Glutamine This information is provided for self educational use only. It has been complied from Internet & other sources
A proliferation of new studies about the amino acid L-Glutamine is making its way into scientific journals, & for good reason. Our understanding of glutamine is turning topsy-turvy as scientists uncover its many unique & powerful roles--from enhancing muscle growth & neutralizing excess body acid to losing weight & combating the effects of aging.
Here is a link to some of the latest information on Glutamine supplementation produced by the Life Extension Foundation.
Amino acids are the building blocks that form body & dietary proteins. Twenty-two different amino acids occur in nature & have traditionally been grouped into two categories--nonessential & essential. Nonessential amino acids are made by the liver from general dietary protein intake & don't have to be consumed directly. In contrast, essential amino acids cannot be made by the liver & therefore must come from diet or supplements to meet the body's daily demands.
Glutamine has traditionally been considered a "nonessential" amino acid, but current research suggests that it may be "conditionally essential" under certain metabolic conditions such as exercise.
Exercise & Muscle Mass
During strenuous exercise the need for glutamine appears to increase beyond the level ordinarily made in the liver. Recent research findings illustrate the dramatic effect exertion has on the body's glutamine reserves. Seven healthy athletes doing intensive anaerobic exercise (a single short-distance sprint) showed a 45 percent drop in plasma glutamine compared to their pre-exercise levels. When the same athletes did intensive aerobic exercise (10 days of long-distance running), their plasma glutamine dropped 50 percent. (1) Some runners still had depressed glutamine levels even six days after recovering from the aerobic program, suggesting that they needed more glutamine than their diets provided.These findings are especially important to athletes, as glutamine is essential to muscle growth. It may help reduce the rate of muscle breakdown (anticatabolic) relative to the rate of muscle growth (anabolic) (2) & increase concentrations of plasma arginine & glutamate, two amino acids linked to muscle-strengthening growth hormone.
Growth Hormone Release
In another study, nine healthy volunteers ages 32 to 64 were given either a beverage containing 2 g of glutamine or a placebo drink. During the next 90 minutes, blood samples were collected & measured for bicarbonate & plasma growth hormone--two substances stimulated by glutamine. Subjects who consumed supplemental glutamine showed significant increases in glutamine (12 percent to 19 percent above presupplement values), bicarbonate (12 percent) & growth hormone (up to 430 percent), whereas those drinking the placebo beverage showed no changes. (3)Muscle Building
Bicarbonate is one of the body's primary base buffers & helps to deactivate excess blood acids such as ammonia or urea that are generated during heavy anaerobic exercises like weight training or sprinting. In addition to stimulating the production of bicarbonate, glutamine itself acts as a buffer--its negative charge negates the net positive charge of an acid. Without this neutralization, blood acids & muscle acid (e.g., lactic acid) might accumulate, leading to fatigue & muscle soreness.During strenuous exercise, however, the liver may not be able to produce enough glutamine to keep up with the amount of acid being generated by the body. New research suggests that glutamine supplements may provide additional buffering power when the acid/base balance becomes more acidic--enabling longer, harder workouts with less muscle soreness the next day. (4)
Fat Burning
This study also showed that subjects taking a glutamine supplement had accelerated fat burning compared to those taking the placebo. No one exercised during the study period. Inducing the body to burn more fat while preserving muscle with growth hormone is one of the most effective, healthy ways to lose weight & keep it off. Of course, nothing replaces a well-balanced diet & regular exercise for weight management, but supplemental glutamine may direct the body's metabolism in a helpful direction. In addition, if a person exercises, even gently, glutamine may maximize the benefits & minimize the discomfort.Retards Aging
Considering all of these effects together, glutamine may have the potential to retard some of the effects of aging by preserving muscle mass & reducing fat accumulation. Its ability to boost growth hormone levels (up to 430 percent) is a case in point. Growth hormone helps build & strengthen muscles & clear acid from body fluids, but starting at age 30, its production declines. This decline is associated with muscle loss (muscle breakdown is accelerated under acid conditions), increased body fat & accelerated aging. (5) Glutamine supplements may help stall such developments.Insulin Resistance
Supplemental glutamine was recently shown to reduce body weight & prevent high blood sugar & high insulin levels in mice fed a high-fat diet. (6) The mice were genetically predisposed to become overweight & develop high blood-sugar levels when consuming a high-fat diet, but these unhealthy outcomes were essentially neutralized for the mice that had glutamine added to their food.Increases in body fat & body weight & high blood sugar are thought to result from persistently high levels of insulin in the blood, a condition known as insulin resistance. Insulin levels skyrocketed in the mice fed a high-fat diet without supplemental glutamine, while those fed the glutamine-supplemented diet showed normal insulin patterns.
Although this is only an animal trial, the potential ability of glutamine supplements to reduce insulin resistance is exciting. Insulin resistance is now estimated to occur in half of all obese people & is considered a major risk factor for heart disease, high blood pressure & diabetes. While it is premature to jump from animal studies to conclusions about humans, the research so far may suggest a safe, nutritional way to adjust metabolism & look & feel healthy.
Mental Energy
Glutamine & other amino acids such as choline, tyrosine & phenylalanine are used by the brain & central nervous system (CNS) to make neurotransmitters--biochemical mediators that stimulate or reduce the brain's electrical impulses that translate into thoughts, sensations & emotions. Different neurotransmitters can also influence perceptions of energy or fatigue.Neurotransmitters appear to get metabolized, or "used up," as a normal part of body function. Heavy mental or physical stress may cause the CNS to metabolize more neurotransmitters, so whether depletion is caused by intensive concentration, a demanding job or exercise, full replenishment of these essential biochemicals is vital to keep the brain "tuned up." However this may not be possible if the above stress, diet or aging caused reduced levels of the basic amino acids used to form the neurotransmitters. So here stress can reduced the level of neurotransmitters and also the building blocks used to form them. Sort of a double whammy.
Neurotransmitter production is thought to increase / be restored to normal levels when the amino acids they are formed from are supplemented in the diet. If this is true for glutamine, nutritional strategies that replenish it may also boost perception of energy or help prevent mental fatigue as additional supplemental Glutamine and other amino acids will help to restore falling intercellular stores of used up neurotransmitters.
Two final points are important for the glutamine story. First, too much glutamine may be counterproductive. In humans, more than two grams is likely to result in less growth hormone production, less bicarbonate buffer, & probably no further energy benefit. In fact, elevated doses may over stimulate brain neurotransmitters somewhat as all control systems have control points (Low, Normal, High) and the resultant levels can vary upward somewhat. So, while glutamine may be beneficial, large amounts may be a waste of money.
Secondly, most of the glutamine studies appearing in scientific journals are conducted with isolated cells or animals. More human clinical research is needed to fill in missing pieces of the glutamine puzzle. Nonetheless, glutamine's emerging picture is exciting & cause for optimism. It may become an essential supplement in years to come.
References
1. Keast, D., Arstein, D., et al. "Depression of plasma glutamine concentration after exercise stress & its possible influence on the immune system," Med J Aust, 162: 15-8, 1995.
2. MacLennan, P.A., Smith, K., et al. "Inhibition of protein breakdown by glutamine in perfused rat skeletal muscle," FEBS Lett, 257: 133-36, 1988.
3. Welbourne, T.C. "Increased plasma bicarbonate & growth hormone after an oral glutamine load," Am J Clin Nutr, 61: 1058-61, 1995.
4. Welbourne, T.C., & Joshi, S. "Interorgan glutamine metabolism during acidosis," Jnl Parent Ent Nutr, 14: 775-855, 1990.
5. Rudman, D., Kutner, M.H., et al. "Impaired growth hormone secretion in the adult population: Relation to age & adiposity," J Clin Invest, 67: 1361-69, 1981.
6. Opara, E.C., Petro A., et al. "L-glutamine supplementation of a high fat diet reduces body weight & attenuates hyperglycemia & hyperinsulinemia in C57BL/6J mice," J Nutr, 126: 273-79, 1996.
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WELBOURNE PAPER ON GH RELEASE FROM 2G OF L-GLUTAMINE
Here is the Welbourne research paper showing good (420% average GH boost in people aged between 32 and 64) using 2g L-Glutamine.
The paper is readable, if you try. I am trying to use a OCR software package to convert the document into test form.Page 1.
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Recently on the Anti-Aging Research email group, questions about the safety of Glutamine supplementation were raised.
Prior to using Glutamine myself and by my family and friends, I did a extensive amount of research on possible toxicity issues surrounding Glutamine. Like anything taken to excess, there are levels of Glutamine intake that I would consider to be unwise. My research suggests that you would need to consume in excess of 20g of Glutamine for some negative effects to happen and much larger levels for serious problems. Many professional athletes and body builders have used 20g doses of Glutamine for many years without any outward negative effects.
The body is composed of many active control systems which work to maintain set levels of their control chemicals and other enzyme conversion systems which are limited in their ability to convert body chemicals from one form to another. The toxic form of Glutamine, Glutamate is enzyme rate limited and the blood levels of Glutamine is feedback limited by conversion to ammonia and elimination by the kidneys.
Here are two Medline papers I found which very clearly support the above opinion. I know of NO medical research which shows ANY toxicity problems with 2g doses of Glutamine. Given that, I still suggest you NEVER use isolated supplements and ALWAYS use ANY supplement with other supplements which work in a synergistic manner to enhance overall body functions.
If you know if any data which you feel shows concerns about ANY supplement, PLEASE send me the info and let me have a read and do some research.
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HOW INTERCELLULAR GLUTAMINE TO GLUTAMATE CONVERSION OCCURS
Intercellular Glutamine to Glutamate conversion is done inside each cell which needs Glutamate. The process is very fast and very tight Glutamate levels are maintained as everthing stays inside the cell.
The Glutamine to Glutamate conversion and control is not at all like the carb to glucose conversion and slowly reacting insulin/gulcagon control system which can be over loaded my high GI carbs, vary widely and has to work over the whole body.
Within each cell that needs Glutamate to work, there is a part of the DNA structure which needs to express enzymes to do the conversion of Glutamine to Glutamate. The DNA will only express these enzymes when the level of intercelluar Glutamate drops below a set point. The cell's DNA will then detect this low level of Glutamate and cause enzymes to be produced to do the conversion. When the Glutamate level increases above its set point, the DNA will stop producing the enzyme and Glutamate levels will stay constant until the cell starts using Glutamate in its operation. This conversion process is very fast, as only a very small amount of Glutamate is needed to be converted, it needs to be so to maintain tight intercellular levels of critical chemicals. As the levels drop again, the above will occur again and so on.......... This way intercellular Glutamate levels, like many other intercellular chemical levels are maintained with-in very tight bounds and widely varing precursor levels.
The only relationship to Glutamine's level here is if there is NOT enough Glutamine to provide sufficient raw stock for the conversion, low Glutamate levels may result. Low Glutamine levels can mean low intercellular Glutamate levels and reduced cellular and neuron performance. Increasing Glutamine levels and/or the rate of increase will have NO effect on the intercellular level of Glutamate. If this were not so, not only for Glutamate but for many other chemicals, we would have died a long time ago.
However low Glutamine levels will reduce CNS and brain neuron functionality. As low Glutamine levels can occur though diet, extensive exercise or aging, supplemental Glutamine will assist the body to restore youthful levels of intercellular Glutamate and help to restore many other Glutamine related body wide functions to youthful levels."
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Glutamine metabolism and its physiologic importance
Smith RJ. J Parenter Enteral Nutr 1990;14:40S-44S
The amino acid glutamine has important and unique metabolic functions. It is the most abundant free amino acid in the circulation and in intracellular pools and a precursor for the synthesis of amino acids, proteins, nucleotides, and many other biologically important molecules. It is the most important precursor for ammoniagenesis in the kidney, the major end product of ammonia-trapping pathways in the liver, a substrate for gluconeogenesis, and an oxidative fuel in rapidly proliferating cells and tissues. Glutamine also may have a number of important regulatory roles, increasing protein synthesis and decreasing protein degradation in skeletal muscle and stimulating glycogen synthesis in the liver. The demonstration that glutamine concentrations decrease and tissue glutamine metabolism increases markedly in many catabolic, stressful disease states has led to a reconsideration of the classification of glutamine as a nonessential amino acid and to the alternative hypothesis that glutamine may be a conditionally essential nutrient. This hypothesis has been supported by recent studies that have shown trophic effects of glutamine-supplemented diets on the growth of specific tissues and on total body nitrogen balance. These observations form the basis for current efforts to define the clinical usefulness of glutamine-supplemented nutrition.
Glutamine and the preservation of gut integrity
Van der Hulst RR, van Kreel BK, von Meyenfeldt MF, et al. Lancet 1993;341:1363-1365
Parenteral glutamine dipeptide improves nitrogen balance in postoperative patients on total parenteral nutrition (TPN). Animal studies show that the structure and function of the gut is preserved by glutamine. It is not known if this is the case in human beings. 20 patients admitted to hospital for total parenteral nutrition were randomly allocated to receive parenteral nutrition enriched with glycyl-L-glutamine (Gln TPN), or standard parenteral nutrition (STPN). Mucosal biopsy specimens were taken from the second part of the duodenum before starting parenteral nutrition, and after two weeks. The ratio between the urine concentrations of lactulose and mannitol after enteral administration was used to measure intestinal permeability. After two weeks of parenteral nutrition in the GlnTPN group, intestinal permeability was unchanged, whereas permeability in the STPN group increased. Villus height was unaltered in the GlnTPN group but in the STPN group it decreased. The addition of glutamine to parenteral nutrition prevents deterioration of gut permeability and preserves mucosal structure.
Selective uptake of glutamine in the gastrointestinal tract: confirmation in a human study
McAnena OJ, Moore FA, Moore EE, Jones TN, Parsons P. Br J Surg 1991;78:480-482
Recent animal data suggest that the gut plays a far more important metabolic role than previously thought. During critical illness, disruption in bowel barrier function may result in a chronic hypermetabolic state and contribute to multiorgan failure. Animal studies have demonstrated that enterocytes of the gastrointestinal tract use glutamine as a respiratory fuel and during critical illness the consumption of glutamine by the gut significantly increases. The selective uptake of glutamine by the gut, to date, has not been confirmed in humans. Seven patients who sustained multisystem trauma necessitating laparotomy underwent portal venous catheterization. This was done by carefully reopening the obliterated umbilical vein and facilitating access to the left branch of the portal vein using a standard central venous catheter. Portal venous and systemic blood samples were recorded for 5 days after operation. Amino acid levels in both circulations were recorded at 48 h and 5 days. Using Student's t test for related samples, the differences between individual amino acids in portal and systemic circulations were compared. At 48 h, mean(s.d.) portal venous glutamine was 85(5) per cent of the systemic levels (253(80) compared with 296(90) mumol/ml, P less than 0.002). At 5 days, portal glutamine was 87(3) per cent of the systemic levels (255(69) compared with 292(83) mumol/ml, P less than 0.003). Levels of citrulline, a breakdown product of glutamine metabolism, were elevated in the portal venous circulation at 48 h (20(4) compared with 16(3) mumol/ml, P less than 0.005) and at 5 days (21(5) compared with 14(3) mumol/ml, P less than 0.002). No significant differences between any of the other amino acids analyzed were identified. This study confirms, for the first time in humans, that selective uptake of glutamine occurs in the gut. In stressed states, glutamine deficiency is associated with gut mucosal atrophy. This has significant implications as glutamine is not provided in most commercially available parenteral and enteral nutrition formulations.
Is glutamine a conditionally essential amino acid?
Lacey JM, Wilmore DW. Nutr Rev 1990;48:297-309
The nonessential amino acid glutamine has recently been the focus of extensive scientific interest because of its importance in cell and tissue cultures and its physiologic role in animals and humans. Glutamine appears to be a unique amino acid, serving as a preferred respiratory fuel for rapidly proliferating cells, such as enterocytes and lymphocytes; a regulator of acid-base balance through the production of urinary ammonia; a carrier of nitrogen between tissues; and an important precursor of nucleic acids, nucleotides, amino sugars, and proteins. Abundant evidence suggests that glutamine may become a "conditionally essential" amino acid in the critically ill. During stress the body's requirements for glutamine appear to exceed the individual's ability to produce sufficient amounts of this amino acid. Provision of supplemental glutamine in specialized enteral or parenteral feeding may enhance nutritional management and augment recovery of the seriously ill while minimizing hospital stay.
Safety and metabolic effects of L-glutamine administration in humans
Ziegler TR, Benfell K, Smith RJ, et al. J Parenter Enteral Nutr 1990;14:137S-146S
A series of dose-response studies was conducted to evaluate the clinical safety, pharmacokinetics, and metabolic effects of L-glutamine administered to humans. Initial studies in normal individuals evaluated the short-term response to oral loads of glutamine at doses of 0, 0.1, and 0.3 g/kg. A dose-related increase in blood glutamine occurred after oral loading and elevation of amino acids known to be end products of glutamine metabolism occurred (including alanine, citrulline, and arginine). No evidence of clinical toxicity or generation of toxic metabolites (ammonia and glutamate) was observed. Glutamine was infused intravenously in normal subjects over 4 hr at doses of 0.0125 and 0.025 g/kg/hr. In addition, glutamine was evaluated as a component of parenteral nutrition solutions (0.285 and 0.570 g/kg/day) administered for 5 days to normal subjects. Intravenous administration of glutamine was well tolerated without untoward clinical or biochemical effects. Subsequent studies in patients receiving glutamine-enriched parenteral nutrition for several weeks confirmed the clinical safety of this approach in a catabolic patient population. In addition, nitrogen retention appeared to be enhanced when glutamine was administered at a dose of 0.570 g/kg/day in a balanced nutritional solution providing adequate calories (145% of basal) and protein (1.5 g/kg/day). Nitrogen balance in patients receiving lower doses of glutamine (0.285 g/kg/day) was similar to that in patients receiving standard formulations. Further controlled clinical trials of the metabolic efficacy, tolerance, and dose response of glutamine in other patient groups are necessary to determine the appropriate use of glutamine enrichment of nutrient solutions.
The role of glutamine in maintaining a healthy gut and supporting the metabolic response to injury and infection
Souba WW, Klimberg VS, Plumley DA, et al. J Surg Res 1990;48:383-391
In the critically ill surgical patient a variety of therapeutic maneuvers is required to maintain a "healthy gut." Provision of adequate amounts of glutamine to the gastrointestinal mucosa appears to be just one of these maneuvers. Other methods utilized to protect the gut from becoming a wound include: (a) minimizing additional systemic insults (such as hypotension, sepsis, multiple operative procedures); (b) aggressive pulmonary care; (c) the judicious use of antibiotics; and (d) aggressive enteral or parenteral feedings. The concept that the gut is an organ of quiescence following surgical stress merits reconsideration. The intestinal tract plays a central role in interorgan glutamine metabolism and is a key regulator of nitrogen handling following surgical stress. Critically ill patients are susceptible to developing gut-origin sepsis, the incidence of which will be diminished by instituting measures and providing treatments which support intestinal structure, function, and metabolism. Provision of glutamine-enriched diets to such patients may be one of these therapies.
Glutamine and cancer
Souba WW. Ann Surg 1993;218:715-728
OBJECTIVE: This overview on glutamine and cancer discusses the importance of glutamine for tumor growth, summarizes the alterations in interorgan glutamine metabolism that develop in the tumor-bearing host, and reviews the potential benefits of glutamine nutrition in the patient with cancer.
SUMMARY BACKGROUND DATA: Glutamine is the most abundant amino acid in the blood and tissues. It is essential for tumor growth and marked changes in organ glutamine metabolism are characteristic of the host with cancer. Because host glutamine depletion has adverse effects, it is important to study the regulation of glutamine metabolism in cancer and to evaluate the impact of glutamine nutrition in the tumor-bearing state.
METHODS: Data from a variety of investigations on glutamine metabolism and nutrition related to the host with cancer were compiled and summarized.
RESULTS: Numerous studies on glutamine metabolism in cancer indicate that many tumors are avid glutamine consumers in vivo and in vitro. As a consequence of progressive tumor growth, host glutamine depletion develops and becomes a hallmark. This glutamine depletion occurs in part because the tumor behaves as a "glutamine trap" but also because of cytokine-mediated alterations in glutamine metabolism in host tissues. Animal and human studies that have investigated the use of glutamine- supplemented nutrition in the host with cancer suggest that pharmacologic doses of dietary glutamine may be beneficial.
CONCLUSIONS: Understanding the control of glutamine metabolism in the tumor-bearing host not only improves the knowledge of metabolic regulation in the patient with cancer but also will lead to improved nutritional support regimens targeted to benefit the host.
Increased plasma bicarbonate and growth hormone after an oral glutamine load
Welbourne TC. Am J Clin Nutr 1995;61:1058-1061
An oral glutamine load was administered to nine healthy subjects to determine the effect on plasma glutamine, bicarbonate, and circulating growth hormone concentrations. Two grams glutamine were dissolved in a cola drink and ingested over a 20-min period 45 min after a light breakfast. Forearm venous blood samples were obtained at zero time and at 30-min intervals for 90 min and compared with time controls obtained 1 wk earlier. Eight of nine subjects responded to the oral glutamine load with an increase in plasma glutamine at 30 and 60 min before returning to the control value at 90 min. Ninety minutes after the glutamine administration load both plasma bicarbonate concentration and circulating plasma growth hormone concentration were elevated. These findings demonstrate that a surprisingly small oral glutamine load is capable of elevating alkaline reserves as well as plasma growth hormone.
Control of glycaemia.
Gerich JE. Baillieres Clin Endocrinol Metab 1993;7(3):551-86.
Maintenance of plasma glucose concentrations within a narrow range despite wide fluctuations in the demand (e.g. vigorous exercise) and supply (e.g. large carbohydrate meals) of glucose results from coordination of factors that regulate glucose release into and removal from the circulation. On a moment-to-moment basis these processes are controlled mainly by insulin and glucagon, whose secretion is reciprocally influenced by the plasma glucose concentration. In the resting postabsorptive state, release of glucose from the liver (equally via glycogenolysis and gluconeogenesis) is the key regulated process. Glycogenolysis depends on the relative activities of glycogen synthase and phosphorylase, the latter being the more important. The activities of fructose-1,6-diphosphatase, phosphoenolpyruvate carboxylkinase and pyruvate dehydrogenase regulate gluconeogenesis, whose main precursors are lactate, glutamine and alanine. In the postprandial state, suppression of liver glucose output and stimulation of skeletal muscle glucose uptake are the most important factors. Glucose disposal by insulin-sensitive tissues is regulated initially at the transport step and the mainly by glycogen synthase, phosphofructokinase and pyruvate dehydrogenase. Hormonally induced changes in intracellular fructose 2,6-bisphosphate concentrations play a key role in muscle glycolytic flux and both glycolytic and gluconeogenic flux in the liver. Under stressful conditions (e.g. hypoglycaemia, trauma, vigorous exercise), increased secretion of other hormones such as adrenaline, cortisol and growth hormone, and increased activity of the sympathetic nervous system, come into play; their actions to increase hepatic glucose output and to suppress tissue glucose uptake are partly mediated by increases in tissue fatty acid oxidation. In diabetes, the most common disorder of glucose homeostasis, fasting hyperglycaemia, results primarily from excessive release of glucose by the liver due to increased gluconeogenesis; postprandial hyperglycaemia results from both impaired suppression of hepatic glucose release and impaired skeletal muscle glucose uptake. These abnormalities are usually due to the combination of impaired insulin secretion and tissue resistance to insulin, the causes of which remain to be determined.
The role of the Crabtree effect and an endogenous fuel in the energy metabolism of resting and proliferating thymocytes.
Guppy M, Greiner E, Brand K. Eur J Biochem 1993;212(1):95-9.
Rat thymocytes have been used to characterize the changes in energy metabolism that occur as cells undergo a resting/proliferation transition. In the resting state, anaerobic ATP production accounts for only 4% of ATP turnover. The remainder is fueled by the oxidation of a mixture of an unidentified endogenous fuel (62%), glucose (18%) and glutamine (16%). 48 h after mitogen stimulation, the ATP turnover has increased twofold. In these proliferating cells, glucose inhibits oxygen consumption by 58%, indicating a profound Crabtree effect which is not present in resting cells. Consequently, proliferating cells, in the presence of glucose and glutamine, fuel the majority (61%) of ATP turnover anaerobically, producing lactate from glucose. The development of a Crabtree effect may be the result of the 8-10-fold increase in glycolytic enzyme activities which occurs with proliferation. Possible advantages of such a proliferative metabolism are a sparing of endogenous fuel, and a minimizing of oxidative metabolism, with its concurrent production of free radicals.
The role of growth hormone and cortisone on glucose and gluconeogenic substrate regulation in fasted hypopituitary children
Haymond MW, Karl I, Weldon VV, Pagliara AS. J Clin Endocrinol Metab 1976;42(5):846-56.
Panhypopituitarism may be associated with spontaneous hypoglycemia and marked insulin sensitivity. Five children with both growth hormone (GH) and adrenocorticotrophin (ACTH) insufficiency were studied in three periods: a) on no therapy; b) during cortisone acetate; and c) during GH and cortisone acetate replacement. With total caloric restriction prior to therapy, all patients became hypoglycemic (109 +/- 18 leads to 37 +/- 3.5 mg/dl, mean +/- SEM) and ketonemic (beta-hydroxybutyrate 0.10 +/-0.02 leads to 3.04 +/- 0.63 mM and acetoacetate 0.05 +/- .01 leads to 0.80 +/- 0.15 mM) within 30 hours. Glutamine and alanine concentrations fell with fasting (511 +/- 13 leads to 293 +/- 26 muM and 394 +/- 58 leads to 137 +/- 12 muM, respectively) but to levels lower than in normal children. However, only alanine was significantly lower (P less than 0.05). With cortisone plus GH therapy, fasting glycemia was improved (73 +/- 6 mg/dl) at 30 hours fasting and was associated with increased alanine and glutamine concentrations (206 +/- 28 muM and 448 +/- 40 muM, respectively) and less ketonemia (beta- hydroxybutyrate 1.13 +/-0.39 mM). Cortisone therapy alone resulted in intermediate improvement of these values. Only combined therapy resulted in increased lactate and pyruvate concentrations, which fell to normal with fasting. Fasting urinary ammonia excretion was unchanged whereas urea nitrogen excretion decreased significantly with therapy. The responses to alanine infusions following each study period in one patient were normal. The glycemic response to iv glucose was similar during each study period; however, post-prandial and glucose-stimulated insulin responses were increased with cortisone and cortisone plus GH therapy. We suggest that the hypoglycemia observed in hypopituitary patients is a substrate-mediated phenomenon, and that cortisone and growth hormone replacement therapy improve fasting glucose homeostasis, increase circulating alanine and glutamine concentrations, and decrease hepatic gluconeogenesis. These effects may be mediated through an increase in fat catabolism.
Low plasma glutamine in combination with high glutamate levels indicate risk for loss of body cell mass in healthy individuals: the effect of N- acetyl-cysteine.
Kinscherf R, Hack V, Fischbach T, Friedmann B, Weiss C, Edler L, Bartsch P, Droge W. J Mol Med 1996;74(7):393-400.
Skeletal muscle catabolism, low plasma glutamine, and high venous glutamate levels are common among patients with cancer or human immunodeficiency virus infection. In addition, a high glycolytic activity is commonly found in muscle tissue of cachectic cancer patients, suggesting insufficient mitochondrial energy metabolism. We therefore investigated (a) whether an "an-aerobic physical exercise" program causes similar changes in plasma amino acid levels, and (b) whether low plasma glutamine or high glutamate levels are risk factors for loss of body cell mass (BCM) in healthy human subjects, i.e., in the absence of a tumor or virus infection. Longitudinal measurements from healthy subjects over longer periods suggest that the age-related loss of BCM occur mainly during episodes with high venous glutamate levels, indicative of decreased muscular transport activity for glutamate. A significant increase in venous glutamate levels from 25 to about 40 microM was seen after a program of "anaerobic physical exercise." This was associated with changes in T lymphocyte numbers. Under these conditions persons with low baseline levels of plasma glutamine, arginine, and cystine levels also showed a loss of BCM. This loss of BCM was correlated not only with the amino acid levels at baseline examination, but also with an increase in plasma glutamine, arginine, and cystine levels during the observation period, suggesting that a loss of BCM in healthy individuals terminates itself by adjusting these amino acids to higher levels that stabilize BCM. To test a possible regulatory role of cysteine in this context we determined the effect of N-acetyl-cysteine on BCM in a group of subjects with relatively low glutamine levels. The placebo group of this study showed a loss of BCM and an increase in body fat, suggesting that body protein had been converted into other forms of chemical energy. The decrease in mean BCM/body fat ratios was prevented by N- acetyl-cysteine, indicating that cysteine indeed plays a regulatory role in the physiological control of BCM.
Regulation of protein metabolism during stress.
Matthews DE, Battezzati A. Curr Opin Gen Surg 1993;72-7:72-7.
Stress induces a hypermetabolic state of increased urinary nitrogen loss and increased metabolic rate. The principal reason for such a response is the mobilization of amino acids and the production of glucose to provide energy for the cells involved in the host immune response and wound repair. The endocrine hormones, eg, cortisol, the catecholamines, and glucagon, are largely responsible for these effects. Insulin and growth hormone administration can produce anabolic effects to block the loss of body protein. Administration of specific amino acids, such as glutamine, also appears to be beneficial. However, the hypermetabolic state goes beyond derangement of endocrine hormone levels. Although the cytokines are also important mediators, it is not clear how these mediators, in concert with hormonal changes, produce all of the manifestations of the hypermetabolic state seen in stress.
Recent developments in metabolism that impinge on research into the nature and treatment of diabetes mellitus
Newsholme EA. Diabetes Care 1992;15 (11):1716-20.
It has been established that adenosine, its agonists, or antagonists can cause dramatic changes in insulin sensitivity in isolated soleus muscle and, moreover, can modify changes in sensitivity caused by pathophysiological conditions. Addition of adenosine deaminase to the incubation medium, which is known to lower the concentration of adenosine, increases the sensitivity of glycolysis to insulin. Addition of an adenosine-receptor agonist decreases sensitivity by about 10- fold, whereas addition of an adenosine-receptor antagonist increases sensitivity by about 10-fold. The latter to glucose utilization to insulin in the isolated soleus muscle obtained from either the genetically obese rat or from the rat fed a high sucrose diet. These findings strongly support the view that changes in insulin sensitivity in muscle can be brought about either by acute changes in the local concentration of adenosine or in the affinity or number of receptors for adenosine in muscle. However, in many of the conditions investigated, in which insulin sensitivity in muscle is changed, there was no correlation between the change in the adenosine content of the muscle and altered insulin sensitivity. It has also been shown that prostaglandin E1 can increase dramatically the sensitivity of glycolysis to insulin and that this is a specific effect of prostaglandins of the E series. It is not produced by prostacyclins, thromboxanes, or leukotrienes. It is unclear if there is a relationship between the effects of adenosine and prostaglandins. Chronic elevation of catecholamines may increase the sensitivity of glucose utilization to insulin and also increase the rate of thermogenesis by substrate cycling.
Stimulatory effect of glutamine on glycogen accumulation in human skeletal muscle.
Varnier M, Leese GP, Thompson J, Rennie MJ. Am J Physiol 1995;269(2 Pt 1):E309-15.
To determine whether glutamine can stimulate human muscle glycogen synthesis, we studied in groups of six subjects the effect after exercise of infusion of glutamine, alanine+glycine, or saline. The subjects cycled for 90 min at 70-140% maximal oxygen consumption to deplete muscle glycogen; then primed constant infusions of glutamine (30 mg/kg; 50 mg.kg-1.h-1) or an isonitrogenous, isoenergetic mixture of alanine+glycine or NaCl (0.9%) were administered. Muscle glutamine remained constant during saline infusion, decreased 18% during alanine+glycine infusion (P < 0.001), but rose 16% during glutamine infusion (P < 0.001). By 2 h after exercise, muscle glycogen concentration had increased more in the glutamine-infused group than in the saline or alanine+glycine controls (+2.8 +/- 0.6, +0.8 +/- 0.4, and +0.9 +/- 0.4 mumol/g wet wt, respectively, P < 0.05, glutamine vs. saline or alanine+glycine). Labeling of glycogen by tracer [U-13C]glucose was similar in glutamine and saline groups, suggesting no effect of glutamine on the fractional rate of blood glucose incorporation into glycogen. The results suggest that, after exercise, increased availability of glutamine promotes muscle glycogen accumulation by mechanisms possibly including diversion of glutamine carbon to glycogen.