International Journal of Sport Nutrition, 1992, 2, 287-291
Ornithine Supplementation and Insulin Release in Bodybuilders Luke R. Bucci, lames F. Hickson lr., Ira Wolinsky, and lames M. Pivarnik Ornithine supplementation has gained popularity with athletes because of its alleged potential to release anabolic hormones, factors governing skeletal muscle hypertrophy. Three female and nine male bodybuilders sewed as subjects in a study to test the effectiveness of oral ornithine in bringing about the release of insulin, an anabolic hormone. After an overnight fast, subjects were administered 40, 100, or 170 mg.kg-' L-ornithine.HC1 by mouth in a random fashion on three consecutive Saturday mornings. Blood samples were drawn at baseline (T=O), 45, and 90 min afterward. Serum ornithine levels were elevated ( ~ ~ 0 . 0 1at) T=45 and 90 min for all three dosage levels. However, serum insulin did not change from baseline levels at any dose of ornithine. The present findings show that ornithine is not an insulin secretagogue.
There has been widespread pressure on athletes to resist using anabolic steroids as ergogenic aids (1, 4, 13). In 1982 Pearson and Shaw (15) published a lay person's text that popularized the use of amino acid supplements as replacements for steroids. Accordingly, certain amino acids, including omithine, were alleged to stimulate the release of growth hormone, which then promoted anabolism of skeletal muscle tissues. In 1990 Hatfield (9) promoted the anabolic activity of insulin when effected by the oral intake of amino acids known to be its secretagogues. Although Hatfield did not specifically cite omithine, some supplement distributors have implied in their advertisements that omithine has anabolic activity mediated by insulin because of its structural similarity to arginine, a known insulin secretagogue (8). The purpose of the present study was to determine whether ornithine is a secretagogue for insulin and, if so, at what practical level of oral administration.
Bucci is with Innerpath Nutrition, 4615 Post Oak Place, Suite 182, Houston, TX 77027. Hickson is with the Dept. of Nutrition and Dietetics, Univ. of Texas Health Science Ctr., 7406 Marinette Dr., Houston, TX 77074. Wolinsky is with the Dept. of Human Development, Univ. of Houston, Houston, TX 77204. Pivarnik is with the Wellness Center, Texas Children's Hosp., 6621 Fannin St., Houston, TX 77030. Request reprints from Dr. Hickson.
288
/ Bucci, Hickson, Wolinsky, and Pivarnik
Table 1 Description of Subjects Height (cm)
Gender
Female
Downloaded by W VA Univ Library on 09/16/16, Volume 2, Article Number 3
M + SD Male
M + SD
Weight (kg)
NPC* rank
30 33 40 34.3 k 5.1
I Level 1 Level II Level Ill
27 28 39 38 23 21 19 32 26 28.1 7.0
Level Ill Level I Level I Level Ill No rank No rank No rank No rank No rank
+
= National Physique Committee.
Methods Three women and nine men volunteered to serve as subjects (Table 1). Each was training regularly with bodybuilding exercise. Seven of the group (three women and four men) had competed in bodybuilding contests and were ranked by the National Physique Committee (NPC) which governs amateur bodybuilding competition worldwide. A ranking of Level I11 indicates successful competition at the local entry level, while Level I indicates success at a local or regional contest, but with highest caliber competition. Three dosages of ornithine (40, 100, and 170 mg.kg-I) were administered by mouth in capsules (L-omithine.HC1, Biotics Research Corp., Houston, TX) with water to subjects in random fashion. These dosages corresponded to 3, 7, and 12 g ornithine for a 70-kg reference man. Dosage levels were selected on the basis of recommendations in the popular bodybuilding literature and from a sample of bodybuilders polled in the Houston metropolitan area. On three consecutive Saturdays, subjects reported to the testing facility at. 7 a.m. in the fasting condition, defined as not having eaten since midnight. Blood samples were drawn by venipuncture by a certified phlebotomist at T=O and T= 45 and 90 min post-intake of the supplement. Subjects were allowed water ad libitum during the testing period, but not food or drink that contained energy. Subjects sat in a chair and read during the testing periods. Blood samples were allowed to clot at room temperature for at least 20 min after being drawn. Afterward they were centrifuged, and serum was removed and frozen at -40 "C pending analysis for insulin by a radioimmunoassay technique (INCStar Corp., Stillwater, MN) and for omithine by a colorimetric method (5).
Ornithine Supplementation / 289
Serum ornithine and insulin data were analyzed by a repeated-measures analysis of variance (ANOVA) design. Significant ( ~ ~ 0 . 0 main 5 ) effects (dose, time) were further analyzed via the '&key HSD test.
Downloaded by W VA Univ Library on 09/16/16, Volume 2, Article Number 3
Results Data for all subjects (males and females) were pooled since individual baseline values for serum ornithine and insulin were similar regardless of sex. The group mean serum ornithine levels were significantly higher (pi0.01) at T=45 and 90 min in response to all three levels of supplementation (Table 2). In contrast to rises in serum omithine levels, group mean serum insulin levels were unchanged from the baseline values at T=45 and 90 min (Table 3). At the highest dose of omithine administered (170 mg.kg-I), 10 of 12 subjects reported gastrointestinal distress. The general symptoms included cramping and diarrhea.
Table 2 Overall Group Mean Serum Ornithine Level (ug . m ~ - ' )(mean in Response to Oral Ornithine Administration
Time (min)
40
rng Ornithine . kg administered 100
+ SEM) 170
Note. Values within columns were all different from one another; values across rows with the same letter superscript did not differ from one another.
Table 3 Overall Group Mean Serum Insulin Level (uU . ml-') (mean k SEM) in Response to Oral Ornithine Administration
Time (min)
40
mg Ornithine - kg administered 100
170
Note. There were no significant differences among means within columns or across rows.
290 / Bucci, Hickson, Wolinsky, and Pivarnik
Downloaded by W VA Univ Library on 09/16/16, Volume 2, Article Number 3
Discussion The findings indicate that oral ornithine, inpractical doses up to bowel tolerance (170 mg.kg-I), did not elicit an insulin response in fasting male or female bodybuilders. These findings are corroborated by the report of Cynober et al. (6, 7) indicating that 6.4-g orally administered omithine (88 mg.kg-I), given to six normal, fasting subjects, did not alter serum insulin levels. The rationale for studying ornithine as an insulin secretagogue is based in part on in vitro work with isolated rat islet cell preparations; high concentrations of the amino acid (2-10 mmo1e.L-I) can elicit the release of the hormone (3, 11). Additionally, omithine-alpha-ketoglutarate (OKG) has been in clinical use in Europe for a number of years as an anticatabolic/anabolicagent (16). Administration of both oral and intravenous OKG to normal subjects has been shown to lead to rapid rises in serum omithine and insulin levels (6, 7, 10). Ornithine-alpha-ketoglutarate has been associated with maintenance of muscle protein synthesis after surgery in humans (17) and has even stimulated albumin synthesis in vitro (12, 14). Recently, insulin infusion during amino acid sufficiency was found to increase muscle protein synthesis and reduce muscle protein breakdown in humans (2). This finding lends support to the proposal that insulin can serve as an anabolic agent for athletes. In fact, some dietary amino acids do elicit insulin release (8). This may be explained in that these other dietary amino acids are utilized in skeletal muscle protein synthesis while ornithine is not. Hence there is no need for insulin to mediate entry of ornithine into skeletal muscle cells for incorporation into proteins. Accordingly, the body does not respond to omithine with insulin release as it would for other amino acids used in protein synthesis. In this way, skeletal muscle is not "tricked" into taking up ornithine, which would only serve to dilute muscle cell amino acid pools and/or adversely affect protein synthesis (14). Conversely, other dietary amino acids are insulin secretagogues in order to ensure entry into skeletal muscle cells for their use in protein synthesis. In any event, the failure of ornithine to elicit insulin release was not due to poor absorption of the amino acid from the gastrointestinal tract, since orally administered omithine was readily absorbed into the bloodstream in a dose-dependent manner (Table 2).
References 1. American College of Sports Medicine. Position statement on the use and abuse of anabolic-androgenic steroids in sports. Med. Sci. Sports 9:xi-xii, 1977. 2. Bennet, W.M., A.A. Connacher, C.M. Scrimgeour, R.T. Jung, and M.J. Rennie. Euglycemic hyperinsulinernia augments amino acid uptake by human leg tissues during hyperaminoacidemia. Am. J. Physiol. 259:E185-E160, 1985. 3. Blachier, F., V. Leclerq-Meyer, J. Marchand, M.C. Woussen-Colle, P.C.F. Mathis, A. Sener, and W.J. Malaisse. Stimulus-secretion coupling of arginine-induced insulin release. Functional response of islets to L-arginine and L-ornithine. Biochim. Biophys. Acta 1013:144-151, 1989. 4. Bucci, L.R. Nutritional ergogenic aids. In Nutrition in Exercise andsport, J.F. Hickson and I. Wolinsky (Eds.), Boca Raton, FL: CRC Press, 1989, pp. 107-184. 5. Bucci, L.R., B.A. Klenda, J.F. Hickson, and I. Wolinsky. Ornithine levels in human
Ornithine Supplementation / 291
6.
7.
Downloaded by W VA Univ Library on 09/16/16, Volume 2, Article Number 3
8. 9. 10.
11.
12.
13. 14.
15. 16. 17.
serum after oral dosing measured by colorimetric assay. J. Nutr. Biochem. 2:363-367, 1991. Cynober, L., C. Coudray-Lucas, J.P. de Bandt, J. Guechot, C. Aussel, M. Salvucci, and J. Giboudeau. Action of omithine alpha-ketoglutarate, omithine hydrochloride, and calcium alpha-ketoglutarate on plasma amino acid and hormonal patterns in healthy subjects. J. Am. Coll. Nutr. 9:2-12, 1990. Cynober, L., M. Vaubourdolle, A. Dore, and J. Giboudeau. Kinetics and metabolic effects of orally administered ornithine-alpha-ketoglutarate in healthy subjects fed with a standardized regimen. Am. J. Clin. Nutr. 39:514-519, 1984. Floyd, J.C., S.S. Fajans, J.W. Conn, R.F. Knopf, and J. Rull. Stimulation of insulin secretion by amino acids. J. Clin. Invest. 45:1487-1502, 1966. Hatfield, F.C. Without insulin, muscles don't grow! Muscle & Fitness 5:69-70, 193, 1990. Krassowski, J., J. Rousselle, E. Maeder, and J.P. Felber. The effect of omithine-alphaketoglutarate on insulin and glucagon secretion in normal subjects. Acta Endocrinol. 98:252-255, 1981. Leclerq-Meyer, V., J. Marchand, and W.J. Malaisse. Stimulus-secretion coupling of arginine-induced insulin release. Resistance of arginine- and omithine-stimulated glucagon and insulin release to D,L-alpha-difluoromethylornithine.Biochem. PharmaC O ~ .39:537-547, 1990. Lescoat, G., B. Desvergne, 0. Loreal, N. Pasdeloup, Y. Deugnier, M. Bourel, and P. Brissot. Modulation of albumin secretion by ornithine alpha-ketoglutarate in adult rat hepatocyte cultures and a human hepatoma cell line (HepGP). Ann. Nutr. Metab. 33:252-260, 1989. National Strength and Conditioning Association. Position statement: Use and abuse of anabolic steroids. National Strength Conditioning Assoc. J. 7(2):27, 1985. Oratz, M., M.A. Rothschild, S.S. Schrieber, A. Burks, J. Mongelli, and B. Matarese. The role of the urea cycle and polyamines in albumin synthesis. Hepatology 3:567571, 1983. Pearson, D., and S. Shaw. Life Extension: A Practical Scientific Approach. New York: Warner, 1982, pp. 192, 477. Silk, D.B.A., and J.J. Payne-James. Novel substrates and nutritional support: Possible role of ornithine alpha-ketoglutarate. Proc. Nutr. Soc. 49:381-387, 1990. Wernerman, J., F. Hammarqvist, A. Decken, and E. Vinnars. Ornithine-alphaketoglutarate improves skeletal muscle protein synthesis as assessed by ribosome analysis and nitrogen use after surgery. Ann. Surg. 206:674-678, 1987.
Ackno wledgmenfs The authors wish to thank Sylvia Capetillo, Beverly Klenda, John McMahon, Dan Stout, and Stewart Tumer for assistance with the radioimmunoassay methodology and facilities.
Ornithine Supplementation and Insulin Release in Bodybuilders Luke R. Bucci, lames F. Hickson lr., Ira Wolinsky, and lames M. Pivarnik Ornithine supplementation has gained popularity with athletes because of its alleged potential to release anabolic hormones, factors governing skeletal muscle hypertrophy. Three female and nine male bodybuilders sewed as subjects in a study to test the effectiveness of oral ornithine in bringing about the release of insulin, an anabolic hormone. After an overnight fast, subjects were administered 40, 100, or 170 mg.kg-' L-ornithine.HC1 by mouth in a random fashion on three consecutive Saturday mornings. Blood samples were drawn at baseline (T=O), 45, and 90 min afterward. Serum ornithine levels were elevated ( ~ ~ 0 . 0 1at) T=45 and 90 min for all three dosage levels. However, serum insulin did not change from baseline levels at any dose of ornithine. The present findings show that ornithine is not an insulin secretagogue.
There has been widespread pressure on athletes to resist using anabolic steroids as ergogenic aids (1, 4, 13). In 1982 Pearson and Shaw (15) published a lay person's text that popularized the use of amino acid supplements as replacements for steroids. Accordingly, certain amino acids, including omithine, were alleged to stimulate the release of growth hormone, which then promoted anabolism of skeletal muscle tissues. In 1990 Hatfield (9) promoted the anabolic activity of insulin when effected by the oral intake of amino acids known to be its secretagogues. Although Hatfield did not specifically cite omithine, some supplement distributors have implied in their advertisements that omithine has anabolic activity mediated by insulin because of its structural similarity to arginine, a known insulin secretagogue (8). The purpose of the present study was to determine whether ornithine is a secretagogue for insulin and, if so, at what practical level of oral administration.
Bucci is with Innerpath Nutrition, 4615 Post Oak Place, Suite 182, Houston, TX 77027. Hickson is with the Dept. of Nutrition and Dietetics, Univ. of Texas Health Science Ctr., 7406 Marinette Dr., Houston, TX 77074. Wolinsky is with the Dept. of Human Development, Univ. of Houston, Houston, TX 77204. Pivarnik is with the Wellness Center, Texas Children's Hosp., 6621 Fannin St., Houston, TX 77030. Request reprints from Dr. Hickson.
288
/ Bucci, Hickson, Wolinsky, and Pivarnik
Table 1 Description of Subjects Height (cm)
Gender
Female
Downloaded by W VA Univ Library on 09/16/16, Volume 2, Article Number 3
M + SD Male
M + SD
Weight (kg)
NPC* rank
30 33 40 34.3 k 5.1
I Level 1 Level II Level Ill
27 28 39 38 23 21 19 32 26 28.1 7.0
Level Ill Level I Level I Level Ill No rank No rank No rank No rank No rank
+
= National Physique Committee.
Methods Three women and nine men volunteered to serve as subjects (Table 1). Each was training regularly with bodybuilding exercise. Seven of the group (three women and four men) had competed in bodybuilding contests and were ranked by the National Physique Committee (NPC) which governs amateur bodybuilding competition worldwide. A ranking of Level I11 indicates successful competition at the local entry level, while Level I indicates success at a local or regional contest, but with highest caliber competition. Three dosages of ornithine (40, 100, and 170 mg.kg-I) were administered by mouth in capsules (L-omithine.HC1, Biotics Research Corp., Houston, TX) with water to subjects in random fashion. These dosages corresponded to 3, 7, and 12 g ornithine for a 70-kg reference man. Dosage levels were selected on the basis of recommendations in the popular bodybuilding literature and from a sample of bodybuilders polled in the Houston metropolitan area. On three consecutive Saturdays, subjects reported to the testing facility at. 7 a.m. in the fasting condition, defined as not having eaten since midnight. Blood samples were drawn by venipuncture by a certified phlebotomist at T=O and T= 45 and 90 min post-intake of the supplement. Subjects were allowed water ad libitum during the testing period, but not food or drink that contained energy. Subjects sat in a chair and read during the testing periods. Blood samples were allowed to clot at room temperature for at least 20 min after being drawn. Afterward they were centrifuged, and serum was removed and frozen at -40 "C pending analysis for insulin by a radioimmunoassay technique (INCStar Corp., Stillwater, MN) and for omithine by a colorimetric method (5).
Ornithine Supplementation / 289
Serum ornithine and insulin data were analyzed by a repeated-measures analysis of variance (ANOVA) design. Significant ( ~ ~ 0 . 0 main 5 ) effects (dose, time) were further analyzed via the '&key HSD test.
Downloaded by W VA Univ Library on 09/16/16, Volume 2, Article Number 3
Results Data for all subjects (males and females) were pooled since individual baseline values for serum ornithine and insulin were similar regardless of sex. The group mean serum ornithine levels were significantly higher (pi0.01) at T=45 and 90 min in response to all three levels of supplementation (Table 2). In contrast to rises in serum omithine levels, group mean serum insulin levels were unchanged from the baseline values at T=45 and 90 min (Table 3). At the highest dose of omithine administered (170 mg.kg-I), 10 of 12 subjects reported gastrointestinal distress. The general symptoms included cramping and diarrhea.
Table 2 Overall Group Mean Serum Ornithine Level (ug . m ~ - ' )(mean in Response to Oral Ornithine Administration
Time (min)
40
rng Ornithine . kg administered 100
+ SEM) 170
Note. Values within columns were all different from one another; values across rows with the same letter superscript did not differ from one another.
Table 3 Overall Group Mean Serum Insulin Level (uU . ml-') (mean k SEM) in Response to Oral Ornithine Administration
Time (min)
40
mg Ornithine - kg administered 100
170
Note. There were no significant differences among means within columns or across rows.
290 / Bucci, Hickson, Wolinsky, and Pivarnik
Downloaded by W VA Univ Library on 09/16/16, Volume 2, Article Number 3
Discussion The findings indicate that oral ornithine, inpractical doses up to bowel tolerance (170 mg.kg-I), did not elicit an insulin response in fasting male or female bodybuilders. These findings are corroborated by the report of Cynober et al. (6, 7) indicating that 6.4-g orally administered omithine (88 mg.kg-I), given to six normal, fasting subjects, did not alter serum insulin levels. The rationale for studying ornithine as an insulin secretagogue is based in part on in vitro work with isolated rat islet cell preparations; high concentrations of the amino acid (2-10 mmo1e.L-I) can elicit the release of the hormone (3, 11). Additionally, omithine-alpha-ketoglutarate (OKG) has been in clinical use in Europe for a number of years as an anticatabolic/anabolicagent (16). Administration of both oral and intravenous OKG to normal subjects has been shown to lead to rapid rises in serum omithine and insulin levels (6, 7, 10). Ornithine-alpha-ketoglutarate has been associated with maintenance of muscle protein synthesis after surgery in humans (17) and has even stimulated albumin synthesis in vitro (12, 14). Recently, insulin infusion during amino acid sufficiency was found to increase muscle protein synthesis and reduce muscle protein breakdown in humans (2). This finding lends support to the proposal that insulin can serve as an anabolic agent for athletes. In fact, some dietary amino acids do elicit insulin release (8). This may be explained in that these other dietary amino acids are utilized in skeletal muscle protein synthesis while ornithine is not. Hence there is no need for insulin to mediate entry of ornithine into skeletal muscle cells for incorporation into proteins. Accordingly, the body does not respond to omithine with insulin release as it would for other amino acids used in protein synthesis. In this way, skeletal muscle is not "tricked" into taking up ornithine, which would only serve to dilute muscle cell amino acid pools and/or adversely affect protein synthesis (14). Conversely, other dietary amino acids are insulin secretagogues in order to ensure entry into skeletal muscle cells for their use in protein synthesis. In any event, the failure of ornithine to elicit insulin release was not due to poor absorption of the amino acid from the gastrointestinal tract, since orally administered omithine was readily absorbed into the bloodstream in a dose-dependent manner (Table 2).
References 1. American College of Sports Medicine. Position statement on the use and abuse of anabolic-androgenic steroids in sports. Med. Sci. Sports 9:xi-xii, 1977. 2. Bennet, W.M., A.A. Connacher, C.M. Scrimgeour, R.T. Jung, and M.J. Rennie. Euglycemic hyperinsulinernia augments amino acid uptake by human leg tissues during hyperaminoacidemia. Am. J. Physiol. 259:E185-E160, 1985. 3. Blachier, F., V. Leclerq-Meyer, J. Marchand, M.C. Woussen-Colle, P.C.F. Mathis, A. Sener, and W.J. Malaisse. Stimulus-secretion coupling of arginine-induced insulin release. Functional response of islets to L-arginine and L-ornithine. Biochim. Biophys. Acta 1013:144-151, 1989. 4. Bucci, L.R. Nutritional ergogenic aids. In Nutrition in Exercise andsport, J.F. Hickson and I. Wolinsky (Eds.), Boca Raton, FL: CRC Press, 1989, pp. 107-184. 5. Bucci, L.R., B.A. Klenda, J.F. Hickson, and I. Wolinsky. Ornithine levels in human
Ornithine Supplementation / 291
6.
7.
Downloaded by W VA Univ Library on 09/16/16, Volume 2, Article Number 3
8. 9. 10.
11.
12.
13. 14.
15. 16. 17.
serum after oral dosing measured by colorimetric assay. J. Nutr. Biochem. 2:363-367, 1991. Cynober, L., C. Coudray-Lucas, J.P. de Bandt, J. Guechot, C. Aussel, M. Salvucci, and J. Giboudeau. Action of omithine alpha-ketoglutarate, omithine hydrochloride, and calcium alpha-ketoglutarate on plasma amino acid and hormonal patterns in healthy subjects. J. Am. Coll. Nutr. 9:2-12, 1990. Cynober, L., M. Vaubourdolle, A. Dore, and J. Giboudeau. Kinetics and metabolic effects of orally administered ornithine-alpha-ketoglutarate in healthy subjects fed with a standardized regimen. Am. J. Clin. Nutr. 39:514-519, 1984. Floyd, J.C., S.S. Fajans, J.W. Conn, R.F. Knopf, and J. Rull. Stimulation of insulin secretion by amino acids. J. Clin. Invest. 45:1487-1502, 1966. Hatfield, F.C. Without insulin, muscles don't grow! Muscle & Fitness 5:69-70, 193, 1990. Krassowski, J., J. Rousselle, E. Maeder, and J.P. Felber. The effect of omithine-alphaketoglutarate on insulin and glucagon secretion in normal subjects. Acta Endocrinol. 98:252-255, 1981. Leclerq-Meyer, V., J. Marchand, and W.J. Malaisse. Stimulus-secretion coupling of arginine-induced insulin release. Resistance of arginine- and omithine-stimulated glucagon and insulin release to D,L-alpha-difluoromethylornithine.Biochem. PharmaC O ~ .39:537-547, 1990. Lescoat, G., B. Desvergne, 0. Loreal, N. Pasdeloup, Y. Deugnier, M. Bourel, and P. Brissot. Modulation of albumin secretion by ornithine alpha-ketoglutarate in adult rat hepatocyte cultures and a human hepatoma cell line (HepGP). Ann. Nutr. Metab. 33:252-260, 1989. National Strength and Conditioning Association. Position statement: Use and abuse of anabolic steroids. National Strength Conditioning Assoc. J. 7(2):27, 1985. Oratz, M., M.A. Rothschild, S.S. Schrieber, A. Burks, J. Mongelli, and B. Matarese. The role of the urea cycle and polyamines in albumin synthesis. Hepatology 3:567571, 1983. Pearson, D., and S. Shaw. Life Extension: A Practical Scientific Approach. New York: Warner, 1982, pp. 192, 477. Silk, D.B.A., and J.J. Payne-James. Novel substrates and nutritional support: Possible role of ornithine alpha-ketoglutarate. Proc. Nutr. Soc. 49:381-387, 1990. Wernerman, J., F. Hammarqvist, A. Decken, and E. Vinnars. Ornithine-alphaketoglutarate improves skeletal muscle protein synthesis as assessed by ribosome analysis and nitrogen use after surgery. Ann. Surg. 206:674-678, 1987.
Ackno wledgmenfs The authors wish to thank Sylvia Capetillo, Beverly Klenda, John McMahon, Dan Stout, and Stewart Tumer for assistance with the radioimmunoassay methodology and facilities.
