Ketogenic Diets Compromise GH and IGF-1: Strategies to Fight Back

 by Dan Gwartney, M.D.

Growth hormone (GH) has been touted as the miracle sought by Ponce de León in his quest for the Fountain of Youth. Once a rare treatment obtained from pituitary glands (brain tissue) of cadavers, technology has advanced to allow laboratories to create a seemingly endless supply of the drug.¹ Bodybuilders have long been early adaptors of pharmaceutical, nutritional, and physical training methods to maximize muscle growth, as well as reduce body fat to extremes well beyond innate physiological limits.

Initially, GH was used in bodybuilding and sports to promote muscle size and strength. As adults dosed themselves based on the clinical guidelines for GH-deficient dwarf children, it was learned that adverse effects accompanied the relatively high dosages. The adverse effects include glucose intolerance (pre-diabetes), edema, carpal tunnel syndrome, elongated hands and feet, and abnormal facial bone growth.² Unfortunately, as an anabolic, GH requires a fairly significant dosing schedule, and the increase in tissue mass is not necessarily commensurate with strength increases— which was especially absent with the use of insulin and/or anabolic steroids.³ Additionally, GH is much more expensive than anabolic steroids and needs to be injected daily or at least several times per week.

Supraphysiologic GH dosing schedules have been abandoned by all but the most extreme bodybuilders. However, as a greater understanding of the use of GH has been gained through practical experience and clinical use in aging and weight loss, an appreciation of GH’s role in fat loss has been acknowledged. Depending on the population (elderly, obese, etc.), a low-to-moderate dose of GH can result in improved body composition and reduced body fat. GH acts directly on receptors on the surface of many different tissues. Of particular significance relative to improving body composition are two receptors— white adipose tissue (fat) and skeletal muscle.
However, one does not need to inject pharmaceutical GH to achieve the fat-loss effect. Fat loss can occur under ‘normal’ conditions including prolonged fasting, exercise, hypoglycemia (low blood sugar), and through stimulation by nutritional or pharmaceutical secretagogues.

GH acts on skeletal muscle to promote tissue anabolism. Most readers will associate this with an increase in contractile protein— the functional component that moves the skeleton (lifts weights). However, GH promotes the growth and repair of numerous structures and components within a cell and affects metabolic function. GH does not act directly on the internal portions of the cell or within the nucleus (the command center of a cell). Instead, GH attaches to a receptor that transmits a signal to the cell interior when it is activated. This receptor signal is another chemical that activates various processes and responses. The messenger(s) created by the GH-stimulation, STAT5, bind to regions of the DNA and turn on cell-building machinery.^4,5

It seems reasonably clear that greater doses of GH would lead to a stronger STAT5 signal and bigger muscles. Yet, GH and muscle do not exist in a vacuum. The fat cell is more sensitive to the effect of GH, responding with a lipolytic (fat-releasing) effect at a lower concentration than the muscle cell’s anabolic response. This is not a significant issue in most physiologic conditions. However, individuals can find themselves— or place themselves— in conditions that extend beyond ‘normal.’ One such condition is prolonged, relative hypoglycemia (low blood sugar) achieved during fasting or while following an extremely low-carbohydrate diet. The most extreme of the low-carbohydrate diets are ketogenic diets, as they force the body to burn not just fat, but also certain amino acids for energy.⁶ These amino acids come from proteins, including contractile proteins from skeletal muscle that are broken down to supply the cellular energy needs of the body. From the point of view of survival, not lapsing into a coma is more critical than a 21-inch set of biceps. Even people consuming a ‘normal’ diet may briefly enter ketosis (to a much lesser degree) overnight if they extend their fast by eating an early dinner and exercise prior to breakfast.^7,8

Much attention is paid to the ketones produced during very low-carbohydrate diets. However, one important and physiologically overwhelming factor that is ignored is the increase in circulating free fatty acids (FFA). FFA, also called non-esterified fatty acids, are the breakdown products of stored fat released from fat cells. Three fatty acids are bound to a glycerol backbone by ester bonds in the stored form, and the breakdown signal generated by GH, epinephrine, glucagon, cortisol and other agents breaks the ester bonds— releasing both the FFA and glycerol into the circulation. These FFA can be taken back up by fat cells, or active tissue— such as muscle— can take in FFA to use for energy (burning the FFA for calories), or even store a limited amount in muscle tissue.

This is the primary function of GH in adults— acting as a counter-regulatory hormone to maintain available energy during periods when blood sugar levels fall. Some describe GH by the very basic term of being an ‘anti-insulin.’ This oversimplifies the issue, but relative to blood sugar control and energy balance, it works.

The body is designed to be very efficient. To avoid the need for an infinite number of hormones, each hormone creates a number of ‘effects.’ Some of these effects are specific to a type of tissue (e.g., fat); some effects depend on the concentration of the hormone; some effects in one cell type may alter the effects in other cell types.

An interesting study illustrates the complexity of GH. The study showed that the response of skeletal muscle to GH is altered by increases in FFA.⁹ Recall that the actions of GH in skeletal muscle are carried out by STAT5 proteins. Dr. Niels Möller and his colleagues in Denmark studied the effect of varying levels of FFA on skeletal muscle response to GH in eight healthy, young adult, male volunteers. The study was designed to control GH, insulin, glucagon, and FFA. The subjects were given drugs that suppressed natural GH and prevented FFA release from fat cells. This allowed scientists to control the blood concentrations of GH and FFA throughout the experiment.

Once the subjects’ natural release of GH and FFA was controlled, they were given GH and glucagon for 8 hours at a steady level. Each subject was treated on four different days, each day given a different concentration of FFA for the 8-hour period, ranging from the lowest to highest physiologic concentrations (what a person might experience). During the last 2 hours, insulin was also provided. At the end of each study day, muscle biopsies were taken and the tissue was analyzed for STAT5 concentration. Theoretically, since the same amount of GH was provided, STAT5 levels should be the same.

The researchers discovered that at the lowest FFA concentration, skeletal muscle was maximally responsive to GH, recording the highest concentration of STAT5 at the end of the treatment period. As FFA concentration increased, STAT5 concentrations in the muscle decreased in a dose-dependent manner. The highest FFA concentration, which would represent what a person might experience long-term on a low-carbohydrate diet, during endurance exercise, or possibly even overnight, suppressed STAT5 response by 40 percent.

What is the impact of this new knowledge? Many bodybuilders and people following a weight-loss diet follow a lower-carbohydrate program as those types of diets (i.e., Atkins, South Beach, etc.) are quicker and may be more effective in the short-term.¹⁰ Hopefully, exercise is part of any weight-loss program, with the intention of increasing lean body mass to improve glucose tolerance, cardiovascular health, and boost metabolism. Bodybuilders, athletes, and fitness enthusiasts obviously have the goal of increasing muscle size and strength. Yet, these findings suggest that entering a phase of fat loss, when stored fat is released into the circulation to be burned as calories, may be sabotaging at least one component of the anabolic phase of muscle growth.

It is too early to state with certainty whether the lower STAT5 response to GH during conditions of higher circulating FFA ultimately reduces the long-term anabolic effect of exercise. The study authors acknowledge that they did not measure beyond the STAT5 signal.⁹ It is possible that the GH-stimulated mechanism of the muscle may be turned on by other signals or be more responsive to lower concentrations of STAT5 during periods of perceived starvation. The authors speculated that the lower sensitivity to GH in muscle may be protective, as the body does not want to be growing an energy-demanding tissue (muscle) in conditions that are perceived as stressful. Gyms are a fairly recent development in the history of mankind. Prior to the last century, if a body was experiencing high concentrations of FFA, it meant that food was scarce and the body was forced to break down stored fat to feed the demands of the brain, heart and other vital organs. Thus, it is reasonable that a survival mechanism is being activated to reduce muscle growth when energy stores (fat cells) are being depleted.

This effect is likely of small consequence for a person who at least eats maintenance calories, including a significant percentage of carbohydrates. However, for the long-term ketogenic dieter, the blunted response to GH may result in reduced growth and recovery from exercise. There are a few strategies that may help avoid sabotaging the muscle-building benefits of exercise during a low-carbohydrate diet.

First, remember that GH is released during exercise, particularly high-intensity resistance training.¹¹ While the STAT5 response to a fixed GH concentration was reduced in resting subjects over 8 hours, it is unknown whether the response to sudden spikes in GH (such as might be induced by weight training) might bypass some of that FFA-induced resistance. Thus, it’s likely that it would be beneficial to focus on low-rep weight training, using power movements to spike GH.

Ketosis is created by reducing carbohydrates to approximately 20-30 grams per day. While some learn to enjoy the sensation and control of following a ketotic diet, similar weight-loss and fat-loss results can be achieved by following a controlled low-carbohydrate diet. The period immediately before and after a workout is unique because any nutrients consumed are preferentially shuttled to muscle. By consuming a moderate amount of carbohydrates 30 minutes prior to a workout to induce an insulin surge, FFA release will be temporarily suppressed.¹²

If the workout is intense and relatively short (30-60 minutes), GH should be released during the period when insulin is still suppressing FFA release, as well as protecting skeletal muscle from breakdown, allowing for the greatest (natural) anabolic effect.

Testosterone also peaks following this type of workout. Flooding the system with a high-quality, rapidly-absorbed protein and carbohydrate meal or drink immediately post-workout is essential to maximize this effect.¹³

The other period when GH is released in significant quantities is during sleep. This makes getting 8 hours of quality sleep vital to maintaining the GH benefit to muscle during low-carbohydrate diets. Nutritional GH releasers have suffered from the ‘over-promise/under-deliver’ marketing campaigns of some companies, but during prolonged release of FFA into the circulation, it may be beneficial to revisit certain common ingredients.

Glutamine is not only an amino acid necessary for protein building, but it’s also an amino acid that can be converted into sugar by the liver.¹⁴ Low-carbohydrate dieters who exercise face an increased demand for glutamine and other gluconeogenic amino acids (ones that can be converted into sugar) to restore muscle and liver glycogen (stored glucose for high-intensity exercise).¹⁵ Glutamine also stimulates GH release, adding to the ‘nutraceutical’ value of this amino acid.¹⁶ Another amino acid, arginine, also stimulates the release of GH but by a different mechanism— by blocking the hormone that suppresses GH release, called somatostatin.¹⁷ Arginine is also the precursor to nitric oxide (the NO supplements) and creatine.

Finally, the B vitamin niacin also aids in GH release. Very relevant to this study, niacin increases GH release by inhibiting FFA release from fat cells.¹⁸ Not only do circulating FFA reduce the response of muscle to GH, but FFA also signal to the brain not to release as much GH. Thus, if maintaining or building muscle is part of the goal while following a ketogenic or low-carbohydrate diet, an immediate release of niacin just prior to sleep and/or a workout may be of benefit.

Niacin causes people to experience an unpleasant flush and tingling, so start with a slow dose. Some have liver problems from the slow-release forms of niacin, so as with all diet and exercise advice, individuals are responsible for discussing this with their own health care provider prior to starting any program.

Of course, the GH signal can also be augmented pharmaceutically, though there are no accepted clinical indications for doing so to enhance exercise or fat loss. Low-dose GH therapy of 1-3 IU/day improves body composition in most studies. The GH releasers— sermorelin, capromorelin and others— as well as oral GH secretagogues, are being studied in certain clinical applications.¹⁹ These drugs have also been used by bodybuilders with varying reports of efficacy.

This all makes sense from the point of view of species adaptation. When the body is starving, stored fat is released as FFA. Regardless of what else is happening (war, competition, etc.), the body will not survive a long-term famine/winter/emigration carrying any excess muscle, as that tissue burns a lot of calories and is not vital to survival. Being aware of the body dynamics and attempting to reduce FFA during periods when GH will be released may help maintain or build muscle even when following a low-carbohydrate diet.

References:

1. Jenkins D, Stewart PM. Advances in medical therapy for pituitary disease: treating patients with growth hormone excess and deficiency. J Clin Pharm Ther, 1993 Jun;18(3):155-63.

2. Van Loon K. Safety of high doses of recombinant human growth hormone. Horm Res, 1998;49 Suppl 2:78-81.

3. Lange KH, Andersen JL, et al. GH administration changes myosin heavy chain isoforms in skeletal muscle but does not augment muscle strength or hypertrophy, either alone or combined with resistance exercise training in healthy elderly men. J Clin Endocrinol Metab, 2002 Feb;87(2):513-23.

4. Lanning NJ, Carter-Su C. Recent advances in growth hormone signaling. Rev Endocr Metab Disord, 2006 Dec;7(4):225-35.

5. Campbell GS. Growth-hormone signal transduction. J Pediatr, 1997 Jul;131(1 Pt 2):S42-4.

6. Manninen AH. Metabolic effects of the very-low-carbohydrate diets: misunderstood “villains” of human metabolism. J Int Soc Sports Nutr, 2004 Dec 31;1(2):7-11.

7. Afaghi A, O'Connor H, et al. Acute effects of the very low carbohydrate diet on sleep indices. Nutr Neurosci, 2008 Aug;11(4):146-54.

8. Keller U, Schnell H, et al. Effect of physiological elevation of plasma growth hormone levels on ketone body kinetics and lipolysis in normal and acutely insulin-deficient man. Diabetologia, 1984 Feb;26(2):103-8.

9. Moller N, Gormsen LC, et al. Free fatty acids inhibit growth hormone/STAT5 signaling in human muscle: a potential feed-back mechanism. J Clin Endocrinol Metab, 2009 Mar 10. [Epub ahead of print].

10. Gardner CD, Kiazand A, et al. Comparison of the Atkins, Zone, Ornish, and LEARN diets for change in weight and related risk factors among overweight premenopausal women: the A TO Z Weight Loss Study: a randomized trial. JAMA, 2007 Mar 7;297(9):969-77.

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

12. Balks HJ, Schmidt A, et al. Temporal pattern of pancreatic insulin and C-peptide secretion and of plasma glucose levels after nutritional stimulation. J Clin Endocrinol Metab, 1992 Nov;75(5):1198-203.

13. Kerksick C, Harvey T, et al. International Society of Sports Nutrition position stand: Nutrient timing. J Int Soc Sports Nutr, 2008 Oct 3;5:17.

14. Curi R, Lagranha CJ, et al. Glutamine-dependent changes in gene expression and protein activity. Cell Biochem Funct, 2005 Mar-Apr;23(2):77-84.

15. Meyer C, Woerle HJ, et al. Paradoxical changes of muscle glutamine release during hyperinsulinemia euglycemia and hypoglycemia in humans: further evidence for the glucose-glutamine cycle. Metabolism, 2004 Sep;53(9):1208-14.

16. Welbourne TC. Increased plasma bicarbonate and growth hormone after an oral glutamine load. Am J Clin Nutr, 1995 May;61(5):1058-61.

17. Fisker S, Nielsen S, et al. The role of nitric oxide in L-arginine-stimulated growth hormone release. J Endocrinol Invest, 1999;22(5 Suppl):89-93.

18. Stokes KA, Tyler C, et al. The growth hormone response to repeated bouts of sprint exercise with and without suppression of lipolysis in men. J Appl Physiol, 2008 Mar;104(3):724-8.

19.  White HK, Petrie CD, et al. Effect of an oral growth hormone secretagogue in older adults. J Clin Endocrinol Metab, 2009;94:1198-1206.