Evidence for a Catabolic Role of Glucagon During an Amino Acid Load

Evidence for a catabolic role of glucagon during an amino acid load. M R Charlton, … , D B Adey, K S Nair J Clin Invest. 1996;98(1):90-99. https://doi.org/10.1172/JCI118782. Research Article Despite the strong association between protein catabolic conditions and hyperglucagonemia, and enhanced glucagon secretion by amino acids (AA), glucagon's effects on protein metabolism remain less clear than on glucose metabolism. To clearly define glucagon's catabolic effect on protein metabolism during AA load, we studied the effects of glucagon on circulating AA and protein dynamics in six healthy subjects. Five protocols were performed in each subject using somatostatin to inhibit the secretion of insulin, glucagon, and growth hormone (GH) and selectively replacing these hormones in different protocols. Total AA concentration was the highest when glucagon, insulin, and GH were low. Selective increase of glucagon levels prevented this increment in AA. Addition of high levels of insulin and GH to high glucagon had no effect on total AA levels, although branched chain AA levels declined. Glucagon mostly decreased glucogenic AA and enhanced glucose production. Endogenous leucine flux, reflecting proteolysis, decreased while leucine oxidation increased in protocols where AA were infused and these changes were unaffected by the hormones. Nonoxidative leucine flux reflecting protein synthesis was stimulated by AA, but high glucagon attenuated this effect. Addition of GH and insulin partially reversed the inhibitory effect of glucagon on protein synthesis. We conclude that glucagon is the pivotal hormone in amino acid disposal during an AA load and, by reducing the availability of AA, […] Find the latest version: https://jci.me/118782/pdf Evidence for a Catabolic Role of Glucagon during an Amino Acid Load Michael R. Charlton, Deborah B. Adey, and K. Sreekumaran Nair Endocrine Research Unit, Mayo Clinic and Foundation, Introduction Rochester, Minnesota 55905; and University of Vermont, Burlington, Glucagon has a well-defined role in glucose homeostasis. In Vermont 05405 contrast, glucagon’s effects on amino acid (AA)1 and protein metabolism are poorly defined. However, there is consider- Abstract able indirect evidence to suggest a catabolic role for glucagon in protein metabolism in humans. Hyperglucagonemia occurs Despite the strong association between protein catabolic in a variety of catabolic conditions. These include trauma, conditions and hyperglucagonemia, and enhanced glucagon burns, sepsis, cirrhosis, glucagonoma, the postoperative state, secretion by amino acids (AA), glucagon’s effects on protein and poorly controlled type I diabetes (1–5). In patients with metabolism remain less clear than on glucose metabolism. glucagonoma, in which glucose metabolism is only minimally To clearly define glucagon’s catabolic effect on protein me- disturbed, there is marked muscle wasting, skin atrophy, and tabolism during AA load, we studied the effects of glucagon hypoaminocidemia (6). In these patients there is a reduction of on circulating AA and protein dynamics in six healthy sub- free intracellular branched-chain amino acids (BCAA) in liver jects. Five protocols were performed in each subject using and muscle (7). It has been postulated that accelerated oxida- somatostatin to inhibit the secretion of insulin, glucagon, tion of BCAA is a cause of their decreased intracellular con- and growth hormone (GH) and selectively replacing these centrations. We have demonstrated previously that high gluca- hormones in different protocols. Total AA concentration gon levels, during insulin deficiency, are associated with an was the highest when glucagon, insulin, and GH were low. increase in leucine oxidation in healthy human volunteers (8). Selective increase of glucagon levels prevented this incre- Given that leucine is not directly involved in gluconeogenesis, ment in AA. Addition of high levels of insulin and GH to this accelerated oxidation of leucine in the setting of hyperglu- high glucagon had no effect on total AA levels, although cagonemia is an especially important finding. In addition, a de- branched chain AA levels declined. Glucagon mostly de- cline in the elevation of glucogenic amino acids that is seen in creased glucogenic AA and enhanced glucose production. pancreatectomized patients occurs with glucagon replacement Endogenous leucine flux, reflecting proteolysis, decreased (9). A catabolic role for glucagon, mainly to incoming protein, while leucine oxidation increased in protocols where AA has been proposed (10). were infused and these changes were unaffected by the hor- In normal physiology, protein meals, with their attendant mones. Nonoxidative leucine flux reflecting protein synthe- amino acid loads, stimulate glucagon, growth hormone, and in- sis was stimulated by AA, but high glucagon attenuated this sulin secretion. It is believed that the purpose of the amino- effect. Addition of GH and insulin partially reversed the in- genic glucagon release is, by stimulating hepatic glucose pro- hibitory effect of glucagon on protein synthesis. We con- duction, to avert hypoglycemia resulting from the concomitant clude that glucagon is the pivotal hormone in amino acid insulin secretion (11, 12). It has been proposed that glucagon is disposal during an AA load and, by reducing the availability involved in the disposal of amino acids after a protein meal. of AA, glucagon inhibits protein synthesis stimulated by Furthermore, glucagon has been reported to increase the dis- AA. These data provide further support for a catabolic role posal of amino acids during mixed amino acids infusions (13). of glucagon at physiological concentrations. (J. Clin. Invest. Direct evidence for and the mechanism of this reported effect 1996. 98:90–99.) Key words: glucagon • protein synthesis • have not yet been elucidated. amino acids • leucine kinetics • glucose The current studies were designed to test the hypotheses that glucagon plays a critical role in the disposal of amino acids during an amino acid load and to determine the mechanism of this AA disposal by performing simultaneous measurement of amino acid concentrations, whole body protein turnover, and glucose kinetics. Address correspondence to K. Sreekumaran Nair, M.D., Ph.D., Mayo Clinic, 200 First Street SW, Endocrine Research Unit, Roches- Methods ter, MN 55905. Phone: 507-255-6515; FAX: 507-255-4828; E-mail: [email protected] Subjects Received for publication 13 February 1996 and accepted in revised We studied six healthy adult volunteers (three male and three fe- form 12 April 1996. male). Age was 22.4 yr (19–25 range), weight 67.8 kg (SEMϮ5.92 kg), and height 165.1 (SEMϮ4.52 cm). All volunteers were within 10% of 1. Abbreviations used in this paper: AA, amino acids; BCAA, ideal body weight for height and were screened by detailed history, branched-chain amino acids; I, insulin; KIC, ketoisocaproic acid; physical examination, and biochemical profile (urine and blood) for SRIH, somatostatin. any overt illness. Subjects on any regular medications were excluded. Studies involving women volunteers were always carried out during The Journal of Clinical Investigation the luteal phase of the menstrual cycle. Volume 98, Number 1, July 1996, 90–99 90 Charlton et al. ketoisocaproic acid (KIC) values obtained from arterial blood (15). A second 18-gauge catheter was placed in the contralateral forearm for infusions. Once baseline blood and expired air samples were obtained, bolus doses of 13C-sodium bicarbonate (1.5 ␮mol/kg) and l-[1-13C]leucine (7.5 ␮mol/kg) were given to prime the respective pools to achieve early isotopic plateaus (16, 17). After isotope boluses had been administered and continuous infusion of l-[1-13C]leucine at a rate of 7.5 ␮mol/kg/h had begun, an infusion of normal saline at a rate of 1.5 ml/kg/h was initiated for the first 2 h of each study. After 2 h of each study, one of the following five infusion protocols was begun and continued for 4 h until completion of the study. A schema for the five protocols is shown in Fig. 1. Protocol I: Mixed amino acids infusion (AA). Infusion of mixed amino acids (Aminosyn 15%; Abbott Laboratories, Chicago, IL) was started at a rate of 1.5 ml/kg/h. This proprietary mixture of amino acids contained the following amino acids in the concentrations shown (mg/100 ml): isoleucine 990, leucine 1,500, lysine 1,575, methionine 258, phenylalanine 447, threonine 600, tryptophan 300, valine 750, alanine 1,490, arginine 1,527, histidine 450, proline 1,083, serine 795, tyrosine 405, glycine 750, glutamic acid 1,107, aspartic acid 1,050. No cysteine, glutamine, asparagine, or taurine was present in the prepa- ration. In addition, sodium 62.7 meq/liter and acetate 107.6 meq/liter were present. Protocol II: AA ϩ somatostatin (SRIH) ϩ basal replacement levels Figure 1. AA’s, mixed amino acid infusion at a rate of 1.5 ml/kg/h of growth hormone, insulin (I), and glucagon. This comprised mixed (Aminosyn 15%); SRIH, 500 ␮g/h; GH, human growth hormone (re- amino acids at a rate of 1.5 ml/kg/h, as above. In addition, concomi- placement dose ϭ 0.5 ␮g/kg/h, high dose ϭ 1.0 ␮g/kg/h); I, regular in- tant infusions of SRIH (Stilamin; Serono Laboratories, Randolph, sulin (replacement dose ϭ 0.10 mU/kg/min, high dose ϭ 0.4 mU/kg/ MA) at a rate of 500 ␮g/h, recombinant human growth hormone (Gen- min); GGON, glucagon (replacement dose ϭ 1.0 ng/kg/min, high entech, South San Francisco, CA) at a rate of 0.5 ␮g/kg/h, insulin at a dose ϭ 6.0 ng/kg/min). Indirect calorimetry was obtained between rate of 0.10 mU/kg/min, and glucagon at a rate of 1.0 ng/kg/min. 300 and 330 min. Normal saline was infused at a rate of 1.5 ml/kg/h Protocol III: AA ϩ SRIH ϩ basal replacement levels of growth for the first 2 h of all five protocols.

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