Nutrition Volume 18, Number 9, 2002
8. Cynober L. Les pharmaconutriments azotés: du tube à essai à la pratique clinique.
Nutr Clin Metabol 2001;15:131
9. Fürst P. New developments in glutamine delivery. J Nutr 2001;131(suppl):2562
10. Houdijk AP, Rijnsburger ER, Jansen J, et al. Randomized trial of glutamine-
enriched enteral nutrition on infectious morbidity in patients with multiple
trauma. Lancet 1998;352:772
11. Cynober L, Coudray-Lucas C, De Bandt JP, et al. Action of ornithine alpha-
ketoglutarate, ornithine hydrochloride and calcium alpha-ketoglutarate on plasma
amino acid and hormonal patterns in healthy subjects. J Am Coll Nutr 1990;9:2
12. Anglade P, Arnaud PH, Brion F, Postaire E. Stabilité de l’␣-cétoglutarate
d’ornithine dans les solutions pour nutrition parentérale. Gastroenterol Clin Biol
1990;14:370
13. Darmaun D. Glutamine and glutamate nitrogen exchangeable pools in cultured
fibroblast: a stable isotope study. J Cell Physiol 1988;134:143
14. Hasebe M, Suzuki H, Mori E, et al. Glutamate in enteral nutrition: can glutamate
replace glutamine in supplementation to enteral nutrition in burned rats? JPEN
1999;23:S78
15. Chambon-Savanovitch C, Farges MC, Raul R, et al. Can a glutamate-enriched
diet counteract glutamine depletion in endotoxemic rats? J Nutr Biochem 1999;
10:331
16. Cynober L. The use of ␣-ketoglutarate salts in clinical nutrition and metabolic
care. Curr Opin Clin Nutr Metab Care 1999;2:33
17. Cynober L. Ornithine ␣-ketoglutarate. In: Cynober L, ed. Amino acid metabolism
and therapy in health and nutritional disease. Boca Raton: CRC Press, 1995:385
18. Wirén M, Adrian F, Hammarqvist KE, et al. The effects of a new amino-acid
dipeptide solution on nitrogen balance and humoral growth factors in the post-
operative state in man. Clin Nutr 1995;14:97
PII S0899-9007(02)00901-2
Amino Acids: Fuel, Building Blocks
for Proteins, and Signals
INTRODUCTION
Amino acid physiology is a field of particular complexity because
of the number of amino acids and their multiple specific func-
tions.1 Based on present knowledge, it is not possible to com-
pletely describe their individual kinetics and metabolic actions and
simultaneously depict their interaction in regulating protein syn-
thesis. As a consequence, the interpretation of plasma amino acid
profiles in pathologic conditions is more phenomenic than mech-
anistic, and the choice of the optimal amino acid mix supplemen-
tation for therapeutic purposes is based largely on empiric criteria.
In this issue of Nutrition, Dr. Cynober describes the state of the art
for using amino acid concentrations as a valuable tool in the
clinical setting. He correctly points out that plasma concentrations
do not necessarily reflect fluxes, the most appropriate parameters
to supply over time the correct amount of a given amino acid.
Serial plasma amino acid measurements in response to a dynamic
test (the enteral supplementation) might improve our insight into
amino acid requirements. It is generally felt that formulating the
correct balance of an amino acid solution for enteral infusion is the
key to meet the requirements in specific clinical situations. The
latter objective, to exactly match each amino acid requirement with
its supplementation, is logical and extremely important to prevent
the potentially harmful effects of amino acid overfeeding or under-
replacement. Present knowledge, however, suggests that some
amino acids (e.g., glutamine, arginine, and branched-chain forms)
could be used as drugs to promote some desirable effects such as
protein anabolism, immunotrophism, or nitric oxide generation.
Amino acid supplementation “beyond their requirements” would
significantly change this approach; even though it is not presently
possible to devise clear clinical procedures for this approach, this
Correspondence to: Alberto Battezzati, MD, Nutrition Section, DiSTAM,
Università degli Studi di Milano, Via G. Colombo, 60, 20131 Milano, Italy.
E-mail: alberto.battezzati@unimi.it
Editorial Opinions 773
perspective should be kept in mind, and amino acid physiology and
pathophysiology should be interpreted in this light.
A comprehensive view of amino acid physiology, pathophys-
iology, and their potential clinical use should take into account at
least three interpretative levels: fuel, building blocks for proteins,
and signals. Amino acids as fuel have been perceived somewhat in
contrast with amino acids as building blocks for proteins. The
diversion of amino acid flux from oxidation into protein incorpo-
ration to preserve protein mass may be desirable because protein
depletion greater than 25% leads to death. Nonetheless, amino
acids are an important fuel for several tissues: postabsorptively,
their oxidation supports 15% of the resting energy expenditure.
During exercise, muscle amino acids may produce significant
amounts of energy via oxidative deamination of aspartate to pro-
vide ammonia for the synthesis of AMP from IMP and interme-
diates for the citric acid cycle. Among the amino acids readily
converted to aspartate, there are glutamine and glutamate, the most
abundant amino acids in the body, especially concentrated in the
muscle. During feeding, the splanchnic bed extracts and immedi-
ately oxidizes a large amount of the enteral non-essential amino
acids, including the totality of glutamate and the majority of
glutamine and alanine. Glutamine in turn is an important fuel for
the intestine and the immune system, and its depletion is synony-
mous with organ dysfunction. Glutamine is a “conditionally es-
sential” amino acid because, in certain conditions, glutamine de
novo synthesis is not sufficient to meet its endogenous require-
ments.2 These lines of evidence support the idea that amino acid
supplementation for oxidation is important, especially when the
requirements increase during pathologic processes.
Amino acids as precursors for protein anabolism is the second
important level at which amino acid metabolism should be con-
sidered. It is well known that the limitation in single amino acid
availability limits the entire protein synthetic rate. The diversion of
specific amino acids into oxidation may imbalance the free pool
available for protein synthesis. The imbalance in turn may reduce
protein synthesis. For this reason, it is necessary that, for each
clinical condition, the amino acid requirements for oxidation are
completely understood and correctly met by amino acid supple-
mentation. However, a balanced pool of amino acids for protein
synthesis is necessary but insufficient to promote protein anabo-
lism. Amino acid administration increases protein synthesis in
healthy humans, but clinical experience shows that amino acid
overfeeding in the critically ill patient simply increases amino acid
oxidation and not protein synthesis. This frustrating event during
catabolic illness reflects an adverse hormonal and cytokine milieu
that increases proteolysis and accelerates the use of specific amino
acids. Among the factors, cortisol is a major protein catabolic
hormone that also increases the glutamine flux.3 A prominent
feature of the protein catabolic mode in critically ill patients is the
resistance to the metabolic actions of insulin. The cellular bases for
the regulation of protein synthesis have been recently elucidated.
Several kinases (p70S6 kinase, mitogen-activated protein kinases,
and PHAS-1) affect ribosomal activity and are regulated in a
complex fashion by upstream mediators depending on hormone
signals.4 The signals resulting from the insulin interaction with its
own receptor and leading to protein anabolism are subject to
modulation by catabolic hormones such as cortisol and by inflam-
matory cytokines such as tumor necrosis factor-␣. In addition to
amino acid precursor availability, intracellular signaling is impor-
tant to regulate protein anabolism, and its modulation should be
taken into account in nutritional strategies.
Interestingly, the intracellular signaling pathways that were
initially described in terms of hormone-responsive transduction
elements also respond to nutrient stimuli. It is now clear that amino
acids are such modulators.5,6 In various mammalian tissues includ-
ing the myocardium, the skeletal muscle, and the liver, amino acids
(branched chain) activate p70S6 kinase and PHAS-1.7–9 Such
important modulators of protein synthesis are affected in a com-
plex fashion and at various levels with insulinlike and insulin
774 Editorial Opinions
antagonistic effects. In particular, amino acids inhibit early pos-
treceptor steps in insulin action, including tyrosine phosphoryla-
tion of insulin receptor substrate proteins and activation of
phosphatidylinositol-3-kinase, ending in insulin resistance for glu-
cose metabolism but in insulin potentiation for protein synthesis.
An important contribution to cell anabolism is provided by glu-
tamine via a peculiar mechanism, i.e., cell swelling mediated by its
cellular inflow. Cell swelling in turn activates mitogen-activated
protein kinases in the liver and promotes the reduction of glyco-
genolysis and proteolysis.10 The glutamine stimulation of
mitogen-activated protein kinases in other tissues has multiple
implications ranging from mitogenic stimulation of enterocytes to
prevention of apoptosis.11 Apoptosis in turn is prevented by nitric
oxide, whose availability is modulated by the precursor amino
acid, arginine.12,13 These are just examples and do not include the
important role that many amino acids have in the generation of
transmitters, especially in the nervous system. All evidence points
to a major role of amino acids in cell signaling. This field is rapidly
evolving, and much more knowledge will be available in the next
few years.
In conclusion, amino acids for clinical purposes should not be
viewed simply as building blocks for protein synthesis, but as the
most important and variegate nutrient modulators of cell functions.
When we understand the rules for manipulating cellular patho-
physiologic processes by their administration, we will have a
powerful and relatively inexpensive tool to revert the catabolic
condition in the critically ill.
Alberto Battezzati, MD
Patrizia Riso, PhD
Università degli Studi di Milano
Istituto Scientifico H. San Raffaele
Milan, Italy
REFERENCES
1. Bier DM. Intrinsically difficult problems: the kinetics of body proteins and amino
acids in man. Diabetes Metab Rev 1989;5:111
2. Lacey JM, Wilmore DW. Is glutamine a conditionally essential amino acid? Nutr
Rev 1990;48:297
3. Matthews DE, Battezzati A. Regulation of protein metabolism during stress. Curr
Opin Gen Surg 1993:72
4. Kimball SR. Regulation of translation initiation by amino acids in eukaryotic
cells. Prog Mol Subcell Biol 2001;26:155
5. Kimball SR, Jefferson LS. Control of protein synthesis by amino acid availabil-
ity. Curr Opin Clin Nutr Metab Care 2002;5:63
6. Patti ME. Nutrient modulation of cellular insulin action. Ann NY Acad Sci
1999;892:187
7. Terruzzi I, Allibardi S, Bendinelli P, et al. Amino acid- and lipid-induced insulin
resistance in rat heart: molecular mechanisms. Mol Cell Endocrinol 2002;190:
135
8. Patti ME, Brambilla E, Luzi L, Landaker EJ, Kahn CR. Bidirectional modulation
of insulin action by amino acids. J Clin Invest 1998;101:1519
9. Hara K, Yonezawa K, Weng QP, et al. Amino acid sufficiency and mTOR
regulate p70 S6 kinase and eIF-4E BP1 through a common effector mechanism.
Biol Chem 1998;273:14484
10. Haussinger D, Graf D, Weiergraber OH. Glutamine and cell signaling in liver. J
Nutr 2001;131:25–09S
11. Rhoads M. Glutamine signaling in intestinal cells. JPEN 1999:S38
12. Gao F, Gao E, Yue TL, et al. Nitric oxide mediates the antiapoptotic effect of
insulin in myocardial ischemia-reperfusion: the roles of PI3-kinase, Akt, and
endothelial nitric oxide synthase phosphorylation. Circulation 2002;105:1497
13. Brune B, von Knethen A, Sandau KB. Nitric oxide and its role in apoptosis. Eur
J Pharmacol 1998;351:261
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Nutrition Volume 18, Number 9, 2002
Metabolic Syndrome X Is Common
in South Asians, But Why and How?
The fact that South Asians (people with ancestry in the countries
of the Indian subcontinent), who comprise more than one-fifth of
the world’s population, are highly likely to develop insulin-
resistance, type 2 diabetes mellitus, essential hypertension, hyper-
lipidemia, and coronary heart disease (CHD), which come under
the umbrella of metabolic syndrome X, as compared with the
Western population is now well established.1–3 As suggested by
Misra,4 there seems to be a coexistence of nutritional deficiencies
and appreciable overnutrition in the form of obesity in South
Asians. Although malnutrition (both malnutrition and overnutri-
tion can be considered malnutrition) explains the high incidence of
metabolic syndrome X to some extent, it is likely that this alone
cannot be the reason for the overall increase in the incidence of this
epidemic. Genetics certainly play a major role in the high preva-
lence of metabolic syndrome X in South Asians. But it is not yet
certain how the so-called genetic factors interact with their nutri-
tional deficiencies, and how such an interaction might translate
ultimately into the onset of various diseases. If this interaction is
understood, then therapeutic and preventive measures can be ini-
tiated that may reduce the incidence and impact of these modern
diseases in this vulnerable population.
The established risk factors in South Asians include low con-
centrations of high-density lipoprotein (HDL) cholesterol, hyper-
triglyceridemia, hypercholesterolemia, abdominal obesity, high
prevalence of type 2 diabetes and hypertension, and lack of exer-
cise (sedentary lifestyle).1,2 Insulin resistance is nearly universal in
all these conditions. Hyperinsulinemia may be a consequence of
this, but insulin resistance may differ and may not occur in all
tissues of the body. For instance, adipose tissue is not resistant to
insulin in the early stages of whole-body insulin resistance,5 but
muscle is resistant very early in the progression of metabolic
syndrome X.6 This emphasized the importance of exercise in the
prevention and treatment of insulin resistance.
South Asians may be more susceptible to established risk
factors, which may in part be determined by genetics. One dom-
inant risk factor that is nearly universal is the presence of abdom-
inal obesity (central deposition of fat) in South Asians, but whether
the development of this type of obesity is genetic, dietary, caused
by lack of exercise, or a combination of these factors has not been
determined. Certainly, abdominal obesity is more prominent in the
South Asian population than in the Western population. A recent
study suggested that transgenic mice overexpressing 11␤ hydrox-
ysteroid dehydrogenase type 1 (11␤HSD-1) selectively in adipose
tissue developed abdominal obesity and exhibited insulin-resistant
diabetes, hyperlipidemia, and hyperphagia despite hyperleptine-
mia.7 It is not known whether adipose tissue from the abdomens of
South Asians show increased 11␤HSD-1 activity. My guess is that
it does. If this is true, peroxisome proliferator-activated receptor-␥
ligands, which markedly reduce adipocyte 11␤HSD-1 activity in
vitro and in vivo and preferentially reduce abdominal fat, may be
the drugs of choice in South Asians to reduce insulin resistance
and obesity. South Asians may be genetically programmed to
overexpress 11␤HSD-1 in their adipose tissue, which may account
for their higher incidence of insulin resistance.
Other risk factors for South Asians include, but are not limited
to, the use of ghee and other cooking oils and the consumption of
low amounts of or deficiency in vitamin C, vitamin E, selenium,
␤-carotene, folic acid, vitamin B12, ␻-3 fatty acids especially
eicosapentaenoic acid (EPA), and docosahexaenoic acid (DHA),
and monounsaturated fatty acids.3,4 This coupled with the obser-
Correspondence to: Undurti N. Das, MD, FAMS, EFA Sciences LLC, 1420
Providence Highway, Suite 266, Norwood, MA 02062, USA. E-mail:
undurti@hotmail.com or undurti@efasciences.com