Note: Descriptions are shown in the official language in which they were submitted.
CA 02558110 2006-08-31
Composition and method for enhancing or promoting the activity of insulin,
enhancing skeletal muscle growth, reducing skeletal muscle loss, and
increasing the energy supply to skeletal muscle.
Field of the Invention
The present invention relates to the composition of a dietary supplement
and methods for enhancing or promoting the activity of insulin, enhancing
skeletal muscle growth, reducing skeletal muscle loss, and increasing the
energy
supply to skeletal muscle.
Background of the Invention
The most common role associated with insulin is the carbohydrate-
induced uptake of glucose by cells. The release of glucose from cells is also
concomitantly inhibited by insulin and its storage as glycogen and
triglycerides is
promoted (Khan AH, Pessin JE. Insulin regulation of glucose uptake: a complex
interplay of intracellular signalling pathways. Diabetologia. 2002
Nov;45(11):1475-83). However, insulin also has an important role with respect
to
the inhibition of muscle protein catabolism, or inhibition of protein
breakdown,
(Volpi E and Wolfe B. Insulin and Protein Metabolism. In: Handbook of
Physiology, L. Jefferson and A. Cherrington editors. New York: Oxford, 2001,
p.
735-757). Insulin drivers are substances which may enhance or promote the
normal activity of endogenous insulin. For example, enhancing or promoting the
action of insulin may promote the development of muscle through several
mechanisms. For example, through the promotion of the uptake of glucose by
muscle cells, insulin supplies muscles with a source of fuel. Additionally,
insulin
1
CA 02558110 2006-08-31
has also been shown to stimulate the uptake of amino acids by muscle cells and
further stimulate protein synthesis (Biolo G, Declan Fleming RY, Wolfe RR.
Physiologic hyperinsulinemia stimulates protein synthesis and enhances
transport of selected amino acids in human skeletal muscle. J Clin Invest.
1995
Feb;95(2):811-9), particularly following exercise (Biolo G, Williams BD,
Fleming
RY, Wolfe RR. Insulin action on muscle protein kinetics and amino acid
transport
during recovery after resistance exercise. Diabetes. 1999 May;48(5):949-57).
Moreover, insulin has been shown to inhibit protein degradation (Hamel
FG, Bennett RG, Harmon KS, Duckworth WC. Insulin inhibition of proteasome
activity in intact cells. Biochem Biophys Res Commun. 1997 May 29;234(3):671-
4; Bennett RG, Hamel FG, Duckworth WC. Insulin inhibits the ubiquitin-
dependent degrading activity of the 26S proteasome. Endocrinology. 2000
Jul;141(7):2508-17) which may lead to muscle loss. The inhibition of
proteolysis
by insulin has experimentally been shown to be due to multiple mechanisms.
First, insulin directly inhibits the catalytic activity of the proteasome by
inhibiting
its peptide-degrading action (Duckworth WC, Bennett RG, Hamel FG. A direct
inhibitory effect of insulin on a cytosolic proteolytic complex containing
insulin-
degrading enzyme and multicatalytic proteinase. J Biol Chem. 1994 Oct
7;269(40):24575-80). Second, insulin has been shown to interfere with and
downregulate the ATP-dependent ubiquitin (Ub) pathway (Price SR, Bailey JL,
Wang X, Jurkovitz C, England BK, Ding X, Phillips LS, Mitch WE. Muscle wasting
in insulinopenic rats results from activation of the ATP-dependent, ubiquitin-
proteasome proteolytic pathway by a mechanism including gene transcription. J
2
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Clin Invest. 1996 Oct 15;98(8):1703-8; Mitch WE, Bailey JL, Wang X, Jurkovitz
C, Newby D, Price SR. Evaluation of signals activating ubiquitin-proteasome
proteolysis in a model of muscle wasting. Am J Physiol. 1999 May;276(5 Pt
1):C1132-8). Third, insulin reduces the expression of MAFbx, a muscle-specific
Ub-ligase required for muscle atrophy. Sacheck JM, Ohtsuka A, McLary SC,
Goldberg AL. IGF-I stimulates muscle growth by suppressing protein breakdown
and expression of atrophy-related ubiquitin ligases, atrogin-1 and MuRFI. Am J
Physiol Endocrinol Metab. 2004 Oct;287(4):E591-601). In combination, the
aforementioned mechanisms may lead to the inhibition of muscle catabolism via
insulin dependent mechanisms.
It would therefore be advantageous to enhance or promote the activity of
insulin for the general preservation or growth of skeletal muscle,
particularly for
individuals involved in physical activity or training. In such individuals,
the
breakdown of muscle protein stimulated by exercise (Rennie MJ, Edwards RH,
Krywawych S, Davies CT, Halliday D, Waterlow JC, Millward DJ. Effect of
exercise on protein turnover in man. Clin Sci (Lond). 1981 Nov;61(5):627-39)
is
of concern and it is desired to be advantageously avoided or minimized.
There are a number of potential processes or variables which may be
affected by insulin drivers in order to enhance or promote the activity of
insulin.
These steps may include, but not be limited to: insulin sensitivity, insulin
secretion, binding of insulin to an insulin receptor, and transporter function
(e.g.
GLUT4 translocation).
3
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Summary of the Invention
The foregoing needs and other needs and objectives that will become
apparent for the following description are achieved in the present invention
which
comprises, according to various embodiments, a dietary supplement for
enhancing or promoting the natural action of insulin or any individual aspect
or
combination of aspects thereof. The dietary supplement is advantageous for
individuals wishing to enhance the growth of skeletal muscle, reduce the loss
of
skeletal muscle or increase the energy supply to active muscles. The
composition of the present invention comprises at least D-Pinitol and Leucine
or
derivatives thereof. Furthermore, the present invention may comprise at least
one of Alpha Lipoic Acid, Glucomannan, D-Myo-Inositol, Guar Gum, Taurine or
derivative thereof, Ketoisocaproic Acid or derivative thereof, Alpha-
Ketoglutarate
or derivative thereof, and a source of Peptide C12.
The present invention also provides, by consumption of the dietary
supplement by an individual, e.g., a human or an animal, a method for
enhancing
or promoting the activity of insulin, enhancing skeletal muscle growth,
reducing
skeletal muscle loss, and increasing the energy supply to skeletal muscle.
Detailed Description of the Invention
The present invention, according to various embodiments, is directed to
enhancing or promoting the natural activity of endogenous insulin within the
body
of an individual, e.g., a human or an animal, enhancing the growth of skeletal
muscle, reducing the loss of skeletal muscle via protein degradation, and
increasing the energy supply of active muscles.
4
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D-Pinitol
OH
0/1,,
CH3
'"
H i_?'y fi H
OH
Pinitol (CAS Registry No 484-68-4) is the active principle found in
Bougainvillea spectabilis, a traditional anti-diabetic plant. It is known to
be in
many legumes and pine wood. Futhermore, Pinitol may also be derived from the
processing of soybeans (Nordin P. Preferential Leaching of Pinitol from
Soybeans during Imbibition. Plant Physiol. 1984 Oct;76(2):313-315). It has
been
demonstrated to have insulin-like effects in animal models of diabetes (Bates
SH,
Jones RB, Bailey CJ. Insulin-like effect of pinitol. Br J Pharmacol. 2000
Aug;130(8):1944-8). When Pinitol has been isolated from soybeans, it has been
clinically shown to reduce risk factors in cardiovascular disease (Kim JI, Kim
JC,
Kang MJ, Lee MS, Kim JJ, Cha IJ. Effects of pinitol isolated from soybeans on
glycaemic control and cardiovascular risk factors in Korean patients with type
II
diabetes mellitus: a randomized controlled study. Eur J Clin Nutr. 2005
Mar;59(3):456-8) and postprandial blood glucose levels in patients with
diabetes
(Kang MJ, Kim JI, Yoon SY, Kim JC, Cha IJ. Pinitol from soybeans reduces
postprandial blood glucose in patients with type 2 diabetes mellitus. J Med
Food.
2006 Summer;9(2):182-6).
5
CA 02558110 2006-08-31
Of particular interest to the invention, Pinitol has also been reported to
increase creatine retention in muscle (Rasmussen C, Greenwood M, Kreider R,
Earnest C, Almada A, Greenhaff P. Influence of D-Pinitol on whole body
creatine
retention. Medicine and Science in Sport and Exercise. 33(5): S204, 2001;
Greenwood M, Kreider RB, Rasmussen C, Almada AL, Earnest CP. D-Pinitol
augments whole body creatine retention in man. J Exerc Physiolonline 2001;
4:41-47).
In an embodiment of the present invention, which is set forth in greater
detail in the example below, the supplemental composition includes D-Pinitol
or a
derivative thereof. A serving of the supplemental composition may include from
about 0.5 pg to about 10 pg of D-Pinitol. The preferred dosage of a serving of
the
supplemental composition comprises about 2 pg of D-Pinitol.
L-Leucine
CH3 h,1H2
OH
H3C
0
Leucine (CAS Registry No 328-39-2) is one of three branched chain
amino acids and is important for skeletal muscle protein synthesis. Leucine is
known to stimulate the mammalian target of rapamycin (mTOR) pathway
(Anthony JC, Yoshizawa F, Anthony TG, Vary TC, Jefferson LS, Kimball SR.
Leucine stimulates translation initiation in skeletal muscle of postabsorptive
rats
6
CA 02558110 2006-08-31
via a rapamycin-sensitive pathway. J Nutr. 2000 Oct;130(10):2413-9), a factor
extremely important in muscle growth. mTOR is a complex protein pathway
containing several regulatory sites as well as sites for interaction with
multiple
other proteins which acts to integrate signals pertaining to the energetic
status of
the cell as well as environmental stimuli to control protein synthesis,
protein
breakdown and, therefore, cell growth (Hay N, Sonenberg N. Upstream and
downstream of mTOR. Genes Dev. 2004 Aug 15;18(16):1926-45). The mTOR
kinase controls the translation machinery, in response to amino acids and
growth
factors, such as insulin. Leucine appears to stimulate mTOR in a manner
similar
to insulin, however acting via different mechanism.
The ingestion of Leucine combined with protein and carbohydrates has
been shown to stimulate a reduction in protein breakdown and an increase in
skeletal muscle protein synthesis to a greater degree than protein plus
carbohydrate and carbohydrate alone (Koopman R, Wagenmakers AJ, Manders
RJ, Zorenc AH, Senden JM, Gorselink M, Keizer HA, van Loon LJ. Combined
ingestion of protein and free leucine with carbohydrate increases postexercise
muscle protein synthesis in vivo in male subjects. Am J Physiol Endocrinol
Metab. 2005 Apr;288(4):E645-53). Furthermore, oral administration of Leucine
has been shown to stimulate protein synthesis in the skeletal muscle of rats
(Crozier SJ, Kimball SR, Emmert SW, Anthony JC, Jefferson LS. Oral leucine
administration stimulates protein synthesis in rat skeletal muscle. J Nutr.
2005
Mar;135(3):376-82). This may be mediated by the ability of Leucine to
phosphorylate elF4G, thereby facilitating the formation of a complex of eIF4G
7
CA 02558110 2006-08-31
with the initiation factor eIF4E, a complex necessary for protein sysnthesis
(Bolster DR, Vary TC, Kimball SR, Jefferson LS. Leucine regulates translation
initiation in rat skeletal muscle via enhanced eIF4G phosphorylation. J Nutr.
2004
Jul;134(7):1704-10).
In an embodiment of the present invention, which is set forth in greater
detail in the example below, the supplemental composition includes Leucine or
derivatives thereof. A serving of the supplemental composition may include
from
about 1 pg to about 15 pg of Leucine or derivatives thereof. The preferred
dosage of a serving of the supplemental composition comprises about 5 pg of
Leucine or derivatives thereof.
Alpha Lipoic Acid
u
H
Fi H
Alpha Lipoic Acid (CAS Registry No 62-46-4) is an enzyme found in the
cellular energy-producing structures, the mitochondria. Additionally, Alpha
Lipoic
Acid works in synergy with vitamins C and E as an antioxidant in both water-
and
fat- soluble environments.
In rats supplemented with Alpha Lipoic Acid the negative age-related
changes in mitochondrial function, accumulated oxidative damage and the
metabolic rate were all improved (Hagen TM, Ingersoll RT, Lykkesfeldt J, Liu
J,
8
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Wehr CM, Vinarsky V, Bartholomew JC, Ames AB. (R)-alpha-Iipoic acid-
supplemented old rats have improved mitochondrial function, decreased
oxidative damage, and increased metabolic rate. FASEB J. 1999 Feb;13(2):411-
8). The antioxidant activity of Alpha Lipoic Acid is likely involved in the
prevention
of cell death due to oxidative stress (Arivazhagan P, Juliet P, Panneerselvam
C.
Effect of dl-alpha-lipoic acid on the status of lipid peroxidation and
antioxidants in
aged rats. Pharmacol Res. 2000 Mar;41(3):299-303) and likely increased
mitochondrial membrane permeability. Possibly related to these effects, Alpha
Lipoic Acid has been linked to a beneficial increase in high-density
lipoproteins
(Wollin SD, Wang Y, Kubow S, Jones PJ. Effects of a medium chain triglyceride
oil mixture and alpha-lipoic acid diet on body composition, antioxidant
status, and
plasma lipid levels in the Golden Syrian hamster. J Nutr Biochem. 2004
Jul;15(7):402-10). Furthermore, Alpha Lipoic Acid appears to possess a dual
action related to hunger and,8-oxidation of fat. First, the activity of AMP-
activated
protein kinase, which acts as an energy sensor in the hypothalamus, is reduced
by Alpha Lipoic Acid in rodents, this results in a profound weight loss by
reducing
food intake and enhancing energy expenditure (Kim MS, Park JY, Namkoong C,
Jang PG, Ryu JW, Song HS, Yun JY, Namgoong IS, Ha J, Park IS, Lee IK,
Viollet B, Youn JH, Lee HK, Lee KU. Anti-obesity effects of alpha-lipoic acid
mediated by suppression of hypothalamic AMP-activated protein kinase. Nat
Med. 2004 Jul;10(7):727-33). Second, Alpha Lipoic Acid increases Uncoupling
Protein-1 in rodent adipocytes while increasing AMP-activated protein kinase
in
skeletal muscle cells and increasing glucose uptake and energy expenditure
(Lee
9
CA 02558110 2006-08-31
WJ, Koh EH, Won JC, Kim MS, Park JY, Lee KU. Obesity: the role of
hypothalamic AMP-activated protein kinase in body weight regulation. Int J
Biochem Cell Biol. 2005 Nov;37(11):2254-9). Thus Alpha Lipoic Acid seemingly
has different effects in different tissues. However, in adipocytes or muscle
cells
Alpha Lipoic Acid increases fatty acid oxidation, leading to an increase in
energy
expenditure and concomitant decreases in body weight and food intake.
U.S. Patent Nos. 6,136,339 and 6,620,425 disclose compositions and
methods for enhancing an athlete's muscle size or strength using a combination
of Creatine, Alpha Lipoic Acid and optionally dextrose, to be taken mixed with
water daily following exercise.
In an embodiment of the present invention, which is set forth in greater
detail in the example below, the supplemental composition may include Alpha
Lipoic Acid or derivatives thereof. A serving of the supplemental composition
may include from about 1 pg to about 30 pg of Alpha Lipoic Acid or derivatives
thereof. The preferred dosage of a serving of the supplemental composition
comprises about 15 pg of Alpha Lipoic Acid or derivatives thereof.
Glucomannan
Glucomannan is a polysaccharide composed of long chains of simple
sugars, primarily mannose and glucose. It is classified as a soluble fiber.
Glucomannan can be obtained from several plants, however, the primary source
is an Asian origin plant named Amorphophallus Konjac.
Glucomannan has been shown to improve glycemic control and offer
potential treatment for type 2 diabetes (Vuksan V, Jenkins DJ, Spadafora P,
CA 02558110 2006-08-31
Sievenpiper JL, Owen R, Vidgen E, Brighenti F, Josse R, Leiter LA, Bruce-
Thompson C. Konjac-mannan (glucomannan) improves glycemia and other
associated risk factors for coronary heart disease in type 2 diabetes. A
randomized controlled metabolic trial. Diabetes Care. 1999 Jun;22(6):913-9;
Chen HL, Sheu WH, Tai TS, Liaw YP, Chen YC. Konjac supplement alleviated
hypercholesterolemia and hyperglycemia in type 2 diabetic subjects--a
randomized double-blind trial. J Am Coll Nutr. 2003 Feb;22(1):36-42) and
improve insulin resistance in humans (Vuksan V, Sievenpiper JL, Owen R,
Swilley JA, Spadafora P, Jenkins DJ, Vidgen E, Brighenti F, Josse RG, Leiter
LA,
Xu Z, Novokmet R. Beneficial effects of viscous dietary fiber from Konjac-
mannan in subjects with the insulin resistance syndrome: results of a
controlled
metabolic trial. Diabetes Care. 2000 Jan;23(1):9-14).
In an embodiment of the present invention, which is set forth in greater
detail in the example below, the supplemental composition may include
Glucomannan. A serving of the supplemental composition may include from
about 0.01 g to about 0.5 g of Glucomannan. The preferred dosage of a serving
of the supplemental composition comprises about 0.09 g of Glucomannan.
D-myo-inositol
H i? OH
HO Ilnu. /' -rll OH
~
~i Cl ~/oH
11
CA 02558110 2006-08-31
D-myo-inositol (CAS Registry No 87-89-8) is a distinct isomer of inositol,
which is vital to a diverse range of biological processes. D-myo-inositol has
the
effect of priming the secretion of insulin (Hoy M, Berggren PO, Gromada J.
Involvement of protein kinase C-epsilon in inositol hexakisphosphate-induced
exocytosis in mouse pancreatic beta-cells. J Biol Chem. 2003 Sep
12;278(37):35168-71; Barker CJ, Berggren PO. Inositol hexakisphosphate and
beta-cell stimulus-secretion coupling. Anticancer Res. 1999 Sep-
Oct;19(5A):3737-41), an effect that is dependent on protein kinase C (Efanov
AM, Zaitsev SV, Berggren PO. Inositol hexakisphosphate stimulates non-Ca2+-
mediated and primes Ca2+-mediated exocytosis of insulin by activation of
protein
kinase C. Proc Natl Acad Sci U S A. 1997 Apr 29;94(9):4435-9). Furthermore,
the glomerular cells of diabetic rats display an increased transport of D-myo-
inositol compared to non-diabetic rats (Whiteside Cl, Thompson JC.
Upregulation
of D-myo-inositol transport in diabetic rat glomerular cells. Am J Physiol.
1992
Mar;262(3 Pt 1):E301-6) which may explain why supplementation may help
individuals with diabetes.
In an embodiment of the present invention, which is set forth in greater
detail in the example below, the supplemental composition may include D-myo-
inositol. A serving of the supplemental composition may include from about
0.05
g to about 1 g of D-myo-inositol. The preferred dosage of a serving of the
supplemental composition comprises about 0.2 g of D-myo-inositol.
Guar Gum
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CA 02558110 2006-08-31
Guar gum (CAS Registry No 9000-30-0) is a water soluble polysaccharide
obtained from the guar bean (Cyamopsis tetragonoloba). In animal models of
diabetes, guar gum has been shown to improve insulin sensitivity (Cameron-
Smith D, Habito R, Barnett M, Collier GR. Dietary guar gum improves insulin
sensitivity in streptozotocin-induced diabetic rats. J Nutr. 1997
Feb;127(2):359-
64). In healthy rats, Guar Gum has the effect of improving insulin response
(Prieto PG, Cancelas J, Villanueva-Penacarrillo ML, Malaisse WJ, Valverde I.
Short-term and Long-term Effects of Guar on Postprandial Plasma Glucose,
Insulin and Glucagon-like Peptide 1 Concentration in Healthy Rats. Horm Metab
Res. 2006 Jun;38(6):397-404). Supplementation with Guar Gum in humans
allowed for better control of diabetes (Aro A, Uusitupa M, Voutilainen E,
Hersio K,
Korhonen T, Siitonen O. Improved diabetic control and hypocholesterolaemic
effect induced by long-term dietary supplementation with guar gum in type 2
(insulin-independent) diabetes. Diabetologia. 1981 Jul;21(1):29-33) and
reduced
the associated cardiovascular risks (Uusitupa M, Tuomilehto J, Karttunen P,
Wolf
E. Long term effects of guar gum on metabolic control, serum cholesterol and
blood pressure levels in type 2 (non-insulin-dependent) diabetic patients with
high blood pressure. Ann Clin Res. 1984;16 Suppl 43:126-31) as shown by long-
term studies. Additionally, the addition of low amounts of Guar Gum to the
diet of
humans has been shown to improve insulin sensitivity (Tagliaferro V, Cassader
M, Bozzo C, Pisu E, Bruno A, Marena S, Cavallo-Perin P, Cravero L, Pagano G.
Moderate guar-gum addition to usual diet improves peripheral sensitivity to
insulin and lipaemic profile in NIDDM. Diabete Metab. 1985 Dec;11(6):380-5).
In
13
CA 02558110 2006-08-31
healthy humans insulin sensitivity is also improved (Landin K, Holm G,
Tengborn
L, Smith U. Guar gum improves insulin sensitivity, blood lipids, blood
pressure,
and fibrinolysis in healthy men. Am J Clin Nutr. 1992 Dec;56(6):1061-5).
The benefits conferred by Guar Gum are believed to be, at least partially,
due to slowed glucose absorption (Russo A, Stevens JE, Wilson T, Wells F,
Tonkin A, Horowitz M, Jones KL. Guar attenuates fall in postprandial blood
pressure and slows gastric emptying of oral glucose in type 2 diabetes. Dig
Dis
Sci. 2003 Jul;48(7):1221-9), thereby improving insulin sensitivity.
In an embodiment of the present invention, which is set forth in greater
detail in the example below, the supplemental composition may include Guar
Gum. A serving of the supplemental composition may include from about 0.1 g
to about 1.5 g of Guar Gum. The preferred dosage of a serving of the
supplemental composition comprises about 0.5 g of Guar Gum.
Taurine
0 0
H2 N OH
Taurine (CAS Registry No 107-35-7) is an amino acid found primarily in
nerve and muscle tissue. Taurine is generally considered to be a conditionally-
essential amino acid, wherein it is only required under certain circumstances.
14
CA 02558110 2006-08-31
Although not utilized for protein synthesis, Taurine is found in free-form or
in
some small peptides.
Moreover, the accumulation of Taurine within cells is mediated by a high
affinity sodium-dependent transporter (Ramamoorthy S, Leibach FH, Mahesh
VB, Han H, Yang-Feng T, Blakely RD, Ganapathy V. Functional characterization
and chromosomal localization of a cloned taurine transporter from human
placenta. Biochem J. 1994 Jun 15;300 ( Pt 3):893-900). The expression of this
Taurine transporter is induced by a differentiation program of myocytes
(muscle
cells) (Uozumi Y, Ito T, Hoshino Y, Mohri T, Maeda M, Takahashi K, Fujio Y,
Azuma J. Myogenic differentiation induces taurine transporter in association
with
taurine-mediated cytoprotection in skeletal muscles. Biochem J. 2006 Mar
15;394(Pt 3):699-706). Exercise-induced hormones also activate the Taurine
transporter (Park SH, Lee H, Park T. Cortisol and IGF-1 synergistically up-
regulate taurine transport by the rat skeletal muscle cell line, L6.
Biofactors.
2004;21(1-4):403-6). Genetically modified mice lacking the Taurine transporter
have depleted Taurine levels in all muscle and have impaired skeletal muscle
function (Warskulat U, Flogel U, Jacoby C, Hartwig HG, Thewissen M, Merx MW,
Molojavyi A, Heller-Stilb B, Schrader J, Haussinger D. Taurine transporter
knockout depletes muscle taurine levels and results in severe skeletal muscle
impairment but leaves cardiac function uncompromised. FASEB J. 2004
Mar;18(3):577-9)
One of the main roles of Taurine is the regulation of fluid balance.
Contracting muscles also release Taurine (Cuisinier C, Michotte De Welle J,
CA 02558110 2006-08-31
Verbeeck RK, Poortmans JR, Ward R, Sturbois X, Francaux M. Role of taurine in
osmoregulation during endurance exercise. Eur J Appl Physiol. 2002
Oct;87(6):489-95) as it has also been shown to modulate the contractile
function
of mammalian skeletal muscle (Bakker AJ, Berg HM. Effect of taurine on
sarcoplasmic reticulum function and force in skinned fast-twitch skeletal
muscle
fibres of the rat. J Physiol. 2002 Jan 1;538(Pt 1):185-94). In rats, the
Taurine
concentration in muscle decreases as a result of exercise (Matsuzaki Y,
Miyazaki
T, Miyakawa S, Bouscarel B, Ikegami T, Tanaka N. Decreased taurine
concentration in skeletal muscles after exercise for various durations. Med
Sci
Sports Exerc. 2002 May;34(5):793-7) and oral supplementation with Taurine can
maintain the concentration of Taurine in muscle and prolong exercise
performance (Miyazaki T, Matsuzaki Y, Ikegami T, Miyakawa S, Doy M, Tanaka
N, Bouscarel B. Optimal and effective oral dose of taurine to prolong exercise
performance in rat. Amino Acids. 2004 Dec;27(3-4):291-8; Yatabe Y, Miyakawa
S, Miyazaki T, Matsuzaki Y, Ochiai N. Effects of taurine administration in rat
skeletal muscles on exercise. J Orthop Sci. 2003;8(3):415-9).
In a model of spontaneous diabetes, Taurine supplemented rats had
improved insulin sensitivity (Nakaya Y, Minami A, Harada N, Sakamoto S, Niwa
Y, Ohnaka M. Taurine improves insulin sensitivity in the Otsuka Long-Evans
Tokushima Fatty rat, a model of spontaneous type 2 diabetes. Am J Clin Nutr.
2000 Jan;71(1):54-8). Furthermore, Taurine improves glucose metabolism in
insulin resistant rats (Nandhini AT, Anuradha CV. Taurine modulates kallikrein
activity and glucose metabolism in insulin resistant rats. Amino Acids.
16
CA 02558110 2006-08-31
2002;22(1):27-38). Supplementation with Taurine has been shown to reduce
exercise-induced oxidative damage and enhance recovery (Zhang M, Izumi I,
Kagamimori S, Sokejima S, Yamagami T, Liu Z, Qi B. Role of taurine
supplementation to prevent exercise-induced oxidative stress in healthy young
men. Amino Acids. 2004 Mar;26(2):203-7).
In an embodiment of the present invention, which is set forth in greater
detail in the example below, the supplemental composition may include Taurine
or derivatives thereof. A serving of the supplemental composition may include
from about 0.02 g to about 1 g of Taurine or derivatives thereof. The
preferred
dosage of a serving of the supplemental composition comprises about 0.1 g of
Taurine or derivatives thereof.
Taurine Ketoisocaproic Acid
C-1
C H3
HfJP I
0 CH3
Taurine Ketoisocaporic Acid serves in the present invention as an
additional source of Taurine in addition to providing Alpha-ketoisocaproate
(CAS
Registry No 816-66-0). Alpha-ketoisocaproate is a keto acid of the branched
chain amino acid, Leucine. Moreover, Ketoisocaproic acid is known to stimulate
insulin release (Heissig H, Urban KA, Hastedt K, Zunkler BJ, Panten U.
Mechanism of the insulin-releasing action of alpha-ketoisocaproate and related
17
CA 02558110 2006-08-31
alpha-keto acid anions. Mol Pharmacol. 2005 Oct;68(4):1097-105; Rabaglia ME,
Gray-Keller MP, Frey BL, Shortreed MR, Smith LM, Attie AD. Alpha-
Ketoisocaproate-induced hypersecretion of insulin by islets from diabetes-
susceptible mice. Am J Physiol Endocrinol Metab. 2005 Aug;289(2):E218-24)
and Ketoisocaproic Acid has been shown to reduce protein catabolism as well as
prevent muscle loss (Stewart PM, Walser M, Drachman DB. Branched-chain
ketoacids reduce muscle protein degradation in Duchenne muscular dystrophy.
Muscle Nerve. 1982 Mar;5(3):197-201).
In an embodiment of the present invention, which is set forth in greater
detail in the example below, the supplemental composition may include
Ketoisocaproic Acid or derivatives thereof. A serving of the supplemental
composition may include from about 0.02 pg to about 5 pg of Ketoisocaproic
Acid
or derivatives thereof. The preferred dosage of a serving of the supplemental
composition comprises about 1 pg of Ketoisocaproic Acid or derivatives
thereof.
Taurine Alpha-Ketoglutarate
o-
Taurine Alpha-Ketoglutarate serves as a source of Taurine as well as a
source providing Alpha-Ketoglutarate. Alpha-Ketoglutarate (CAS Registry No 64-
15-3) is an intermediate formed during the metabolism of glutamate. Alpha-
18
CA 02558110 2006-08-31
Ketoglutarate also has a role in energy production via entry in to the
tricarboxylic
acid-cycle and oxidation to CO2. Additionally, Alpha-Ketoglutarate is
important for
tissue healing (Aussel C, Coudray-Lucas C, Lasnier E, Cynober L, Ekindjian OG.
alpha-Ketoglutarate uptake in human fibroblasts. Cell Biol Int. 1996
May;20(5):359-63), particularly in muscle (Wernerman J, Hammarqvist F,
Vinnars E. Alpha-ketoglutarate and postoperative muscle catabolism. Lancet.
1990 Mar 24;335(8691):701-3) where Alpha-Ketoglutarate can preserve protein
synthesis and prevent muscle loss (Hammarqvist F, Wernerman J, von der
Decken A, Vinnars E. Alpha-ketoglutarate preserves protein synthesis and free
glutamine in skeletal muscle after surgery. Surgery. 1991 Jan;109(1):28-36).
Mutations in glutamate dehydrogenase, an enzyme involved in the formation of
Alpha-Ketoglutarate, leads to the accumulation of Alpha-Ketoglutarate. This
leads to chronic hyper-insulinemia which subsequently results in severe
hypoglycemia (Stanley CA, Lieu YK, Hsu BY, Burlina AB, Greenberg CR,
Hopwood NJ, Perlman K, Rich BH, Zammarchi E, Poncz M. Hyperinsulinism and
hyperammonemia in infants with regulatory mutations of the glutamate
dehydrogenase gene. N Engl J Med. 1998 May 7;338(19):1352-7). It is further
believed that the formation of Alpha-Ketoglutarate by glutamate dehydrogenase
stimulates insulin secretion by supplying substrate for the tricarboxylic acid-
cycle
(Anno T, Uehara S, Katagiri H, Ohta Y, Ueda K, Mizuguchi H, Moriyama Y, Oka
Y, Tanizawa Y. Overexpression of constitutively activated glutamate
dehydrogenase induces insulin secretion through enhanced glutamate oxidation.
Am J Physiol Endocrinol Metab. 2004 Feb;286(2):E280-5).
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CA 02558110 2006-08-31
In an embodiment of the present invention, which is set forth in greater
detail in the example below, the supplemental composition may include Alpha-
Ketoglutarate or derivatives thereof. A serving of the supplemental
composition
may include from about 5 pg to about 30 pg of Alpha-Ketoglutarate or
derivatives
thereof. The preferred dosage of a serving of the supplemental composition
comprises about 15 pg of Alpha-Ketoglutarate or derivatives thereof.
Promoting the Activity of Insulin to Enhance Skeletal Muscle Growth
Based on the aforementioned research, it has been determined by the
inventors of the present invention that substances which enhance or promote
the
activity of insulin, or similar such insulin drivers, would be of benefit in
terms of
the natural role of insulin. In an embodiment of the present invention,
insulin
drivers may promote the growth of skeletal muscle in response to resistance
exercise. It is an object of the present invention that insulin drivers may
promote
the maintenance of skeletal muscle during periods of inactivity. Another
object of
the present invention it that insulin drivers may promote the uptake of
glucose by
skeletal muscle to provide ample energy during strenuous or prolonged physical
activity. From consideration of this specification and the foregoing example,
other
embodiments may be obvious to those skilled in the art.
Furthermore, Leucine, and other branch chain amino acids are known to
activate the mTOR pathway of protein synthesis and decrease protein
catabolism. Therefore, in terms of muscle building, it has been determined by
the inventors of the present invention that it may be advantageous to provide
compounds such a D-pinitol and derivatives thereof, which are known to mimic
CA 02558110 2006-08-31
the actions of insulin and compounds such Leucine which are known be
initiators
of protein synthesis and inhibitors of protein catabolism. Through the
concomitant administration of insulin-mimicking compounds and initiators of
protein synthesis pathways and inhibitors of protein catabolism, it has been
determined by the inventors of the present invention that nutrients can be
more
readily taken into the cell to facilitate the synthesis of protein commenced
by
known initiators of the mTOR pathway. Moreover, both insulin and Leucine act
to inhibit the catabolism of protein. Therefore, it has been determined by the
inventors of the present invention that the co-administration of insulin-
mimicking
substances and initiators of the mTOR pathway is advantageous in terms of
muscle building.
According to various embodiments of the present invention, the
dietary supplement may be consumed in any form. For instance, the dosage
form of the diet supplement may be provided as, e.g., a powder beverage mix, a
liquid beverage, a ready-to-eat bar or drink product, a capsule, a liquid
capsule, a
tablet, a caplet, or as a dietary gel. The preferred dosage forms of the
present
invention is as a powdered beverage mix. The dietary supplement may be
provided alone or as part of a larger composition.
Furthermore, the dosage form of the dietary supplement may be provided
in accordance with customary processing techniques for herbal and dietary
supplements in any of the forms mentioned above. Additionally, the diet
supplement set forth in the example embodiments herein may contain any
appropriate number and type of excipients, as is well known in the art.
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Preferably, the dietary supplement is consumed by an individual in
accordance with the following method: As a diet supplement, a serving of said
dietary supplement may be taken with an 8 oz. glass of water at least one time
daily wherein each serving is comprised of approximately 1 g of said dietary
supplement. Said dietary supplement may be consumed approximately 30 to 60
minutes before each meal, preferably in the morning and afternoon as well as
after a workout. In this manner, the dietary supplement may enhance the growth
of skeletal muscle, reduce the loss of skeletal muscle or increase the energy
supply to active muscles of an individual, e.g. a human or an animal for an
extended period of time, e.g., all day.
The present diet supplement or those similarly envisioned by one of skill in
the art, may be utilized in compositions and methods to enhance the growth of
skeletal muscle, reduce the loss of skeletal muscle or increase the energy
supply
to active muscles in an individual, e.g. a human or an animal.
Although the following example illustrates the practice of the present
invention in one of its embodiments, the example should not be construed as
limiting the scope of the invention. Other embodiments will be apparent to one
of
skill in the art from consideration of the specifications and example.
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Example 1
The ingredients of the dietary supplement, supplied in dry powder form, may be
mixed with 8 ounces of water for consumption. The composition of the dietary
supplement includes: D-Pinitol (2 pg), L-Leucine (3 pg), Leucine methyl ester
HCI
(1 pg), Leucine ethyl ester HCI (1 pg), Alpha Lipoic Acid (15 pg), Glucomannan
(0.09 g), D-Myo-Inositol (0.2 g), Guar Gum (0.5 g), Taurine (0.05 g), Taurine
Ketoisocaproic Acid (0.025 g), Taurine Alpha-Ketoglutarate (0.025 g) and
Peptide C12 (1 pg). The dietary supplement may be consumed two to three
times daily and prior to exercise.
In the foregoing specification, the invention has been described with specific
embodiments thereof, however, it will be evident that various modifications
and
changes may be made thereto without departing from the broader spirit and
scope of the invention.
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