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Nutritional Therapy & Metabolism 2010 ; 28 ( 1): 7-11
Review Article
Metabolic effects of glutamine on insulin sensitivity
Alessio Molfino, Ferdinando Logorelli, Maurizio Muscaritoli, Antonia Cascino, Isabella Preziosa,
Filippo Rossi Fanelli, Alessandro Laviano
Department of Clinical Medicine, Sapienza University of Rome, Rome - Italy
ABSTRACT. Glutamine, the most abundant free amino acid in human plasma, has outstanding
nutritional and non-nutritional properties. Glutamine regulates immune function and modulates cell
metabolism. In particular, its administration showed a positive effect on glucose oxidation and on
insulin resistance in different experimental and clinical studies. In humans, glutamine acts as both
a substrate and modulator of its metabolism to glucose. In trauma patients and in critical illness,
parenteral glutamine supplementation improved insulin sensitivity and enhanced the release of insulin
by pancreatic β-cells. In a recent clinical study, also, oral L-glutamine supplementation ameliorated
the glucose profile in obese patients and those with type 2 diabetes. The mechanisms underlying
these specific effects are still unknown. Further clinical trials investigating the role of glutamine on
glucose/insulin metabolism are needed. Several diseases, such as obesity and diabetes, may receive
important benefits from glutamine supplementation, possibly in association with conventional therapy.
(Nutritional Therapy & Metabolism 2010; 28: 7-11)
KEY WORDS: Diabetes mellitus, Glucose metabolism, Glutamine, Insulin resistance
Received: May 4, 2009; Accepted: July 9, 2009
INTRODUCTION
Glutamine (Gln) is a non-essential amino acid that plays
a relevant role as a central metabolite for amino acid
transamination and is a crucial constituent of proteins.
Gln, the most abundant amino acid in human plasma,
accounts for almost 6% of bound amino acids (1). Its
primary source is the skeletal muscle from where it is
released and transported to different organs (2, 3). Gln
promotes and maintains the function of different cells
and tissues, including the intestines (4), liver (5), neurons
(6), lymphocytes (7), and kidney (8). Gln is a precursor of
proteins, peptides, amino sugars, purines, and pyrimidines
involved in nucleic acids and nucleotide synthesis (9).
Gln is synthesized ubiquitary into cell cytoplasm
predominantly from glutamate and branched-chain amino
acids. Gln is an important stimulator of immune function,
and in particular, it stimulates lymphocyte proliferation
(10). Gln depletion blocks the lymphocyte cell cycle during
differentiation (11) and impairs cellular stress responses (12).
Gln also influences monocyte differentiation (13) and is one
of the most important precursors of glutathione, thereby
influencing the redox potential of the cell (14). Gln carbon
is utilized as a precursor for lipid synthesis in adipocytes
(15). Fatty acids produced from Gln are incorporated into
triacylglycerol in incubated adipocytes (7).
Gln plays an important role in cell proliferation activating
nucleotide synthesis (16), and it increases contractile protein
synthesis and, in particular, extracellular matrix proteins
(17). The direct effect of Gln on collagen biosynthesis
includes a dose-dependent increase of collagen types I
and III (17).
Gln regulates the expression of a group of proteins essential
for cellular survival during several stress conditions,
referred to as heat shock proteins, by enhancing the
stability of mRNA. In experimental and human studies, Gln
has already been indicated as a non-nutritive amino acid
with potential positive effects on glucose metabolism and
on insulin resistance (1).
Aim of this review is to analyze the specific role of Gln
in the regulation of glucose and insulin metabolism. We
will consider both experimental and human data for any
possible implications of Gln in the clinical approach to
insulin resistance.
Wichtig Editore - © 2010 SINPE-GASAPE - ISSN 1828-6232
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Gln and glucose homeostasis
GLUTAMINE AND GLUCONEOGENESIS
In humans, Gln plasma concentrations are twice those
of alanine which is considered the most important
gluconeogenic amino acid (18, 19). Gln basal turnover in
the postabsorptive state of normal subjects is greater than
that of alanine (20, 21). In vivo and in vitro studies showed
that Gln is the major gluconeogenic precursor in the kidney.
The Gln carbon skeleton derives mainly from other amino
acids and proteins and is the major contributor to the
newly synthesized glucose pool (21). Gln plasma levels are
determined by its release into, and uptake from, plasma by
cells and tissues. The most important tissue releasing Gln
into plasma is the skeletal muscle. Kidney and gut are the
principal organs controlling Gln uptake. Liver regulates Gln
homeostasis and, in association with muscle, may increase
its uptake. Unlike gluconeogenesis from other substrates,
Gln mediated–gluconeogenesis represents an exergonic
reaction with a net yield of 8 mol adenosine triphosphate
(ATP) per mole of synthesized glucose (22, 23).
GLUTAMINE AND INSULIN METABOLISM
Gln enhances glucose-stimulated insulin secretion via the
metabolism of the gamma-glutamyl cycle, glutathione
synthesis and mitochondrial function (24). It has already
been demonstrated that Gln modulates the glucoseinduced loss of maximal insulin responsiveness (25). In fact,
hexosamine, a product of glucose and Gln metabolism,
is involved in the development of insulin resistance (25).
Gln, in association with insulin and glucose, increases the
activity and mRNA levels of pyruvate kinase involved in
glucose metabolism (26).
EXPERIMENTAL DATA ON THE ROLE OF GLUTAMINE ON GLUCOSE/INSULIN PROFILE
Infusion of 28 g/4 hours of Gln, resulting in 3-fold increased
Gln plasma levels, caused a 7-fold increase in glucose
formation with no alterations in insulin and glucagon plasma
concentrations (27). Opara et al demonstrated that dietary
Gln supplementation during high fat feeding prevented the
development of overweight and hyperglycemia in a mouse
model. In particular, 2 months of Gln supplementation
reduced weight gain and attenuated hyperglycemia and
hyperinsulinemia in overweight hyperglycemic mice even
with continuous high fat intake. The mechanisms by which
Gln causes these effects are still uncertain (28).
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In another animal study, it was hypothesized that Gln
plays a critical role as a signaling molecule in amino
acid– and glucose-stimulated insulin secretion, and that
β-cell depolarization and subsequent intracellular calcium
elevation are required for this Gln effect to occur (29).
HUMAN DATA REGARDING THE METABOLIC
ROLE OF GLUTAMINE IN GLUCOSE/INSULIN
PROFILE
Infusion of insulin in normal volunteers suppressed
systemic Gln gluconeogenesis by 50%. The fact that Glnbased gluconeogenesis in the liver was reduced by 25%,
whereas that in the kidney was reduced by almost 75%,
indicates that renal Gln gluconeogenesis is more sensitive
to insulin than hepatic (30).
The stimulatory effect of Gln on glycogen synthesis is
attributed not only to liver but also to muscle. In humans
whose muscle glycogen and Gln stores were depleted by
exercise, infusion of Gln increased net muscle glycogen
storage 3-fold compared with saline infusion, but had not
effect on the fractional rate of blood glucose incorporation
into glycogen (31).
GLUTAMINE AND INSULIN RESISTANCE IN
CRITICAL ILLNESS
A multicenter, randomized, double-blind, controlled trial of
surgical and trauma intensive care unit patients (n = 114)
demonstrated that supplementation of total parenteral
nutrition with l-alanyl-l-Gln dipeptide led to a significant
reduction in hyperglycemia and a significant reduction
in the number of patients requiring insulin; patients also
had reduced infectious complications in association with
the amelioration of glucose intolerance (32). Bakalar et al
specifically investigated the role of Gln supplementation in
40 trauma patients and found an improvement in insulin
sensitivity with a parenteral supplementation of 0.4 g of Gln/
kg body weight per day (33). Several mechanisms could
explain these effects in critically ill patients. In particular, Gln
can influence intestinal and immune function, decreasing
intestinal permeability in stressed patients (34) leading to a
possible reduction of glucose plasma levels. Experimental
evidence indicates that Gln modulates inflammatory
cytokine production by decreasing gut mucosa interleukin-8
levels (35) or increasing antiinflammatory cytokines such
as interleukin-10 (36).
All of these clinical results appear to be in agreement and
Molfino et al
focus on the positive role of Gln supplementation in critically
ill patients. On the other hand, recent data suggest that
the relationship between Gln and insulin resistance could
be bidirectional, the former influencing the latter and vice
versa. Indeed, Biolo et al showed that euglycemia in cancer
patients undergoing surgery improves skeletal muscle
protein metabolism, resulting in increased de novo muscle
glutamine synthesis and plasma glutamine concentrations
(37). These results question whether tight glycemic control
would prevent the need for Gln supplementation in critically
ill patients, or whether Gln may confer per se some clinical
benefits. More studies are needed to solve this issue, but
the available evidence suggests that we cannot ignore
exogenous glutamine provision, and that perhaps Gln
and tight glycemic control are complementary, with each
facilitating the other (38).
GLUTAMINE AND DIABETES MELLITUS
In type 1 diabetes, plasma Gln concentrations are not
reduced (39-41). In type 2 diabetes, increased Gln conversion
to glucose and to alanine was observed, but decreased
oxidation was also demonstrated (42).
In a recent elegant clinical study, type 2 diabetes patients,
obese individuals, and obese nondiabetic control subjects
were given oral Gln supplementation. Gln increased
circulating glucagon-like peptide 1 (GLP-1), glucosedependent insulinotropic polypeptide, and insulin
concentration (43). Interestingly, the GLP-1 response to Gln
was not different in the diabetic group compared with the
obese and the lean control subjects, suggesting that it might
be possible to circumvent the diabetes-associated GLP-1
secretory defect with agents that target alternative pathways
in the L-cells releasing GLP-1 (43). The mechanism by which
Gln stimulates GLP-1 release in vivo remains uncertain.
These data are consistent with a study of Reiman et al
investigating cell cultures. In this setting, supplementation
with Gln was demonstrated to represent a more potent
GLP-1 secretagogue than glucose or other amino acids
(44). Similarly, another experimental study showed that
insulin and Gln attenuate the expression of inflammatory
cytokines such as tumor necrosis factor-α and interleukin-8,
and reduce the oxidative stress of hyperglycemia (45).
CONCLUSION
Gln is the major metabolic source of the gut and has
positive effects on GLP-1, glucagon, and insulin release.
Both animal and human studies have shown several
benefits of Gln supplementation on insulin resistance
and hyperglycemia. This glucose-ameliorating effect
may be related to a specific Gln effect on fat metabolism,
such as the inhibition of fatty acid oxidation and
lipolysis (46). Also, Gln in association with insulin is
significantly more effective in reducing the expression
of proinflammatory cytokines and oxidative stress than
insulin or Gln alone. Considering the results of these
experimental and human data, the clinical relevance of
Gln supplementation becomes self-evident. In particular,
considering the elevated number of patients affected by
different diseases associated with insulin resistance,
such as type 2 diabetes, metabolic syndrome, obesity,
critical illness, etc., it appears to be essential to give this
information to clinicians. Evidence has shown that both
parenteral and enteral Gln administration are effective
in glucose and insulin metabolism. An interesting role
may be found for oral L-Gln supplementation, which
can be prescribed in individuals and patients preserving
oral nutrition. L-Gln might be useful in association with
traditional pharmacological approaches to improve
patients’ glucose and insulin profiles. We strongly
recommend larger controlled clinical trials to investigate
the efficacy and safety of Gln administration.
Conflict of interest: none declared.
Financial support: none.
Address for correspondence:
Alessandro Laviano, MD
Associate Professor of Internal Medicine
Department of Clinical Medicine
Sapienza University of Rome
Viale dell’Università 37
00185 Rome, Italy
e-mail: [email protected]
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Gln and glucose homeostasis
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