26 March 2009

Feast and Fast: the dichotomy of insulin and growth hormone

At its heart the human body is a machine. A very complicated machine to be sure, unknowable in completion given our current basis of knowledge, but it still obeys certain engineering concepts in the end. One of those concepts is that the operation of a machine is governed by its control system. When it comes to health, the hormonal system is the control system that governs just how well we feel. We stimulate it in various ways and it causes our bodies to react to those stimulus. Trying to pick apart these relationships is, in my opinion, the key to understanding how to obtain good health throughout our lives.

Today I'm going to write predominately about growth hormone and how it metabolizes fat. I got the idea primarily from the writings of Brad Pilon. I have not read his book; I worked from review articles in scientific journals.


The human body has two signaling systems:
  1. The nervous system, which primarily controls fast actions such as motion and thought.
  2. The endocrine (or hormonal) system, which primarily handles slower processes..
The characteristic time scale of the nervous system is milliseconds. It operates on the principle of action potentials: electrical impulses driven by the fast pumping of sodium and potassium ions. Hormones do not travel down specialized pathways, instead they use the circulatory system. In the endocrine system, the characteristic time is on the order of minutes or hours as hormones decay within the blood stream. From an evolutionary perspective, the endocrine system is much older, since even bacteria use a variety of signaling peptides to control their operation. The nervous system had to await the development of such advanced animals as the mighty squid.

When it comes to metabolism, the endocrine system is the one in control. There is a portion of the nervous system that controls the gut, the autonomic nervous system, but it acts largely independently of the brain. It controls aspects like opening sphincters, e.g. stomach emptying.

If the nervous system is a digital system, then the endocrine system is very much like an analogue circuit composed of resistors, capacitors, and inductors (in biological analogue circuits these are usually called push-pots). These elements can be formed into circuits that perform various functions (amplification, integration, differentiation, etc.). However, there are many, many elements that compose the endocrine system of the human body. If you were to draw a circuit diagram of the human body it would resemble not so much a Pentium CPU as a Gordian knot with its mass of interconnections.

Conceptually the hormone system is divided into the whole-body hormones (endocrine), local tissue hormones (paracrine), and single cell hormones (autocrine). I am mostly concerned with endocrine system since it is the one that affects multiple types of tissues such as fat, muscle, and vital organs. There are certain hormones related to digestion and metabolism that can be considered the premiere, most vital hormones to control such tasks.

Examples of top-tier hormones involved in the process of eating include:
  • Macronutrient metabolism hormones (insulin, growth hormone)
  • Sex hormones (testosterone, estrogen)
  • Appetite hormones (ghrelin, leptin)
  • Basal metabolism (thyroid)
  • Stress hormones (cortisol, epinephrine) (Jensen et al., 1987)
Many of these hormones interrelate with each other, either directly or through the mechanism of secondary, lower-tier hormones, in a very complicated system that is difficult to pick apart. Typically the hormonal system operates on the principle of negative feedback, so if production of one hormone surges, that will in turn generate feedback that will eventually damp it back to normal levels.

For people who are trying to lose fat, a reasonable objective is to tweak one or more hormonal levels to upset the existing equilibrium. A kilo here, a kilo there, and pretty soon you're talking about real weight loss. However, like any complex system, you have to feed it the proper inputs for it to function properly: Garbage in = garbage out.

The feast and fast cycle

Insulin is the primary regulator of carbohydrate and protein metabolism. (Human) growth hormone (abbreviated GH) is the primary regulator of fatty acid metabolism. Today, we're going to talk mostly about GH since most people already know a fair amount about insulin. If you don't, you can get started with my review of Gary Taubes' book, "Good Calories, Bad Calories."

So, to review, insulin is the hormone responsible for regulating the metabolism of glucose and most amino acids (exceptions are lysine and leucine) derived from the protein in your diet that are converted to glucose for the purpose of fuel (Gröschl et al., 2003). High levels of insulin also prevent your muscles from absorbing fatty acids in the blood: the body prefers to burn the low-energy density carbohydrates first and hold onto the superior fatty acids for lean times. A person with high levels of insulin in their blood is said to be in the feasted state.

The opposite to the feasted state is the fasted state. The hormone that characterizes the fasted state is growth hormone (review: Møller and Jørgensen, 2009). The general course of progressing from feasted to fasted goes something like this:
  1. You eat a meal with carbohydrates and protein. Digestion occurs over the course of several hours and insulin levels rise in response to the absorption of these macronutrients.
  2. Insulin sensitive tissues absorb glucose from the blood-stream. Glucagon, a second-tier hormone, causes the liver to break down the glycogen it stores into glucose, releasing it into the blood. This slows the rate at which insulin drops.
  3. Insulin continues to drop as the liver's supply of carbohydrate is reduced. Ghrelin (which I'll discuss later) is produced, which promotes appetite and the production of growth hormone. If the increase in appetite caused by ghrelin causes you to eat, you go back to stage 1. Otherwise, you make the transition into the fasted state as GH levels rise and blood sugar levels drop (Roth et al., 1963).
Growth hormone is basically the hormone that controls when your adipose (fat) tissues release fatty acids to be metabolized by the rest of your body. No growth hormone, no significant fat loss.
Figure 2. from Møller and Jørgensen (2009) on the interrelation of growth hormone, insulin growth factor, and insulin in the fed and fasted cycle.

However, this is not all growth hormone does. As the name suggests, GH, in conjunction with insulin-like growth factor, is involved in the growth of lean body mass: it increases the amount of protein in your muscles and vital organs, it increase the uptake of calcium by bones, etc. Growth hormone alone is insufficient to boost protein synthesis, however. I'll probably save the discussion of IGF-1 for another time (for further reading, start with Gibney, Healy, and Sönksen, 2007). In this context, growth hormone may be poorly named.

In addition to promoting fatty acid metabolism, GH shuts down the uptake of glucose into muscle tissue and stops the conversion of amino acids into glucose (Rabinowitz, Klassen, and Zieler, 1965). The fact that GH shuts down not just carbohydrate metabolism but also protein metabolism is critically important. It means that when one enters the fasted state, your muscle and organs are protected against being consumed to fuel your body (Nørrelund et al., 2006). This clearly illustrates the greatest failing of the high-carbohydrate, calorie-restricted "semi-starvation" diet that Taubes pans: if you maintain high insulin levels but insufficient calories, there's little to protect the protein in your muscles and vital organs from being consumed while your fat tissue goes untouched.

Furthermore, once a person becomes insulin resistant (and most obese individuals are), they become locked in a vicious cycle: insulin levels remain high for a long time after a meal, and stay high until the next meal, so the body never makes the transition from feasted to fasted and hence never burns any body fat. Let me reiterate: once you are obese, you will have a harder time losing body fat than a thinner individual. Unsurprisingly, growth hormone levels in obese people are depressed (Scacchi et al., 1999). The number one priority for losing weight then is improving insulin sensitivity. As an aside, this is a good reason to avoid supplementation with synthetic growth hormone: it may leave you with unnaturally elevated blood sugar for an extended period of time. Essentially growth hormone makes your tissues insulin resistant, but it normally only does so when blood glucose levels are depleted.

Body composition — whether you are lean or fat, i.e. the ratio of fat mass to lean body mass — is basically a function of the ratio of time you spend in the feasted state versus time you spend in the fasted state. Now, on the face of it, this statement is self-evident and rather useless. However, it's also very fundamental. In the natural situation, insulin and human growth hormone levels are reciprocal: GH is low when insulin is high, insulin is low when GH is high. A meta-analysis of GH found that high levels of growth hormone led to an increased basal metabolic rate of 141 [69-213] kcal/day (Liu et al., 2007). This corresponds to roughly a pound of fat per month.

What controls growth hormone levels?

So if growth hormone controls the release of fat from your fat tissues, what controls the release of growth hormone? Growth hormone is typically released in pulses from the pituitary gland. This pulsitile nature of growth hormone is similar to that of insulin in a healthy individual.

Figure 4 from Ho et al., 1988, showing the Fourier transform of GH secretion. Filled boxes are (24-hr) fasted subjects, open boxes are fed controls. Normally the horizontal axis of a Fourier transform is frequency but in this case it is period. This plot shows peaks at 110 min, 206 min, and 24 hr. The 24 hour cycle is likely caused by sleeping, the sources of the other peaks are less clear.

Growth hormone is primarily up-regulated by growth hormone releasing hormone (GHRH) and growth hormone releasing peptide, better known as ghreline. Growth hormone is primarily down-regulated by human growth inhibiting hormone (GHIH), typically known as somatostatin, and high blood glucose levels. I eagerly await the discovery of growth hormone releasing hormone releasing hormone (GHRHRH). Ok, I jest, low-levels of growth hormone and insulin stimulate GHRH.

Notice something interesting: ghrelin is an appetite controlling hormone. When you fast, GH production goes up and up and ghrelin goes down. When fasting, the hardest part is about six hours after your last meal when your insulin levels have dropped down and you have a strong appetite. However, if you get over this 'hump' you will find that your appetite largely goes away as the ghrelin circulating in your blood starts the secretion of GH. You will still get thirsty, but not ravenously hungry. I would generally recommend sleeping through this stage.

So what's the difference between controlling your body's overall insulin/GH levels very controlling your appetite to avoid binge eating? Can we actually separate the appetite hormones, leptin and ghrelin from the metabolism control hormones, insulin and growth hormone? As far as I can tell, appetite and blood sugar levels are basically the same thing. Trying to separate the two as wholly independent variables and then claiming that fat people simply lack self control when it comes to food is very very wrong. The science clearly shows that the two are deeply inter-related.
Figure 4. from Hartmann et al., 1992, showing the negative correlation between GH release and body-mass index in fasted subjects.

Production of growth hormone typically declines as we age. However, research has shown that growth hormone levels are more tightly correlated with visceral fat (belly fat) than age (Vahl et al, 1997). So do we get fat because we get old or do we get old because we get fat? Both answers appear to be correct, each to a degree. No one will live forever, but most of us would like to age gracefully. I'm about a decade younger than I was at this time one year ago.

Real-world means of increasing growth hormone levels

There are three basic ways to increase the amount of GH your body produces:
  1. Get adequate sleep. GH production spikes during sleep. Try not to eat before bedtime.
  2. Fast occasionally, for relatively short durations.
  3. Conduct intense exercise. Don't eat before or during your exercise.
'Intense' exercise in this context means you should exceed 75 % of your VO2 max lactate threshold (Pritzlaff et al., 1999). VO2 max Lactate threshold is the level at which the demands of your exercise exceeds your body's ability to breath in oxygen, causing the body to go anaerobic and produce lactic acid. Note that VO2 max lactate threshold is for your whole body, so you need to exercise your whole body or at least the biggest muscles (core, glutes, quads). You can do bicep curls until your arms fall off but since they're small muscles you won't get much of a GH boost from doing so. The best exercise for putting your whole body into the anaerobic threshold is probably sprint intervals.

Figure 1. from Pritzlaff et al., showing GH secretion pulses as a function of lactate threshold (LT) reached.

Of course, (2) and (3) can be combined. A word of warning, if you exercise hard at the end of a fast, be prepared for sore muscles (i.e. delayed onset muscle soreness) the next day.

A low-carbohydrate diet may have the advantage in this situation as the overall insulin pulse should be small and of shorter duration. The reason is fairly obvious: the body's tissues will be less insulin resistant and hence absorb glucose from the blood stream more readily. Hence one should enter the fasted state quicker after a low-carbohydrate diet than not. The more time you spend in the fasted state, the faster you're going to shed body fat.

The $64,000 dollar question is then, what effect does dietary fat have on growth hormone secretion? It appears that dietary fat intake increases the production of somatostatin from the gut, otherwise known as growth-hormone inhibiting hormone, although somatostatin down-regulates many many other hormones (Cappon et al., 1993). Anecdotal evidence from people who regularly fast is that fasting is easier to handle on a low-carbohydrate diet than a low-fat diet. I dug around for awhile on PubMed, but I wasn't able to find any research where subjects were fed diets of pure glucose and pure triglycerides and then their transition from feasted to fasted tested. It would be a good Master's thesis for someone if it really hasn't been done before. I did find tests that tested intravenously applied fatty acids in fasting but since somatostatin is produced by the digestive system their relevance isn't clear. The Hartman study from 1992 seems to be the best starting point for this line of research.

in alphabetical order:

Cappon JP, et al. "Acute effects of high fat and high glucose meals on the growth hormone response to exercise." J Clin Endocrinol Metab. 1993 Jun;76(6):1418-22.

Gibney J, Healy ML, Sönksen PH. "The growth hormone/insulin-like growth factor-I axis in exercise and sport." Endocr Rev. 2007 Oct;28(6):603-24.

Gröschl M, et al., "Endocrine responses to the oral ingestion of a physiological dose of essential amino acids in humans.", J Endocrinol. 2003 Nov;179(2):237-44.

Hartman ML, et al., "Augmented growth hormone (GH) secretory burst frequency and amplitude mediate enhanced GH secretion during a two-day fast in normal men." J Clin Endocrinol Metab. 1992 Apr;74(4):757-65.

Ho KY, et al. "Fasting enhances growth hormone secretion and amplifies the complex rhythms of growth hormone secretion in man."J Clin Invest. 1988 Apr;81(4):968-75.

Jensen MD, et al., "Lipolysis during fasting. Decreased suppression by insulin and increased stimulation by epinephrine." J Clin Invest. 1987 Jan;79(1):207-13.

Liu H, et al. "Systematic review: the effects of growth hormone on athletic performance."
Ann Intern Med. 2008 May 20;148(10):747-58.

Pritzlaff CJ, et al. "Impact of acute exercise intensity on pulsatile growth hormone release in men." J Appl Physiol. 1999 Aug;87(2):498-504.

Møller N, Jørgensen JO, "Effects of Growth Hormone on Glucose, Lipid, and Protein Metabolism in Human Subjects." Endocr Rev. 2009 Mar 19.

Nørrelund H, et al., "The protein-retaining effects of growth hormone during fasting involve inhibition of muscle-protein breakdown." Diabetes. 2001 Jan;50(1):96-104.

Jesse Roth, et al., "Hypoglycemia: A Potent Stimulus to Secretion of Growth Hormone." Science 140(3570):987 - 988 (May 1963).

Scacchi M, Pincelli AI, Cavagnini F. "Growth hormone in obesity." Int J Obes Relat Metab Disord. 1999 Mar;23(3):260-71.

Vahl N, et al., "Abdominal adiposity rather than age and sex predicts mass and regularity of GH secretion in healthy adults." Am J Physiol. 1997 Jun;272(6 Pt 1):E1108-16.

David Rabinowitz, Gerald A. Klassen and Kenneth L. Zierler, "Effect of Human Growth Hormone on Muscle and Adipose Tissue Metabolism in the Forearm of Man." J. Clin. Invest. 44(1): 51-61 (1965).

19 March 2009

Economic Limits to Energy Reserves

If you have a passing familiarity with energy policy, you probably are aware that the scale of potentially available resources is enormous. For example, the USA is purported to maintain coal reserves sufficient for 250 years of consumption, or 1600-3600 billion metric tons. From wind, the total world resource that is considered to be commercially viable is about 72 TerraWatts. However, that figure only includes the wind resources that exceed some average velocity (probably 7 m/s) so the actual total resource is somewhere around 500 TW. An enormous figure.

The viability of renewable power is largely a function of the price of fossil fuel commodities, the action of government in regulation and subsidy/taxation, and the technology level of the renewable sector. The conception that renewable power will be composed of a mélange of many different sources does not fully illustrate the likely outcome.

The term, commercially viable, then is key. What matters is not how big a resource is in absolute terms, but how that resource is distributed in terms of quality relative to alternative energy resources.

One possible metric for energy resource quality would be the EROEI (Energy Return On Energy Invested) which is especially popular in the Peak Oil community. It is an expression which can be derived in engineering terms so it is quantitative. However, the metric that really matters is the economic one: how many dollars do I have to spend to get my unit of energy? How can I further parametrize an alternative energy resource to evaluate when it will become economical to exploit?

Inertia and vested interests will have an influence over the short-term but eventually the cheaper source of energy will win. It's much more fuzzy than EROEI, since adding money adds many more degrees of freedom (i.e. value of fiat currency, cost of credit, cost of technology, etc.) and anything money related has a big rationalization factor, but it's fundamentally closer to the truth. If the EROEI metric was the determining factor, we'd all be powered by hydroelectric dams (and yes I am aware that after you amortize, hydro power is dirt cheap... smart ass).

The real metric then for energy quality is going to be the rate of return in dollars, not energy. Unfortunately, dollars per unit of energy is going to be a datum with many degrees of freedom behind it, making analysis complicated and prone to change on a month to month basis. Still, we can construct some hand-waving arguments based on best guesstimates to make some general conclusions.
Figure 1: Schematic of renewable energy resource economic distribution. Not to scale, seriously based on established data, etc. but rather a illustration for the eye. There's no reason for these curves to be symmetrical, it just looks better.

Most resources can be described as a sharp peak with heavy tails. For wind, you have some select areas where the terrain funnels katabatic winds coming off of mountain ranges and you find a strong, consistent wind resource. On the other hand, much of the Earth is covered in forests which increase the surface drag and results in a poor quality wind resource. On the geothermal power front, you have a few select areas where vents circulate magma from the Earth's mantle near to the surface and a lot of heat power can be extracted. However, most deep geothermal is going to be pulling heat energy out of the crust which isn't replenished quickly. Most rocks only conduct around 30 mW/m2 so it's easy to exhaust the resource. It's not clear, then, if deep geothermal can easily amortize the capital costs of drilling. Solar is an exception, in that not only does it dwarf all other resources in total potential but it's also very stubby.

If you look at the scale of various renewable and non-renewable power sources it quickly becomes obvious that solar dwarfs them all. There is about 190000 TW of solar power incident on the earth at any one time. Even when you factor in scattering from the atmosphere and clouds, it's still ~ 125x greater than the wind resource. Moreover, solar is also the most uniformly distributed. The best solar resources in the world, such as Arizona and North Africa, only receive about 3x more power than cloudy Northern Germany. This means that any graph of solar resource quality as a function of the total available resource is very squat and shallow. It's the Olympus Mons of power quality-potential curves. So why am I going on and on about solar? Well, it provides an economic floor to all other sources of power. Any portion of a resource that economically falls below the top of the solar curve, won't be significantly exploited, due to the extreme width of the solar curve.

The significance of the above statement is mostly of interest as a tool for formulating public energy policy. Should all alternative energy technologies be pursued with the aid of the public purse? Primary research at the academic level should not be funded on the whim of politicians, but when it comes to issues like production subsidies, the introduction of politics is unavoidable. Thus, I would like to propose a check-list for all those prospective deciders out there (and of course investors in the private funding world):
  1. How large is the renewable resource that lies significantly above the solar resource and how does that compare to the amount of proposed investment? Note that this will change significantly from region to region. Britain isn't a great solar resource, but it has a much larger wave power resource than most. So for Britain you have a wider effective wave power peak and a lower solar base-line.
  2. Is there a significant body of academic research (typically 10-20 years) behind the concept or is it pie in the sky? Too many big energy ideas/start-ups try and do research and development without doing the research part. Needless to say, it usually ends in tears. Lithium-ion iron-phosphate batteries didn't pop out out of the ether, and neither did First Solar.
  3. What sort of (general) technologies developments on on the horizon that may effect the size and shape of the resource's economic curve? This is a really tough question for a politician to answer unfortunately. My advice is to keep it simple: only the really big changes matter on a macro scale.
  4. Does the technology deliver power at night? Statistically, wind and solar power have an almost identical standard deviation, the difference is solar is predictable. Looking forward, it seems inevitable that electrical power will be cheaper during the day than at night. This may necessitate, for example, plug-ins at work — we already have such things in Edmonton, but for powering the block heater in your car so the oil pan doesn't freeze into a solid pane of grease.
And what of the non-renewable resources? Well those curves are actively being consumed, with the highest quality reserves (i.e. the peaks of the mountains) going first. Of course, with improving technology, their are fossil reserves that are becoming more economic at the same time. It took a fairly enormous investment to get the oil sands of Alberta viable, but here we are now, making oil from asphalt.

There are also a number of more auxiliary issues that can have a significant impact on how edit( economical a particular technology can be in a given locale. Some are simply a function of geography, such as how concentrating solar power only works in terrain that sees little cloud cover. ) These parameters make the situation fuzzier than before, but we can at least account for them in some qualitative, if inadequate, sense. An example that I've discussed is the increased speed of deployment and improvement of energy technologies that can be deployed in an incremental fashion.

Inertia of existing technologies is one of the most important parameters. Inertia in terms of an existing energy technology can be summed up as: embedded capital costs. As an example, buying an electric car or a plug-in hybrid costs quite a lot of money. Even buying a depreciated used SUV compared to a new Prius requires a huge number of miles driven to recoup the price premium between the two. The nature of inertia means that as the best of the fossil resources continue to be consumed, there will naturally be some overshoot before the renewables come to the fore.

Arbitrage opportunities should also be a great way of making money in the future. The giant disadvantage of renewable technologies like photovoltaic solar and wind is that they are not dispatchable (and in the case of wind, not reliably predictable). If 100 % of your generating capacity has to be backed with natural gas turbines, that adds a great deal of capital cost to your power generating infrastructure. I.e. it makes wind more expensive than the cost of the turbines alone would imply. However, balancing supply and demand with a reserve of turbines is probably the most expensive path you could take.

If you are an investor and want to start a new thin-film photovoltaic company, you are probably too late to catch the leaders. The depression of global trade and financial services will slow down the existing photovoltaic manufacturers, but you still have to navigate an uncertain minefield of failed technologies and patents. However, there's still plenty of opportunity to find niche applications to match daytime electricity generation to nighttime demand. Plug-in hybrids are generally seen as an excellent means of smoothing out the supply and demand curves, especially because they can justify a higher battery cost since they are purchased primarily for driving and not regulating the electrical grid. There are also other demand shaping potential means of arbitrage out there.