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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 influencing the redox potential of the cell (14). Gln carbon is utilized as a precursor for lipid synthesis in adipocytes Glutamine (Gln) is a non-essential amino acid that plays (15). Fatty acids produced from Gln are incorporated into a relevant role as a central metabolite for amino acid triacylglycerol in incubated adipocytes (7).
transamination and is a crucial constituent of proteins. Gln plays an important role in cell proliferation activating Gln, the most abundant amino acid in human plasma, nucleotide synthesis (16), and it increases contractile protein accounts for almost 6% of bound amino acids (1). Its synthesis and, in particular, extracellular matrix proteins primary source is the skeletal muscle from where it is (17). The direct effect of Gln on collagen biosynthesis released and transported to different organs (2, 3). Gln includes a dose-dependent increase of collagen types I promotes and maintains the function of different cells and tissues, including the intestines (4), liver (5), neurons Gln regulates the expression of a group of proteins essential (6), lymphocytes (7), and kidney (8). Gln is a precursor of for cellular survival during several stress conditions, proteins, peptides, amino sugars, purines, and pyrimidines referred to as heat shock proteins, by enhancing the involved in nucleic acids and nucleotide synthesis (9). stability of mRNA. In experimental and human studies, Gln Gln is synthesized ubiquitary into cell cytoplasm has already been indicated as a non-nutritive amino acid predominantly from glutamate and branched-chain amino with potential positive effects on glucose metabolism and acids. Gln is an important stimulator of immune function, and in particular, it stimulates lymphocyte proliferation Aim of this review is to analyze the specific role of Gln (10). Gln depletion blocks the lymphocyte cell cycle during in the regulation of glucose and insulin metabolism. We differentiation (11) and impairs cellular stress responses (12). will consider both experimental and human data for any Gln also influences monocyte differentiation (13) and is one possible implications of Gln in the clinical approach to of the most important precursors of glutathione, thereby Wichtig Editore - 2010 SINPE-GASAPE - ISSN 1828-6232 In another animal study, it was hypothesized that Gln plays a critical role as a signaling molecule in amino In humans, Gln plasma concentrations are twice those acid– and glucose-stimulated insulin secretion, and that of alanine which is considered the most important β-cell depolarization and subsequent intracellular calcium gluconeogenic amino acid (18, 19). Gln basal turnover in elevation are required for this Gln effect to occur (29).
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 Infusion of insulin in normal volunteers suppressed cells and tissues. The most important tissue releasing Gln systemic Gln gluconeogenesis by 50%. The fact that Gln- into plasma is the skeletal muscle. Kidney and gut are the based gluconeogenesis in the liver was reduced by 25%, principal organs controlling Gln uptake. Liver regulates Gln whereas that in the kidney was reduced by almost 75%, homeostasis and, in association with muscle, may increase indicates that renal Gln gluconeogenesis is more sensitive its uptake. Unlike gluconeogenesis from other substrates, Gln mediated–gluconeogenesis represents an exergonic The stimulatory effect of Gln on glycogen synthesis is reaction with a net yield of 8 mol adenosine triphosphate attributed not only to liver but also to muscle. In humans (ATP) per mole of synthesized glucose (22, 23). 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).
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 glucose- induced loss of maximal insulin responsiveness (25). In fact, hexosamine, a product of glucose and Gln metabolism, A multicenter, randomized, double-blind, controlled trial of is involved in the development of insulin resistance (25). surgical and trauma intensive care unit patients (n = 114) Gln, in association with insulin and glucose, increases the demonstrated that supplementation of total parenteral activity and mRNA levels of pyruvate kinase involved in 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 Infusion of 28 g/4 hours of Gln, resulting in 3-fold increased sensitivity with a parenteral supplementation of 0.4 g of Gln/ Gln plasma levels, caused a 7-fold increase in glucose kg body weight per day (33). Several mechanisms could formation with no alterations in insulin and glucagon plasma explain these effects in critically ill patients. In particular, Gln concentrations (27). Opara et al demonstrated that dietary can influence intestinal and immune function, decreasing Gln supplementation during high fat feeding prevented the intestinal permeability in stressed patients (34) leading to a development of overweight and hyperglycemia in a mouse possible reduction of glucose plasma levels. Experimental model. In particular, 2 months of Gln supplementation evidence indicates that Gln modulates inflammatory reduced weight gain and attenuated hyperglycemia and cytokine production by decreasing gut mucosa interleukin-8 hyperinsulinemia in overweight hyperglycemic mice even levels (35) or increasing antiinflammatory cytokines such with continuous high fat intake. The mechanisms by which Gln causes these effects are still uncertain (28).
All of these clinical results appear to be in agreement and focus on the positive role of Gln supplementation in critically Both animal and human studies have shown several ill patients. On the other hand, recent data suggest that benefits of Gln supplementation on insulin resistance the relationship between Gln and insulin resistance could and hyperglycemia. This glucose-ameliorating effect be bidirectional, the former influencing the latter and vice may be related to a specific Gln effect on fat metabolism, versa. Indeed, Biolo et al showed that euglycemia in cancer such as the inhibition of fatty acid oxidation and patients undergoing surgery improves skeletal muscle lipolysis (46). Also, Gln in association with insulin is protein metabolism, resulting in increased de novo muscle significantly more effective in reducing the expression glutamine synthesis and plasma glutamine concentrations of proinflammatory cytokines and oxidative stress than (37). These results question whether tight glycemic control insulin or Gln alone. Considering the results of these would prevent the need for Gln supplementation in critically experimental and human data, the clinical relevance of ill patients, or whether Gln may confer per se some clinical Gln supplementation becomes self-evident. In particular, benefits. More studies are needed to solve this issue, but considering the elevated number of patients affected by the available evidence suggests that we cannot ignore different diseases associated with insulin resistance, exogenous glutamine provision, and that perhaps Gln such as type 2 diabetes, metabolic syndrome, obesity, and tight glycemic control are complementary, with each 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 In type 1 diabetes, plasma Gln concentrations are not oral nutrition. L-Gln might be useful in association with reduced (39-41). In type 2 diabetes, increased Gln conversion traditional pharmacological approaches to improve to glucose and to alanine was observed, but decreased patients’ glucose and insulin profiles. We strongly oxidation was also demonstrated (42).
recommend larger controlled clinical trials to investigate In a recent elegant clinical study, type 2 diabetes patients, the efficacy and safety of Gln administration.
obese individuals, and obese nondiabetic control subjects were given oral Gln supplementation. Gln increased circulating glucagon-like peptide 1 (GLP-1), glucose-dependent insulinotropic polypeptide, and insulin concentration (43). Interestingly, the GLP-1 response to Gln conflict of interest: none declared.
Financial support: none.
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 cel 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).
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