Intermittent Thoughts on Intermittent Fasting - The Fast #1: Metabolic and Endocrine Response(s) During the Fast.

Image 1: "Fasting? Man, everyone knows that this makes you fat and miserable - gimme that frickin' Big Mac I need to keep my metabolic rate elevated!" 
(photo boners.com).

While the initial three installments of the Intermittent Thoughts on Intermittent Fasting series focused on dispelling three of the most commonly held beliefs that would speak against the use of an intermittent fasting regimen, as it is proposed by Martin Berkhan and others, as the silver bullet to "lean gains" (personally I would see IF rather as a means to maintain lean mass, while getting rid of unwanted body fat, though), I want to use this, as well as the following installments, to verify my promise and dissect established and purported underlying mechanisms of a dietary regimen, which - and this stands out of questions - produced amazing results in some of its adherents, like Duong Nguyen, JJ22 who posted a link to his own intermittent fasting log in the comment section of part II of this series and, of course, Adelfo Cerame about whose initial experiences with his raw-foods powered intermittent fasting regimen you have read last Thursday, here at the SuppVersity.

Digging into the metabolic and endocrine effects of "fasting"

Illustration 1: Click here to read up on the previous three installments on (1) Calorie Expenditure; (2) Fat gain; (3) Performance decreases

Before, we are finally getting into the endocrine and metabolic effects, it appears prudent to revisit what our understanding of "fasting" in general and an "intermittent fast", in particular, actually is. In the first installment of this series I referred to the definition of "fasting" from the venerable Oxford English Dictionary. The same source tells us that the noun "fasting" relates back to the verb "to fast", the etymology of which can be traced back to the old Germanic *fastêjan which originally signified "to keep, to observe". Now, the fundamental thing, or I should say, "rule" an intermittent faster has to observe is the abstinence of food within a predetermined time-window, the size of which usually is ~16h (I have elaborated on the underlying reasons for that in detail in the context of liver glycogen stores in the second part of this series). What I will try to do (I want to emphasize "try" here, because one of the major databases for scientific fulltexts is down at the very moment I am writing this article) in this fourth installment of the series is to scrutinize the fundamental, as well as subordinate effects this kind of carefully planned and well-timed food abstinence has on your body. 

An important qualification we have to make, when we are trying to get to the nitty gritty of intermittent fasting is a clear-cut distinction between "not being eating constantly" and being in a "fasted state". After all, the actual fasting period begins with the "postabsorptive period", which, in turn, does not start before all of the nutrients ingested from the last meal have either been absorbed or passed your intestines undigested. Depending on the meal composition, this process can take anywhere between 3-4h and 7-8h, which - in view of the longer digestion time of proteins and fats, supports the idea that longer intermittent fasts would require higher amounts of proteins + fats (we will get back to that in one of the next installments)...

According to Maughan et al. (Maughan. 2010) the "early phase of fasting" comprises roughly 24h and is characterized by sufficient glycogen supply from the liver (you will be familiar with this concept from the previous installments of the Intermittent Thoughts on Intermittent Fasting series), with the liver releasing about 4g of glucose per hour in the initial phase of fasting. In oder to spare the precious glycogen stores (Maughan estimates the average liver glycogen stores with only 44g/kg liver tissue, or about 60g for an average human liver) an upregulation in fatty acid oxidation takes place even in this early stages of fasting (Cahill. 1966). Consequently the concentration of circulating free fatty acids and glycerol (both released from white adipose tissue) in the blood increases and fatty acids and glycerol become available as a potential alternate fuel source for muscle and substrate for glyconeogenesis in the liver.

Figure 1: Effects of 8 days of fasting on glucose, free fatty acid, glycerol, insulin and growth hormone (secondary axis) levels in six perfectly healthy subjects from the Cahill study (Cahill. 1966)

As the data in figure 1 goes to show, Cahill at al. observed a continuous shift towards fat/glycerol as the preferred energy source (free fatty acids) and substrate for gluconeogenesis (glycerol) to keep blood sugar levels within the normal range, when they studied the effect of 8 days of fasting on six healthy male subjects. These observations stand in line with what Maughn et al. state about the "integrated metabolic response" to Ramadan (=intermittent) fasting...

[...] that involves mobilisation [sic] of fat stores and hepatic gluconeogenesis is regulated by changes in the hormonal environment, including a reduction in the plasma insulin concentration and increased circulating concentrations of glucagon, catecholamines, growth hormone, thyroid-stimulating hormone and corticosteroids.

Of these changes, the decrease in serum insulin levels (in the Cahill study about -40-50%) facilitates, while the increases in circulating catecholamines, glucagon, growth hormone, thyroid-stimulating hormone and corticosteroids trigger the release of fat from adipose tissue and promote hepatic gluconeogenesis.

Image 2: The thyroid, generally regarded as the metabolic "gas pedal" of your body, is particularly sensible to energy shortages. It is thus a surprising, yet pleasant and fundamentally important observation that intermittent fasting does not induce significant reductions in thyroid metabolism. (img src wikipedia.org)

I suppose that many of you may be surprised, to read of an "increase in thyroid-stimulating hormone" (TSH) associated with "fasting". And, in fact, "normal" fasting, i.e. not eating over an extended period of time, or a constant and profound decrease in calorie intake have been known to trigger decreases in TSH and, more importantly,  thyroxine (T₄) and triiodothyronine (T₃) levels since the first studies of iodine metabolism in the 1960s (e.g. Alexander. 1964) and have also been implicated in the etiology of the "euthyroid sick syndrome" (De Groot. 1999). It does yet appear to be a uniquely beneficial characteristic of intermittent fasting that despite gradual increases in TSH, as they were observed by Sajid et al. in their 1991 study on the effects of Ramadan fasting on thyroid hormone profile, "[t]here was no significant change in T3 and T4 levels" (Sajid. 1991) with fasting periods below 24h. A study on the effects of Ramadan fasting on thyroid function in 28 healthy male subjects by Sulimani that was conducted back in 1987, yet published (in English) only 5 years ago, corroborates these results (Sulimani. 2006):

[...] there was no significant change in the results of the thyroid function tests done before and at the end of Ramadan. The values respectively for plasma T4, T3, free T4 and TSH before and after Ramadan were 7.0±1.08 μg% and 7.1±1.34 μg%; 1.1±0.17 ng/ml and 1.1±17 ng/ml; 1.1±0.21 ng/dL and 1.1±0.15 ng/dL; 1.7±0.62 mu/ml and 1.4±0.81 mu/ml; P>0.1 for all comparisons.

And in a more recent study on the effects of religious fasting on elite athletes (15 male judo player), intermittent fasting even increased "the mean blood level of thyroid-stimulating hormone and free thyroxine [...] significantly" (Chaouachi. 2009). In view of these results, it is unlikely that a decrease in thyroid function could become a sticking point for someone who wants to improve his body composition on an intermittent fast.

GH, thyroid, cortisol... "What about testosterone? And other sex hormones?" I knew you would ask that. Unfortunately the data on testosterone levels and related hormones is relatively inconclusive. While Ghaderi and Khameneh report that testosterone levels were "significantly greater than baseline one (p=0.007, p=0.025 respectively)" (Ghaderi. 2006) in 32 single men (age 24-26) and Shahabi et al. found no effects of Ramadan fasting on hormone secretion in women (Shababi. 2010), Mesbahzadeh et al. state in a short communication that "[t]estosterone level was lower, significantly so for the 20th and 28th of the month (P < 0.05)" (Mesbahzadeh. 2005). Other studies report shifts in the circadian rhythm of cortisol and testosterone release, which could partly explain differences, if before and after levels were measured only once and at the same time of the day - the complicated shift in circadian pattern is yet a topic for another installment of the Intermittent Thoughts on Intermittent Fasting series ;-)

Growth hormone - major or minor player in the beneficial effects of intermittent fasting?

Figure 3. Blood Glucose, Insulin, Hematocrit, GH, IGF-1 and IGFBP-3 in rugby players at rest and after HIIT training on a an cycle ergometer on week 1 and week 4 of Ramadan fasting relative to baseline (data calculated based on Bouhlel. 2008)

Among the hormonal changes observed in the Cahill study the increase in growth hormone stands out not only because of its profoundness (GH levels were elevated 29-fold after 5 days of fasting), but also because similar effects observed in other studies are commonly listed among the fundamental benefits ambitious gymrats could derive from (intermittent) fasting. A 2008 study by Bouhlel et al. (Bouhlel. 2008) on the effects Ramadan fasting (cf. parts II-III of this series for information on why Ramadan is a particularly good model for the effects of intermittent fasting) that involved 9 trained male rugby players (age 19 +/- 2 years, height 1.78 +/- 0.74 m) does yet show pretty conclusively that the GH increase that is seen in long-term fasting probably won't even occur with intermittent fasts.

[...] Ramadan is an intermittent fast, and the severity of food restriction and dehydration may therefore be insufficient to induce changes in the GH/IGF-1 axis. (Bouhlel. 2008)

As the data in figure 3 goes to show, even after 4 weeks of intermittent fasting, GH levels at rest were elevated by "only" 40%; an elevation, which, due the cyclic nature of growth hormone secretion, does not even reach a p-value (probability that it is not plain statistical coincidence) of p < 0.05 and must thus be considered statistically non-significant. In view of the fact that the exercise induced rise in GH was blunted during the fast (ca. -30% compared to pre-Ramadan values), the absence of accompanying increases in IGF-1 and the slight increase in IGF-binding-protein-3 (which is still believed to make it impossible for IGF to bind to the receptor to do its anabolic magic, cf. Elgin. 1987) at rest, it is altogether unlikely that intermittent fasters would see benefits from increases in growth hormone that go beyond the previously mentioned shift towards a muscle sparing and fat-burning.

Figure 4: Changes in body composition (left) as a consequence of 4 weeks of Ramadan fasting at the given (self-selected) macronutrient amounts (right) in rugby players (data calculated based on Bouhlel. 2008)

A pros pos shift, the shift in body composition Bouhlel et al. saw in their 9 trained rugby players (cf. figure 4, left) seems by far not so favorable as most people who consider doing an "intermittent fast" would expect. Upon having a closer look at the time course of the changes in fat- and lean mass, you may yet realize that there is no statistical significant difference between the "lean mass" in the first week of fasting (which already went down by -1.32%) and the 4th week, something the scientist take as a sign of fluid and not "real" muscle loss, so that overall

[t]his shows that 1 week of Ramadan fasting is not long enough to induce changes in body composition, and that the decrease in body mass seen at this stage is likely related to a reduction in body fluids. Fat had been lost by the end of Ramadan, but lean tissue was still preserved.

In this context it is also worth mentioning that dehydration blunts the release of growth hormone, you would see on a fitness oriented (vs. a religious) intermittent fast, where sufficient hydration obviously is of paramount importance and the consumption of calorie-free beverages is mandatory, even during the fasting period. Now, with the established body-recompositioning effect of growth hormone (e.g. Meinhard. 2010) in mind, we may safely assume that evn adequate fluid consumption alone could have had beneficial effects on the changes in body composition Bouhlel et al. observed in their study.

IF and exercise a dynamic duo for the perseverance of muscle mass on a diet

As far as the reasons for the perseverance of muscle mass is concerned Bouhlel et al. highlight the importance of the "continuation of a substantial training regimen during Ramadan" [my emphasis], which obviously countered the protein-catabolic effect of fasting (I'd rather say malnutrition, because a -28% in energy intake is pretty substantial for high level athletes) that has been observed in more or less related studies in the sedentary population.

Image 3: Diet and exercise are key components of body recompositioning.

Did you know that it has been established that exercise prevents, not amplifies, fasting induced protein degradation? In a 2006 paper, Kasperek et al. report that (Kasperek. 2006)

Exercise did prevent the increase in the rate of total protein degradation caused by food restriction, which may have important implications in weight reduction diets.

And indeed, any type of fast (even an intermittent one) that is intended to improve body composition makes little sense without the exercise component.

Blunting protein degradation in the fasted state, is yet not the only benefit of exercise during an intermittent fast. In view of the metabolic shift towards fatty acid oxidation, working out also helps to get rid of the increased levels of fatty acids via mytochondrial beta-oxidation. Although the majority of manufacturers of stimulant-based "fat burners" do not mention this in their adds, a 5x, 10x or even 100x liberation of free fatty acids is not worth a single square centimeter of the high gloss paper respective (non-FDA approved) advertisement claims are printed on. If your body does not "burn" the fat those "stressors" (in essence this is what caffeine, ephedrine, dimethylamiline ~ geranium) pump into your blood stream, it will not only be stored again, but will also have blunted your insulin (Boden. 2001) and leptin sensitivity (Shintani. 2000) in the mean time.

Physiologic increases in plasma FFA levels cause insulin resistance in both diabetic and nondiabetic subjects by producing several metabolic defects: (1) FFA inhibit insulin-stimulated glucose uptake at the level of glucose transport or phosphorylation (or both); (2) FFA inhibit insulin-stimulated glycogen synthesis; and (3) FFA inhibit insulin-stimulated glucose oxidation.[...] FFA probably also cause hepatic insulin resistance, which results in increased rates of endogenous glucose production in relationship to the prevailing degree of hyperinsulinemia. (Boden. 2001)

The obvious question, now, is: Would intermittent fasting have similarly detrimental effects on insulin sensitivity? After all, fasting is stressing and we have previously identified the increase in free fatty acids as a consequence of fasting induced metabolic adaptations that will allow your body to feed preferentially on fat, instead of carbs. It thus seems to be reasonable to assume that intermittent fasting would predispose its practitioners to insulin resistance.

It should be noted that the temporary insulin resistance actually is a fundamental and important mechanism by which intermittent fasting works its fat burning, muscle sparing magic. In fact, the combination of increased free fatty acids and the ensuing decrease in glucose uptake by skeletal muscle in the initial phase of fasting (and intermittent fasting does not go beyond this initial phase) have been shown to ramp up uncoupling proteins and thus fatty acid oxidation in slow-twitch oxidative muscles (Samec. 1998) and thusly set the scene for improvements in body composition, as long as you are in a caloric deficit (read more on the significance of total caloric intake in future episodes of this series).

While data from the Cahill study, where 8 days of fasting reduced the coefficient of glucose disappearance from 2.1%/min to 0.63%/min (-70%), would support this idea, further research reveals that this is another case, where "normal" fasting with its prolonged periods of food abstinence differs fundamentally from its "intermittent" incarnation with fasting periods of 12-24h, of which a group of Danish scientists were able to show that it "increases insulin-mediated glucose uptake rates" (Halberg. 2005).

The Halberg study did however use an alternate-day fasting regimen (for my thoughts on alternate-day vs. intermittent fasting cf. part II of this series), which is obviously characterized by ~50% longer fasting periods. Similar data (cf. figure 5) does yet come from another Ramadan fasting study (12-16h fasting), in which 55 subjects with metabolic syndrome crammed their habitual caloric intake (this is an important difference to most of the other Ramadan studies, where mostly healthy participants automatically decreased their calorie intake !) into the two meals this kind of religious fasting allows for. 

Figure 5: Changes in waist circumference, BMI, HDL, triglycerides, fasting glucose, QUICKI (quantitative insulin sensitivity check index) and 1/HOMA-IR after non-calorie-restricted (not even unconsciously) Ramadan fasting in 55 subjects with metabolic syndrome (data adapted from Shariatpanahi. 2008)

The beneficial effect on insulin resistance (as measured by a +44% increase in the inverse of the long-term marker of insulin resistance 1/HOMA-IR and the slight increase in QUICKI) is obvious and, together with the slight decreases in BMI and waist circumference in absence of any dietary restrictions, speaks to the potential application of one or another way of intermittent fasting in the "treatment" the ever-increasing number of (morbidly) obese adults and adolescents (Sturm. 2007) ....

In view of the fact that I have already spent the major part of this precious day-off thinking, researching and blogging about Intermittent Fasting, I will yet postpone any further elaborations on the health benefits of (intermittent) fasting and the subsequent analysis of what happens when you finally "break the fast" to the next installments of this series. In the mean time, I hope you got some new points to think about and repeat my invitation to post your comments, questions and suggestions as to where this series should be heading on Facebook, Twitter or in the comments area of this page.