Fructose as a Dieting Tool: 100g Fructose Per Day Exert Sign. Protein Sparing Effects & Ameliorate the Decline in Thyroid Hormones During Starvation Diet in the Obese

Fructose as an injectable Dieting Aid? Sounds crazy, but it works!

Would you ever have remotely considered that a high-fructose corn-syrup based sugar-sweetened beverage could help seven health obese women who are 35%-90% over their ideal weight lose weight? No, ...?

Well, honestly, me neither and if we take a closer look at the experimental design of a 1986 study by Robert A. Gelfand and Robert S. Sherwin from the prestigious Yale University, we will have to relativize the aforementioned claim. Coke alone may not do the trick. Pure fructose, if it's infused right into the bloodstream, on the other hand will "abolishes the entire hormone-substrate response to fasting, and spares body protein without raising insulin above postabsorptive levels." (Gelfand. 1986)

Learn more about fructose at the SuppVersity

Bad Fructose not so Bad, After All! Learn its Benefits.

Fructose From Fruit is NOT the Problem

Americans Don't Eat More Fructose These Days!

An Apple A Day, Keeps... & More (Guestpost)

Fructose is Not Worse Than Sugar

The Obesogenic Fructose Fat Connection

Before we are pondering the results, let's first have a closer look at the actual design of a study was conducted to "examine the influence of low-dose fructose infusion on nitrogen economy and the metabolic response to fasting in man" (Gelfand. 1986 | I know that you should do that in "man", not rodents, but that's costly and has the aforementioned limitations).

To this ends, the aforementioned overweight to obese women who were not diabetic and normal blood glucose and insulin levels, had normal thyroid and liver function and had been consuming a weight maintenance diet with at least 200g of carbohydrates per day before they were recruited for the study, were fasted for a period of 10 days (they did get a multivitamin, a folic acid and a potassium chloride tablet to eat, though ;-) and randomly divided into 2 groups using a crossover design:

• Group 1 (n = 4) received intravenous fructose during the last 3 days of the IO-day fasting period, while 
• Group 2 (n = 3) received fructose for the initial 7 days of the fast 

In all subjects, fructose was administered by continuous intravenous infusion of a 10% solution in water (American McGaw), delivering 100 g of fructose (375 kcal) per day.

Figure 1: Changes in plasma glucose and insulin (left) and active thyroid hormone T3 (right) during the fast with and without fructose (Gelfand. 1986)

As you can see in Figure 1 the first thing the fructose did was to keep the blood sugar and insulin stable and the levels of the active thyroid hormone T3 (iodothyronine) from plummeting. In addition, the levels of the glycogen liberating hunger hormone glucagon remained stable over the course of the whole study period in the fructose arm(s) of the study, while it increased by more than 80% in the women who didn't receive the fructose infusion.

Hormonal changes and real world effects!

Now hormonal changes are one thing. Real world effects which cannot always be predicted solely by endocrine parameters are yet often a whole different animal. What you would maybe have expected, though, is the decrease in ketone production during the supplement phases, which are indicative of "less starvation" (Blood beta-hydroxybutyrate is only a sign positive ketosis, when you actually eat tons of fat, not when you fast - in that case they are a starvation response; see Table 1)?

Table 1: Inhibitory Effect of Fructose on Starvation-Induced Ketosis. FFA Elevation,
Acidosis. and Hyperuricemia (Gelfand. 1986)

What you probably also expected are are the decreases in bicarbonate and increases in uric acid, of which the latter have previously been reported to contribute to the metabolic derangements that occur with high fructose intakes on top of an already obesogenic diet (Sahebjami. 1971; Nakagawa. 2006).

Figure 2: Urinary ammonium loss with sodium bicarbonate (G2) or potassium + calcium carbonate (G3) vs. no buffer (G1) on a 93g all protein starvation diet (Gougeon-Reyburn. 1991)

Did you know that the addition of sodium bicarbonate or a combination of potassium bicarbonate and calcium carbonate can "buffer" the increased acidity that occurs on very low energy diets and minimize the urinary nitrogen loss in form of ammonia (see Figure 2)? No, well... I guess it's about time you learn more about sodium bicarbonate, then ;-) It can, for example, also buffer the reduction in growth hormone production that occurs, when the acid level in your body is rising (see Figure 3 in previous article). Plus: It's obviously a neat ergogenic.

What is way more important than the previously described changes in serum parameters is the effect the infusion of fructose had on the energy expenditure, of which all of you know that it plummets, when you starve yourself. An effect that has long been touted as the main "risk factor for body-weight gain" (Ravussin. 1988) and thus unsuccessful dieting by scientists.

One of the factors that contributes to the "reduced rate of energy expenditure" is the the previously mentioned decline in thyroid hormone levels, of which you've just learned that it can be ameliorated by fructose injections (see Figure 1). Another one that is partly related to the decline in T3 is the loss of muscle mass - a process of which Byerley et al. (1996) argue showed that it does not have the protein sparing effects many people believe it would have.

Figure 3: Fructose decreases the total urinary nitrogen loss by ~40% (Gelfand. 1986).

In view of the results of Byerley & Heber's human study that investigated the metabolic effects of triiodothyronine replacement during fasting in obese subjects and found no effects when the protein intake was >70g/day (or 50g were complemented by 76g carbohydrates), it is thus much less surprising that the provision of fructose increased the triiodothyronine levels and decreased theh net urinary protein loss. A brief look at the serum amino acid levels of the subjects (not shown in Figure 3) suggests that fructose may have had a BCAA sparing effect, as well.

Bad Fructose? Increased Glycogen Synthesis, Reduced Glycemia, Higher Glucose Oxidation - When Do These Beneficial Effects Occur? And Why Don't They Prevail? | Read more!

Bottom line: Overall, it is unquestionably remarkable how effectively less than 375kcal of energy from fructose can reverse major components of the starvation response in human beings, i.e. abolishes the entire hormone-substrate response (specifically the decline in T3), spare body protein, and reduce urinary mineral (specifically sodium) loss.

Unfortunately, one very important question remains: What will happen if the fructose has to pass by the liver first, i.e. if it is ingested orally, not injected? 

The absence of corresponding research and the question, whether the same effects will be observed if small amounts of fructose are added to a saner form of "crash dieting", e.g. a protein modified fast, make the results of the study at hand interesting, but difficult to interpret.

References:

• Byerley, L. O., and D. Heber. "Metabolic effects of triiodothyronine replacement during fasting in obese subjects." The Journal of Clinical Endocrinology & Metabolism 81.3 (1996): 968-976. 
• Gelfand, Robert A., and Robert S. Sherwin. "Nitrogen conservation in starvation revisited: Protein sparing with intravenous fructose." Metabolism 35.1 (1986): 37-44.
• Gougeon-Reyburn, Réjeanne, François Larivière, And Errol B. Marliss. "Effects Of Bicarbonate Supplementation On Urinary Mineral Excretion During Very Low Energy Diets." The American Journal Of The Medical Sciences 302.2 (1991): 67-74.
• Nakagawa, Takahiko, et al. "A causal role for uric acid in fructose-induced metabolic syndrome." American Journal of Physiology-Renal Physiology 290.3 (2006): F625-F631.
• Ravussin, Eric, et al. "Reduced rate of energy expenditure as a risk factor for body-weight gain." New England Journal of Medicine 318.8 (1988): 467-472.
• Sahebjami, Hamid, and Raymond Scalettar. "Effects of fructose infusion on lactate and uric acid metabolism." The Lancet 297.7695 (1971): 366-369.

Are Elevated Iron and Uric Acid Levels Too Much of a Price to Pay for a Creatine-Induced 11% Performance Increase?

Video 1 (GSSI): Notre Dame's Michael Floyd goes all out on the Wingate test (click to watch)

I guess you could say that these are the "classic days", here at the SuppVersity, contrary to my previous post on choline, which is - judged by the few people who still use it today, an "old school supplement" (cf. "Choline: Stronger, Faster, Leaner & More Muscular, or Just Another Dumb-and-Barbell Story?") - yesterday's post on caffeine highlighted the efficacy of a potent ergogenic aid and metabolic activator, with the effects of which most of us are so familiar that we are alway tempted to turn to useless crap like raspberry ketones, when what we are already doing is not only tried and proven, but based on respectable scientific data even more effective than the latest "innovation" from the snake oil industry. And let's be honest, haven't we all been tempted by one or another "new creatine", as well?

+11% peak performance in one week, solely from 5x4g of creatine per day!

A a matter of fact, creatine monhydrate does in fact share the same fate of being proven, but "boring" staple supplement and although that alone should be incentive enough to address the unquestionably outstanding +11% in anaerobic peak performance, +5% in continuous anaerobic performance and a +6% increase in total workload in a classic wingate anaerobic performance test speak, Barros et al. observed in a group of trained male subjects in response to a 7-day creatine loading protocol (20g creatine monohydrate, in 5 doses spread across the day, not glucose / sugar added; cf. Barros. 2012) After all, my gut tells me that the contemporary changes in the concentration of iron in the blood of the subjects in the the creatine arm of the study could revoke the mainstream-media fearmongerish hoopla over the purported dangers of the #1 natural ergogenic.

Figure 1: Basal iron, FRAP, malondialdehyde (MDA) and uric acid levels before and after 7-day supplementation with 5x4g of creatine monohydrate per day (based on Barros. 2012)

I mean, there is no debating, the level of iron in the blood of the creatine supplemented undergraduate students (age, 23.1 ± 5.8 years; height, 175.4 ± 2.3 cm; weight, 81.1 ± 9.3 kg) all of whom had been avid trainees for at least 6 months did increase by no less than 94.3%, while the subjects in the placebo group experienced a -21% reduction of these highly reactive molecules (Just as an aside, the decline in serum iron in the placebo group and the significant difference in baseline levels between the random groups, alone, render any implications at least questionable; I mean, wouldn't you expect the serum parameters to stay the same, when you do nothing extraordinary, aside from popping some sugar pills?).

Figure 2: Changes in wingate anaerobic performance (left) and exercise induced changes iron, FRAP, malondialdehyde (MDA) levels during the wingate test at the end of the supplementation period (based on Barros. 2012)

In conjunction with the likewise highly significant increase in uric acid levels, conventional (blogosphere-)wisdom, which constantly ignores the antioxidative nature of uric acid, which acts as efficient antioxidant and chelating agent for iron ions (Karlsson. 1997), limits the oxidation of polyunsaturated fatty acid in the erythrocyte membrane and prevents hemolysis (= the rupture of red blood cells) in vitro (Einsele. 1987), would suggest that taking creatine takes a close second to fructose on the list of the villains of the bad, bad "neolithic" century.

How dangerous is the creatine induced increase in iron?

Image 1 (Paramount Pictures): I guess, it must have been creatine monohydrate, then, that turned Robert Downey Jr. into Ironman ;-)

Now, despite the as of late publicly propagated concerns about increased iron levels and their potential causative role in the etiology of insulin resistance and diabesity (obesity + diabetes), recent scientific evidence suggests that "high iron", such as all previous scapegoats people like to hold liable, just to make sure not to admit that it is the sickening combination of laziness, convenience and unsound dietary advice that is at the heart of the current obesity epidemic.

Huang et al., for example, did observe a direct effect of iron overload on diabetes risk - the latter was however a result of hereditary hemochromatosis (a genetic defect in iron metabolism) in their 2011 rodent trial (Huang. 2011). Results from two more recent studies by Silva et al. also indicate that the metabolic disturbances lead to differential expressions of the proteins involved in the metabolism of iron and thus substantiate the associative (and not causative) nature of the relation between high iron / ferritin and the metabolic syndrome (Silva. 2011; Silva. 2012).

Iron not causative? So why does phlebotomy help, then? If you read my post on the recently published data from the first controlled human trial that investigated the effects of phlebotomy on markers of blood glucose management, you will be aware that the measures they took, e.g. the HOMA-IR, are not really appropriate to assess the effects of this particular treatment (cf. "Phlebotomy: Can You Bleed Yourself Healthy and Lean?"). Furthermore, it is only logical that the removal of some of this "highly inflammable stuff" from an inflamed body will provide health benefits, even if the latter was totally benign for someone who has a lot less inflammation going on.

What is even more important, though, is that the difference between exercise-induced increases in serum iron and diet and diabesity-related increases in the storage form of iron, ferritin, in the liver. This is particularly true in view of the fact that our understanding of the former, i.e. the exercise induced release of iron into the blood stream is more than limited (Roberts. 1989; Smith. 1994). What we do see in the Barros study, however, is that the overall effect of creatine is rather anti- than pro-oxidative, since the increase in overall antioxidative capacity (as indicated by the changes in the iron-specific FRAP essay; cf. figure 1) did not just...

• negate the potential negative effects of increased basal iron levels (see lowered baseline MDA levels post supplementation in figure 1), it also 
• countered the exercise-induced lipid oxidation during the 2nd wingate test (as indicated by lower MDA levels; cf. figure 2). 

Eventually, the scientists say, the increase in antioxidant activity that is brought about by the ingestion of 20g/day creatine irrespective of whether you exercise or not could actually yield "general health benefits" (Barrios. 2012); and I would like to add that evidence for Parkinson's disease, Alzheimer's disease, amyotrophic lateral sclerosis, recovery from ischemia and, guess what, diabetes already exists (Tarnopolsky. 2000;"Creatine Ameliorates Type II Diabetes")! Certainly not bad for one of those bodybuilding supplements, "anabolics" or "gateway drugs", as creatine is often mislabeled , when a 100% clueless "journalist" tries to get the attention of his editor-in-chief, wouldn't you agree?

Suggested readings (some also mentioned in the text):

• The Pharmacology of Creatine (Part 1 and Part 2) 
• Supercharging Creatine With Baking Soda (click here to read)
• 5g/day Creatine for Type II Diabetics? (click here to read)
• All posts tagged with "creatine" (click here to read)
• Phlebotomy: Can You Bleed Yourself Healthy and Lean? (click here to read)

References:

1. Barros MP, Ganini D, Lorenço-Lima L, Soares CO, Pereira B, Bechara EJ, Silveira LR, Curi R, Souza-Junior TP. Effects of acute creatine supplementation on iron homeostasis and uric acid-based antioxidant capacity of plasma after wingate test. J Int Soc Sports Nutr. 2012 Jun 12;9(1):25. 
2. Huang J, Jones D, Luo B, Sanderson M, Soto J, Abel ED, Cooksey RC, McClain DA. Iron overload and diabetes risk: a shift from glucose to Fatty Acid oxidation and increased hepatic glucose production in a mouse model of hereditary hemochromatosis. Diabetes. 2011 Jan;60(1):80-7.
3. Orozco MN, Solomons NW, Schümann K, Friel JK. Response of urinary biomarkers of systemic oxidation to oral iron supplementation in healthy men. Food Nutr Bull. 2012 Mar;33(1):53-62. 
4. Roberts D, Smith DJ. Effects of high-intensity exercise on serum iron and α1-antitrypsin in trained and untrained men. Clin Sports Med 1989, 1:63–71.
5. Silva M, Bonomo Lde F, Oliveira Rde P, Geraldo de Lima W, Silva ME, Pedrosa ML. Effects of the interaction of diabetes and iron supplementation on hepatic and pancreatic tissues, oxidative stress markers, and liver peroxisome proliferator-activated receptor-α expression. J Clin Biochem Nutr. 2011 Sep;49(2):102-8.
6. Silva M, de Brito Magalhães CL, de Paula Oliveira R, Silva ME, Pedrosa ML. Differential expression of iron metabolism proteins in diabetic and diabetic iron-supplemented rat liver. J Biochem Mol Toxicol. 2012 Mar;26(3):123-9. 
7. Smith DJ, Roberts D. Effects of high volume and/or intense exercise on selected blood chemistry parameters. Clin Biochem 1994, 27:435–440.
8. Tarnopolsky MA. Potential benefits of creatine monohydrate supplementation in the elderly. Curr Opin Clin Nutr Metab Care. 2000 Nov;3(6):497-502.