fold, q= 0.038) were enriched after RS4 intervention
• changes in the individual proportions of the SCFAs, butyric (69.5%, p= 0.03), propionic (50.2%), valeric (44.1%), isovaleric (20.3%), and hexanoic (19.2%) acids increased post intervention from baseline in the RS4 group (p< 0.05) but not in the CF group (data not shown)
• correlations between significant changes in the gut microbiota composition induced by RS4 and altered SCFA level that were not observed after the control treatment

provide reasonable evidence for the use of RS4 as a food additive (in place of regular starches, obviously). In that, it is also important point out is that the changes in body composition, lipoproteins, glucose control and the bacterial composition of the subjects' microbiome occured in the absence of significant differences in macronutrient intake,... well, aside from the dietary fibre intake, which was obviously significantly higher in the RS4 group (p< 0.001). After all, RS4 is officially being classified as a prebiotic dietary fibre.

Figure 2: Differential gut microbial composition after RS4 intervention at the species level (left) and correlations with important metabolic outcomes from total cholesterol (TC) to adiponectin (right | Upadhyaya. 2016).

Overall, the average calories (~1,774 Kilocalories) consumed at baseline were estimated to come from carbohydrate (~49%), protein (~17%), and fat (~34%) - values you may criticize, but of which the authors rightly point out that they "fall within the Dietary Reference Intakes (DRI) for macronutrients, which are 45–65%, 10–35%, and 20–35% for carbohydrate, protein, and fat", respectively.

Is RS4 different from other prebiotics?It obviously is structurally different, so it is not 100% surprising that a previous parallel design study u-sing other prebiotics, na-mely inulin and oligofruc-tose, suggests that the ensuing improvement in metabolic functions and body composition are more pronounced with RS4 compared to other prebiotics.

Bottom line: In sum the two studies provide reasonable evidence for the addition of RS4 to your diet and/or functional foods. There is one thing you should keep in mind: the potential ergolytic effect that comes with the intestinal side effects in those who cannot handle the RS4-laden Gatorade alternative. Before you buy a few pounds of RS4 at the bulk-supplier of your trust, you should thus better test-drive your individual RS4 tolerance.

Since similar effects were not observed by Nichenametla and Updahyaya in their 2014 and 2016 studies, it is yet safe to assume that this effect may be exposure dependent with the use of  30% v/v RS4 in flour - a strategy that could also be employed in processed foods having no significant effect on the digestive health of the average customer, but a sign. effect on his waist circumference | Comment!

References:

• Baur, Daniel A., et al. "Slow-Absorbing Modified Starch before and during Prolonged Cycling Increases Fat Oxidation and Gastrointestinal Distress without Changing Performance." Nutrients 8.7 (2016): 392.
• Dewulf, Evelyne M., et al. "Insight into the prebiotic concept: lessons from an exploratory, double blind intervention study with inulin-type fructans in obese women." Gut (2012): gutjnl-2012.
• Fernandes, J., et al. "Adiposity, gut microbiota and faecal short chain fatty acids are linked in adult humans." Nutrition & diabetes 4.6 (2014): e121.
• Nichenametla, Sailendra N., et al. "Resistant starch type 4‐enriched diet lowered blood cholesterols and improved body composition in a double blind controlled cross‐over intervention." Molecular nutrition & food research 58.6 (2014): 1365-1369.
• Upadhyaya B, et al. "Impact of dietary resistant starch type 4 on human gut microbiota and immunometabolic functions." Sci Rep. 2016 Jun 30;6:28797. doi: 10.1038/srep28797.

Cheese & Your Health: CVD, Cancer & Metabolic Syndrome - Cheesy Science or Scientific Revelation? A Brief Review

Cheese & Your Health: CVD, Cancer & Metabolic Syndrome - Cheesy Science or Scientific Revelation? A Brief Review

cheese dairy diet health healthy diet healthy eating lose fat

Cheeses come in all forms and colors.

Cheese is not exactly the first food that comes to mind when we think about "healthy eating". Rightly so? Today's overview of recent cheese studies tries to answer this question.

The article will, among other things, also address the claim that cheese was addictive (see red box) and / or that the consumption of a dairy product with a saturated fat content that is second only to that of butter would harm your cardiovascular and metabolic health.

So, where do we start? Netherlands? Well, even though the Dutch are famous for the many different types of cheese they produce and consume, they are probably not the ones who "invented" it. Rather than that it appears to be certain that the first cheeses were produced 5,000 BC - accidentally.

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Back in the day, humans had not invented pottery and thus stored their foods - including their milk - in animal stomachs, ... stomachs the cuagulating enzyme content of which turned milk into curd during storage (Fox. 1993). The first recorded "production" of cheese, in that case Gorgonzola dates back to the year 897, however (see Table 1).

Table 1: First Recorded Date for some Major Cheese Varieties (Fox. 1993).

Another cheesy fact about the Netherlands is that the Dutch would be the world's #1 cheese producer and consumer. Both is not the case! Rather than that, France holds both the title of the greatest producer (1.3 m tonnes) and consumer (22kg / per capita | Fox. 1993 // relative to their total dairy consumption, the Italians are the kings of cheese w/ up to 28% and 33%  of the dairy intake from cheese of women and men in the province Ragusa | Hjartåker. 2002). It is thus also France, where we will probably find the most significant evidence with regards to the health effects of cheese consumption. The most prominent study investigating this issue comes from the Aarhus University (Zheng. 2015)..

Is cheese the reason for the "French paradox"?

In said study, Zheng et al. used an NMR-based metabolomics approach "to investigate the differentiation between subjects consuming cheese or milk and to elucidate the potential link to an effect on blood cholesterol level" (Zheng. 2015). To this ends, the researchers recruited fifteen healthy young men for a full crossover study during which all subjects consumed three isocaloric diets with similar fat contents that were either (1) high in milk, (2) high in cheese or (3) contained only limited amounts of dairy for 14 days.

Only the fat "Norvegia" gouda has cholesterol-lowering effects in an 8 week RCT (Nilsen. 2015).

Question 1 - Does the type of cheese matter? High fat may matter. Well, "fake cheese" that's made from vegetable oils + tons of additives, as you will find it on most frozen Pizza from the supermarket is obviously not an option, but even among "real" cheeses there appear to be differences in terms of their individual health effects. The results of a 2015 study from Norway, for example, show that only fat gouda (80g/day), yet not fat- and salt-free Gamalost, a traditional form of Norwegian cheese will significantly reduce elevated cholesterol levels in non-medicated men and women over 18 years of age (Nilsen. 2015).

As the data from the scientists urine and feces analyses shows, the cheese diet significantly reduced the urinary citrate, creatine, and creatinine levels and significantly increased the microbiota-related metabolites butyrate, hippurate, and malonate compared to the milk diet. Overall, the study shows...

"[...] that cheese consumption is associated with an increased level of SCFAs in the gut, possibly induced by stimulation of beneficial gut microbiota, as well as an increased extent of lipid excretion with resultant beneficial effects on cholesterol metabolism"(Zheng. 2015 | my emphasis).

In conjunction with the significant reduction of the subjects' TMAO production [Trimethylamine N-oxide has been associated with increased CVD and even cancer risk] of which the authors rightly say that it could "also contribute to potential beneficial effects of cheese intake on the risk of CVD" (Zheng. 2015), the results of this controlled human trial are in stark contrast to the cheese = "high cholesterol" = "bad for your heart" myth that's still so prevalent:

"Overall, this metabolomics study suggests that cheese could be an important piece in the French paradox puzzle. However, further studies are needed to explore the exact metabolic mechanisms linking cheese consumption, stimulation of the gut microflora, and cholesterol metabolism" (Zheng. 2015 | my emphasis)

Just as many other researchers working in this area, Zheng et al. received support for their study from the dairy industry - a factor that is as prevalent in other areas of nutrition research, but interestingly most heavily criticized for dairy (Armstrong. 2005) and, obviously, artificial sweeteners.

Percentages of women reporting a craving for a given food at four different timepoints during their menstrual cycle (Rodin. 1991). 

Question 2 - Is cheese addictive? Prolly not! Even though the whole concept of food addiction is still contested (Rogers. 2000; Corwin. 2009; Albay-rak. 2012; Ziauddeen. 2012; Hebebrand. 2014), the Internet is full of "information" about the addictive nature of cheese. Claims that are not really backed up by science, as the data from Judith Rodin et al.'s study of the food cravings of women during different phases of the menstrual cycle in the Figure (left) shows (Rodin. 1991) - the real world does thus not confirm the relevance of the theor. addictive potential of casomorphines (Freye. 2004).

In general, rather than a role for individual molecules, the existing data appears to suggest "addictive", or rather hyperpalatable foods share common macronutrient compositions that distinguish a dairy queen chocolate ice cream cone with 34 g sugar 10 g fat and 160 mg sodium (+22 extra ingredients) per serving from roasted chicken breast or an apple (Gearhardt. 2011). This does not exclude that you can be "addicted" to cheese, but the same goes for carrots of which Kaplan reported 10 years ago that they got a 49-year-old woman addicted (Kaplan. 1996).

The reasons why I would argue that you can still put faith into the accuracy of the results Zheng et al. present in their paper are: (1) they openly declared the funding, i.e. support by The Danish Council for Strategic Research, Arla Foods, and the Danish Dairy Research Foundation in the project “FIAF - Milk in regulating lipid metabolism and overweight. Uncovering milk’s ability to increase expression and activity of fasting-induced adipose factor” (10-093539) and (2) the supporting evidence from various previous studies:

• Beneficial effect on CVD health - "The majority of prospective studies and meta-analyses examining the relationship between milk and dairy product consumption and risk of CVD show that milk and dairy products, excluding butter, are not associated with detrimental effects on CVD mortality or risk biomarkers that include serum LDL-cholesterol" (Lovegrove. 2016).
  

  

  Figure 1: Unlike 40 g dairy fat from butter, 40g of fat from matured cheddar cheese do not sign. affect the levels of total cholesterol and LDL in a 4 weeks cross-over study in healthy subjects (Nestel. 2005).

  With the latest evidence for this claim coming from an impartial source, namely Iran, where Sadeghi et al. found that higher cheese intakes are are associated with 19% reduced risk of metabolic syndrome and 13% reduced risk of suffering from (too) low HDL-C level, one may still doubt the objectivity of this claim being made at a conference about animal products, but can hardly argue that there was only potentially biased research to support Lovegrove's claim and the conclusions of the latest meta-analysis of its effects on blood lipids (de Goede. 2015):

  "Compared with butter intake, cheese intake (weighted mean difference: 145.0 g/d) reduced low-density lipoprotein cholesterol (LDL-C) by 6.5% (−0.22 mmol/l; 95%CI: −0.29 to −0.14) and high-density lipoprotein cholesterol (HDL-C) by 3.9% (−0.05 mmol/l; 95%CI: −0.09 to −0.02) but had no effect on triglycerides" (de Goede. 2015).

  In addition every regular gouda (and many other classic cheeses) contains peptides that have proven to have anti-hypertensive effects (Saito. 2000) and will thus lower the #1 risk factor for stroke and related cardiovascular problems - including death (Fagard. 2008).
• Reduced breast cancer risk -  A case-control study from the Netherlands suggests that each 60g increase in gouda intake will reduce the breast cancer risk of 25-64 year-old women (analysed according to age groups) with a 34% reduced risk of breast cancer.
  

  

  Figure 2 A high intake of gouda is associated with highly significant reductions in breast cancer risk even after adjusting for familial history, smoking,education, contraceptive use, age at menarche and first full-term pregnancy, parity, body mass index, and geographic area in Dutch women (van't Veer. 1989)

  What is also interesting about the effects plotted in Figure 2 is that a similar beneficial effect was not observed for milk (had no negative effect, either) or similarly low intakes of other fermented dairy (van't Veer).
• Anti-NAFLD and prometabolic effects - At least in comparison to a butter-fat based diet a similarly low fat (20%) likewise AIN76 (that's std. rodent chow) based diet with freeze-dried cheese powder significantly reduced the accumulation of triglyceride and cholesterol in the liver (P = 0.016 and P < 0.001, respectively) of rats who received the cheese or control diet in a 9-week study.
  

  

  Figure 2: Liver triglyceride (a) and total cholesterol (b) concentrations in rats fed control or cheese diet. Mean ± standard error. Asterisks indicate significant differences between groups (Higurashi. 2016)

  Just like the previously reported human studies, the rodent study als found significant increases in HDL and decreases in non-high-density lipoprotein (non-HDL) cholesterol, as well as elevated levels of metabolically healthy serum adiponectin concentration at week 9 in rats fed the cheese diet. To which degree this effect was due to or related to the increase in fat excretion in the feces will have to be determined in future studies. What appears to be clear, though, is that these "results suggest that cheese mediates various beneficial effects for preventing the development of metabolic syndrome by suppressing the accumulation of fat in the liver" (Higurashi. 2016).
• High nutritional value - Cheese is a low carbohydrate food that's packed with high concentration of essential amino acids saturated fats that could be good, not bad for your health (e.g. conjugated linoleic acid and sphingolipids present in cheese may have anti-carcinogenic properties, too), a lot of highly bioavailable calcium with beneficial effects on bone, teeth, blood pressure and weight loss (when combined with low-energy diets). Reason enough for researchers to state that "[c]heese is an important dairy product and an integral part of a healthful diet due to its substantial contribution to human health" (Walther. 2008).

Whether the average young, whites, female knows all the above or whether there's another reason that this part of US society consumes the highest amounts of cheese (Glanz. 1998) is something I cannot tell you. What I can tell you, though, is that the previously presented evidence suggests that weight concerns should not, as they still were in 1998 in the US (Glanz. 1998), be a reason for you not to consume cheese (in controlled amounts). Rather than that you should follow the example of the rich and intelligent of which a more recent study shows that they tend to consume the most cheese in Europe (Sanchez-Villegas. 2003).

A high cheese will also increase the level of the "good lipoproteins" HDL and apo A-I (Thorning. 2015a).

Bottom line: Don't get me wrong. The purpose of today's article is not to promote a "cheese only diet" or to tell you to consume at least X amounts of cheese per day. It is rather meant to critically evaluate the irrational fear that still characterizes the relationship of many health-conscious dieters to (esp. fatty) cheeses.

When consumed in moderation, cheese is not just a highly nutritious food, but can, as a lot of the more recent studies indicate, even have beneficial effects on your cardiovascular and metabolic health that are probably mediated by key nutrients and the beneficial effect cheese will have on your microbiome | Comment!

References:

• Albayrak, Ö., Sebastian Mathias Wölfle, and Johannes Hebebrand. "Does food addiction exist? A phenomenological discussion based on the psychiatric classification of substance-related disorders and addiction." Obesity facts 5.2 (2012): 165-179.
• Corwin, Rebecca L., and Patricia S. Grigson. "Symposium overview—food addiction: fact or fiction?." The Journal of nutrition 139.3 (2009): 617-619.
• de Goede, Janette, et al. "Effect of cheese consumption on blood lipids: a systematic review and meta-analysis of randomized controlled trials." Nutrition reviews 73.5 (2015): 259-275.
• Fagard, Robert H., et al. "Daytime and nighttime blood pressure as predictors of death and cause-specific cardiovascular events in hypertension." Hypertension 51.1 (2008): 55-61.
• Fox, P. F. "Cheese: an overview." Cheese: chemistry, physics and microbiology. Springer US, 1993. 1-36.
• Freye, Enno. "Exorphine (exogene Opioidpeptide) und β-Casomorphine." Opioide in der Medizin. Springer Berlin Heidelberg, 2004. 323-324.
• Gearhardt, Ashley N., et al. "Can food be addictive? Public health and policy implications." Addiction 106.7 (2011): 1208-1212.
• Glanz, Karen, et al. "Why Americans eat what they do: taste, nutrition, cost, convenience, and weight control concerns as influences on food consumption." Journal of the American Dietetic Association 98.10 (1998): 1118-1126.
• Hebebrand, Johannes, et al. "“Eating addiction”, rather than “food addiction”, better captures addictive-like eating behavior." Neuroscience & Biobehavioral Reviews 47 (2014): 295-306.
• Higurashi, Satoshi, et al. "Cheese consumption prevents fat accumulation in the liver and improves serum lipid parameters in rats fed a high-fat diet." Dairy Science & Technology (2016): 1-11.
• Hjartåker, A., et al. "Consumption of dairy products in the European Prospective Investigation into Cancer and Nutrition (EPIC) cohort: data from 35955 24-hour dietary recalls in 10 European countries." Public health nutrition 5.6b (2002): 1259-1271.
• Lovegrove, Julie A., and Ditte A. Hobbs. "Plenary Lecture 2: Milk and dairy produce and CVD: new perspectives on dairy and cardiovascular health." Proceedings of the Nutrition Society (2016): 1-12.
• Nestel, P. J., A. Chronopulos, and M. Cehun. "Dairy fat in cheese raises LDL cholesterol less than that in butter in mildly hypercholesterolaemic subjects." European journal of clinical nutrition 59.9 (2005): 1059-1063.
• Nilsen, Rita, et al. "Effect of a high intake of cheese on cholesterol and metabolic syndrome: results of a randomized trial." Food & nutrition research 59 (2015).
• Rodin, Judith, et al. "Food cravings in relation to body mass index, restraint and estradiol levels: a repeated measures study in healthy women." Appetite 17.3 (1991): 177-185.
• Rogers, Peter J., and Hendrik J. Smit. "Food craving and food “addiction”: a critical review of the evidence from a biopsychosocial perspective." Pharmacology Biochemistry and Behavior 66.1 (2000): 3-14.
• Saito, T., et al. "Isolation and structural analysis of antihypertensive peptides that exist naturally in Gouda cheese." Journal of Dairy Science 83.7 (2000): 1434-1440.
• Sanchez-Villegas, A., et al. "A systematic review of socioeconomic differences in food habits in Europe: consumption of cheese and milk." European journal of clinical nutrition 57.8 (2003): 917-929.
• Thorning, Tanja K., et al. "Diets with high-fat cheese, high-fat meat, or carbohydrate on cardiovascular risk markers in overweight postmenopausal women: a randomized crossover trial." The American journal of clinical nutrition 102.3 (2015): 573-581.
• Thorning, Tanja K., et al. "Cheddar Cheese Ripening Affects Plasma Nonesterified Fatty Acid and Serum Insulin Concentrations in Growing Pigs." The Journal of nutrition 145.7 (2015b): 1453-1458.
• van't Veer, Pieter, et al. "Consumption of fermented milk products and breast cancer: a case-control study in The Netherlands." Cancer research 49.14 (1989): 4020-4023.
• Zheng, Hong, et al. "Metabolomics investigation to shed light on cheese as a possible piece in the French paradox puzzle." Journal of agricultural and food chemistry 63.10 (2015): 2830-2839.
• Ziauddeen, Hisham, I. Sadaf Farooqi, and Paul C. Fletcher. "Food addiction: is there a baby in the bathwater?." Nature Reviews Neuroscience 13.7 (2012): 514.

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

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

anti-diabetes artificial sweeteners diabetes diabetes cure glucose glycemia hyperglycemia hypoglycemia hypoglycemic lose fat stevia sweetener sweeteners

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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Stevia, the Healthy Sweetener?

Sweeteners In- crease Sweet- ness Threshold

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.

TRT - How Healthy, Lean and Muscular Will Testosterone Replacement Make You? Data from Recent Meta-Analysis

TRT - How Healthy, Lean and Muscular Will Testosterone Replacement Make You? Data from Recent Meta-Analysis

androgens andropause build muscle lose fat male health mens health menshealth t-gel testosterone testosterone enanthate testosterone gel testosterone undecanoate tgel TRT

TRT - What to expect in terms of its effects on a man's body composition?

If you hear people talk about "gear" (=performance enhancing drugs | PED), you get the impression that one injection of testosterone, nandrolone and co would turn a scrawny beginner into an Olympian. Reality, however, looks much different ... in fact, the number of people who ruin their health with (often oral) designer steroids without seeing any of the results they expect has been increasing continuously over the past years (Baker. 2006a,b; Graham. 2008; Rahnema. 2014) and that despite the fact that the "Anabolic Steroid Control Act" of 2004 was originally meant to prevent exactly that from happening (Herschthal. 2012).

In spite of the fact that the introduction of today's SuppVersity article focused on PED, the purpose of the meta-analysis and thus its summary was "systematically review [...] available observational and register studies reporting data on body composition in studies" in men with low or at least suboptimal testosterone levels.

This is what most studies were lacking: Exercise to shed fat and gain muscle.

Tri- or Multi-Set Training for Body Recomp.?

Alternating Squat & Blood Pressure - Productive?

Pre-Exhaustion Exhausts Your Growth Potential

Full ROM ➯ Full Gains - Form Counts!

Battle the Rope to Get Ripped & Strong

Hula Hooping to Spot Reduce in the Midsection

The original meta-analysis by Corona et al. (2016) was published in the Journal of Endocrine Investigation, only a few days ago. It involved "an extensive MEDLINE, Embase, and Cochrane search [that] was performed including the following words: testosterone and body composition. And is thus not focussing exclusively on testosterone as a "new anti-obesity medication", which is how the authors refer to it in the very first sentence of the abstract, because "all observational studies comparing the effect of TS on body weight and other body composition and metabolic endpoints were considered" (Corona. 2016) in the scientists' meta-analysis. Here's an overview of the studies, their design an results, as they were summarized by Corona et al.:

• 

  Suggested Read: Testosterone Gel Augments Increases in Lean Mass Gains (+3.9kg in 6 Months) in Older Intensely Training Men, but Testim Blocks Decrease in Marker of Heart Disease Risk | more

  Valdermasson et al. (1987) - no placebo group, 10 subjects, 9 months, late onset hypogonadism (LOH) w/ baseline T of 1.8 nmol/l receiving TE 250 mg/3–4 weeks
• Rebuffé-Scrive et al. - no placebo group, 11 subjects, 1.5 months, mean age 42y, overweight/obese subjects, mean baseline T 13.8nmol/l, receiving TU 120–160 mg/day
• Forbes et al. (1991) - no placebo group, 7 subjects, 4 months, healthy, normal T levels, receiving TE 42 mg/kg/week
• Marin and Krotkievski et al. (1992) - no placebo group, 11 subjects, 1.5 months, mean age 42y, obese subjects, low T at 13.8 nmol/l, receiving TU oral 160 mg/day
• Marin and Krotkievski et al. (1996) - no placebo, 8 subjects, 3 months, mean age 42y, obese, low T at 14.1 nmol/l on T gel 250 mg/day
• Brodsky et al. (1996) - no placebo, 5 subjects with late onset hypogonadism (LOH) and T-levels of only 3.7 nmol/l on TC 3 mg/kg/2 weeks
• Katznelson et al. (1996) - no placebo, 29 subjects, 13 months, mean age 57, LOH w/ testosterone levels of 6.4 nmol/L on TE or TC 100 mg/week
• Wang et al. (1996) - no placebo, 67 subjects, for 6 months, LOH w/ starting T levels of 4.1 nmol/l taking T sublingually at 15 mg/day
• Zgliczynski et al. (1996) - no placebo, 22 subjects, 12 months, mean age 58.5y, normal elderly men with very low T (4.3 nmol/l) taking TE 200 mg/2 weeks
• Bhasin et al. (1997) - no placbeo, 7 subjects, 2.5 months, mean age 34.7y, LOH at initially 2.5 nmol/l receiving TE at a dosage of 100 mg/week
• Tan et al. (1998) - no placebo, 11 subjects, 4 months, mean age 33.3y, LOH w/ initially 5.5 nmol/l receiving TE at a dosage of  250 mg/4 weeks
• Brill et al. (2002) - no placebo, 10 subjects, 1 month, mean age 68.1y, but T-levels of 15 nmol/l treated with T patches at 5 mg/day
• Minnemann et al. (2007) - no placebo 25 subjects, mean age 57y w/ LOH and initial T levels of pretty high 14.3 nmol/l receiving TU 1000 mg/12 weeks from week 6

• 

  Suggested Read: Tribulus Boosts Testosterone (+12%), IGF-1 (+20%), Sheds 2kg (7%) Body Fat and Maintains Lean Mass in 12 Wk RCT | more

  Naharci et al. (2007) - no placebo, 24 subjects, 6 months, mean age 20.7y, low T at 5.7 nmol/l treated with mixed ester at 250 mg/3 weeks
• Saad et al. (2007) - no placebo, 28 subjects, 13 months, LOH with erectile dysfunction (ED), low  T at initially 7.5 nmol/l treated with  TU at 1000 mg/12 weeks from week 6
• Saad et al. (2008) - 27 subjects, 9 months, mean age 60y LOH with ED and initial T levels of 7.5 nmol/l treated with TU 1000 mg/12 weeks from week 6 or T gel 50mg/day
• La Vignera et al. (2009) - no placebo, 7 subjects, 3 months, mean age 58y, LOH with MetS and unknown baseline T levels treated with T gel 50 mg/day
• Moon et al. (2010) - no placebo, 133 subjects, 6 months, mean age 54y baseline T of 8.6 nmol/l treated with TU at 1000 mg/12 weeks from week 6
• Permpongkosol et al. (2010) - no placebo, 161 subjects, 13.5 months, mean age of 60.4y and LOH consulting urological center w/ T at 9.4 nmol/l on TU 1000 mg/12 weeks from week 6
• Garcia et al. (2011) - no placebo, 29 subjects, treated for 25.5 months,  mean age 55.5y, LOH and diabetes, no baseline T available, treated with TU 1000 mg/12 weeks from week 6
• Schwarz &Willix (2011) - no placebo, 56 subjects, 18 months, mean age 52.3y, overweight or obese with baseline T of 15 nmol/l receiving TC 80–200 mg/week + diet + training
• Arafa et al. (2012) - no placebo, 56 subjects, 12 months, mean age 55.5y w/ T2DM and unknown baseline T treated w/ TU 1000 mg/12 weeks from week 6
• Schroeder et al. (2012) - no plaebo 29 subjects, 4 months, mean age 71y, baseline T of 13.1 nmol/l treated with T patch 5 or 10 mg/day
• Jo et al. (2013) - no placebo, 18, 26.8 months, mean age 35.9y and suffering from Klinefelter syndrome, with low T at 3.1 nmol/l at baseline treated w/ TU 1000 mg/12 weeks from week 6

What is the Klinfelter syndrome? That's a genetic disorder that affects males. Klinefelter syndrome occurs when a boy is born with one or more extra X chromosomes. Most males have one Y and one X chromosome. Having extra X chromosomes can cause a male to have some physical traits unusual for males.

• Ko et al. (2013) - no placebo, 246 subjects, 14.7 months, mean age 58.5y  treated w/ TU 1000 mg/12 weeks from week 6
• Rodriguez-Tolrà et al. (2013) - no placebo, 50 subjects, 12 months, mean age 59.1y, LOH, mean T at baseline 10.2 noml/l treated w/ T gel 25–100 mg/day

• 

  Suggested Read: Hormonal Response to Exercise, Revisited: A Consequence, not a Determinant of Your Mood, Effort & Performance | more

  Saad et al. (2013) - no placebo, 255 subjects, 60 months, mean age 58y, mixed urological population, low T at 10.0 nmol/l treated with TU 1000 mg/12 weeks from week 6
• Tirabassi et al. (2013) - no placebo, 15 subjects, 18.5 months, mean age of 55.7y, LOH w/ baseline T levels of 5.2 nmol/l on TU 1000 mg/12 weeks from week 6
• Zitzmann et al. (2013) - no placebo, 1438 subjects, 10.5 months, mean age 49.2y, LOH w/ baseline T levels of 9.6 nmol/l on TU 1000 mg/12 weeks from week 6
• Francomano et al. (2014) - no placebo, 20 subjects, 60 monhts, mean age 57.5y, MetS and basline T of 8.3 nmol/l on TU 1000 mg/12 weeks from week 6
• Pexman-Fieth et al. (2014) - 669 subjects, 6 months, 53y, LOH on  T gel 50, 75 or 100 mg/day
• Yassin et al. (2014) - no placebo, 261 subjects, 54 months, mean age 59.5y, LOH w/ baseline T levels of 7.7 nmol/l treated w/ TU 1000 mg/12 weeks from week 6
• Zitzmann et al. (2014) - no placebo, 381 subjects, treated for 60 months, mean age 42.6y w/ LOH and low T at 5.2 nmol/l on TU 1000 mg/12 weeks from week 6

Figure 1: Influence of trial duration (a, b), age (c, d) and testosterone levels at enrollment (e, f) on weighted mean differences (with 95 % CI) of body weight (a, c, e) and waist circumference (b, d, f) at endpoint after testosterone supplementation. The size of the circles reflects the sample dimension (Corona. 2016).

Why did the scientists prefer observational trials over RCTs? "The peculiar study design of these RCTs might, as the authors point out justify the lack of efficacy of testosterone supplementation on weight parameters in previous meta-analyses. In fact, RCTs are performed under idealized and rigorously controlled conditions, which are different from everyday clinical practice. Hence, results of RCTs offer an indication of the efficacy of an intervention rather than its effectiveness in everyday practice. [...] In contrast, observational and register studies maintain the integrity of the context in which medical care is provided. As a result, whereas RCTs provide an indication of the minimal effect of an intervention, observational studies offer an estimate of the maximal one," Corona et al. write.

Table 1: Number and proportion (%) men reporting use of AAS, life-time, past 12 months and past 30 days, in different subgroups (Leifman. 2011).

All in all, we are talking about 32 out of 824 initially retrieved articles and 4513 patients whose mean age of 51.7 ± 6.1 years is yet far above that of the average PED (ab-)user whose age appears to be somewhere between 25 and 29, likely to have visited only "compulsory school" and a friend of alcohol and dietary supplements (Leifman. 2011 | see Table 1) and a very obvious result, i.e. that the supplementation of testosterone "was associated with a time-dependent reduction in body weight and waist circumference (WC).

To be more specific, "[t]he estimated weight loss and WC reduction at 24 months were −3.50 [−5.21; −1.80] kg and −6.23 [−7.94; −4.76] cm, respectively" (Corona. 2016). In addition, the provision of testosterone was, as you would probably have guessed based on previous SuppVersity articles, "also associated with a significant reduction in fat and with an increase in lean mass as well as with a reduction in fasting glycemia and insulin resistance" that were accompanied by reductions in fasting glycemia and insulin resistance (IR), as detected by HOMA-IR index - especially in studies enrolling a diabetic subject clientele at baseline (Corona. 2016).

Figure 2: Effects of TRT on blood pressure, lipids and glucose metabolism (Corona. 2016).

But isn't testosterone supplementation (TS) bad for your cholesterol and blood pressure? Even though nobody really appears to care about cholesterol on the interwebs, these days, the claim that testosterone would ruin your blood lipids and, maybe more importantly, one's blood pressure, is still propagated on "the boards". In the studies Corona et al. reviewed for their latest meta-analysis, however, the provision of exogenous testosterone (albeit in not necessarily superphysiological levels) triggered sign. improvements of the subjects' lipid profiles (reduction in total cholesterol as well as of triglyceride levels and an improvement in HDL cholesterol levels) and in both systolic and diastolic blood pressure was observed.

You're scratching your head, I see... Are you disappointed of the effect sizes? Well, you should take a closer look at the full spectrum of the results. Let's take the reduction in waist circumference, for example (Figure 3):

Figure 3: Effect of TS on waist circumference (cm) in the studies that were part of the meta-analysis (Corona. 2016).

As you can see, the latter ranged from ZERO in La Vignera (2009), who didn't even measure the waist circumference ;-) to HERO,... ah, I mean -19.6 cm in Zitzmann (2014), who studied the tolerability and effectiveness of injectable testosterone undecanoate for the treatment of male hypogonadism in a worldwide sample of 1,438 men. With a baseline waist circumference of relatively moderate 99.5 +/ - 15.25 cm, we are talking about a ~20% reduction in waist circumference, here!

Figure 4: Zitzmann et al. also found sign. improvements in mood (left) and the ability to concentrate (right) in their previously (mostly) hypogonodal subjects (Zitzmann, 2014).

Physical changes that were accompanied by significant improvements in the subjects' mood (Figure 4, right) and ability to concentrate (Figure 4, right) - results that had the authors conclude that their "study corroborates and strengthens the modern view on the desirability and efficacy of substitution therapy in men with proven hypogonadism, also in a “real-life” setting" (Zitzmann. 2014).

You to know more about superphysiological doses?

If that's not "good enough" for you, let me remind you of my previous review of a seminal paper by Bhasin et al.  who conducted (to my knowledge) the only "dose-escalation" study that comes remotely close to being a "PED"-RCT, i.e. a controlled trial that may give us some insights into the effects T at dosages that are used by performance enhancing drug users would have.

Figure 5: Dose response relationship of muscle gain (in kg) per mg of testosterone enanthate (left) , the white line indicates a dose that would probably have produce testosterone levels identical to baseline; and relative change in lean and fat mass in response to changes in serum testosterone levels (right | Bhasin. 2001)

While I've reprinted the most important data in Figure 5, I'd still suggest you take a closer look at the corresponding SuppVersity Classic article, if you want to learn more - especially about the interpretation of the graph on the right hand side that shows the relative change in lean and fat mass in response to changes in serum testosterone levels.

Overview of factors controlling muscle gains (Moussa. 2012)

If you want to know what's possible in healthier people, I suggest you go back to my articles in the "Intermittent Thoughts on Building Muscle" series. More specifically, the articles "Zoning in on "The Big T" - Does Testosterone (Alone) Build Muscle?" (read it), "Quan-tifying "The Big T" - Do Testosterone Increases Within the Physiological Range Really Matter? And How Much is too Much?" (read it) and the conclusion "Exercise, mTOR/AKT/MAPK, IGF-1, Testosterone, Estrogen, DHT, Nutrition, Supps & Sleep" (read it) from which I have copied the overview of different mechanism that contribute to / control muscle growth on the right | Comment

References:

• Baker, Julien S., Michael Graham, and Bruce Davies. "Gym users and abuse of prescription drugs." Journal of the Royal Society of Medicine 99.7 (2006a): 331-332.
• Baker, J. S., M. R. Graham, and B. Davies. "Steroid and prescription medicine abuse in the health and fitness community: A regional study." European journal of internal medicine 17.7 (2006b): 479-484.
• Bhasin, Shalender, et al. "Testosterone dose-response relationships in healthy young men." American Journal of Physiology-Endocrinology And Metabolism 281.6 (2001): E1172-E1181.
• Corona, G., et al. "Testosterone supplementation and body composition: results from a meta-analysis of observational studies." Journal of Endocrinological Investigation (2016): 1-15.
• Graham, Michael R., et al. "Anabolic steroid use." Sports medicine 38.6 (2008): 505-525.
• Herschthal, Adam. "From Rats to Riches: How the Anabolic Steroid Control Act of 2004 Unjustly Punished the Gym Rat and How a New Prescription Is the Road to Salvation." Syracuse L. Rev. 63 (2012): 437.
• La Vignera, S., et al. "Andrological characterization of the patient with diabetes mellitus." Minerva endocrinologica 34.1 (2009): 1-9.
• Rahnema, Cyrus D., et al. "Anabolic steroid–induced hypogonadism: diagnosis and treatment." Fertility and sterility 101.5 (2014): 1271-1279.
• Zitzmann, Michael, et al. "IPASS: a study on the tolerability and effectiveness of injectable testosterone undecanoate for the treatment of male hypogonadism in a worldwide sample of 1,438 men." The journal of sexual medicine 10.2 (2013): 579-588.