To compare glutamine and alanine as gluconeogenic precursors, we simultaneously measured their systemic turnovers, clearances, and incorporation into plasma glucose, their skeletal muscle uptake and release, and the proportion of their appearance in plasma directly due to their release from protein in postabsorptive normal volunteers. We infused the volunteers with [U-14C] glutamine, [3-`3C] alanine, [2H5] phenylalanine, and [6-3H] glucose to isotopic steady state and used the forearm balance technique. We found that glutamine appearance in plasma exceeded that of alanine (5.76+0.26 vs. 4.40+0.33 ,Amol kg-l mind, P < 0.001), while alanine clearance exceeded glutamine clearance (14.7±1.3 vs. 9.3+0.8 ml kg-1 min', P < 0.001). Glutamine appearance in plasma directly due to its release from protein was more than double that of alanine (2.45±0.25 vs.1.16+0.12 jAmol kg-'lmin', P < 0.001). Although overall carbon transfer to glucose from glutamine and alanine was comparable (3.53+0.24 vs 3.47+0.32 atoms kg-'mind'), nearly twice as much glucose carbon came from protein derived glutamine than alanine (1.48±0.15 vs 0.88+0.09 atoms-kg-l mind1, P < 0.01). Finally, forearm muscle released more glutamine than alanine (0.88±0.05 vs 0.48±0.05Amol 100 ml`-min -1, P < 0.01). We conclude that in postabsorptive humans glutamine is quantitatively more important than alanine for transporting protein-derived carbon through plasma and adding these carbons to the glucose pool. (J. Clin. Invest. 1995. 95:272-277.)

Gluconeogenesis is increased in NIDDM. We therefore examined the metabolism of glutamine and alanine, the most important gluconeogenic amino acids, in 14 postabsorptive NIDDM subjects and 18 nondiabetic volunteers using a combination of isotopic ([6-3H]glucose (20 microCi, 0.2 microCi/min), [U-14C]glutamine (20 microCi, 0.2 microCi/min), [3-13C]alanine (99% 13C, 2 mmol, 20 micromol/min), [ring-2H5]phenylalanine (99% 2H, 2 micromol/kg, 0.03 micromol x kg(-1) x min(-1)), and limb balance techniques. Alanine turnover (4.54 +/- 0.24 vs. 5.64 +/- 0.33 micromol x kg(-1) x min(-1)), de novo synthesis (3.00 +/- 0.25 vs. 4.01 +/- 0.33 micromol x kg(-1) x min(-1)), and conversion to glucose (1.02 +/- 0.09 vs. 1.56 +/- 0.17 micromol x kg(-1) x min(-1)) were increased in NIDDM subjects (all P < 0.01), while its forearm release (0.45 +/- 0.04 vs. 0.39 +/- 0.04 micromol x kg(-1) x min(-1)) was unaltered. Although glutamine turnover (4.81 +/- 0.23 vs. 4.40 +/- 0.31 micromol x kg(-1) x min(-1)) was unaltered in NIDDM, its conversion to glucose (0.57 +/- 0.04 vs. 1.08 +/- 0.10 micromol x kg(-1) x min(-1)) and to alanine (0.10 +/- 0.01 vs. 0.34 +/- 0.04 micromol x kg(-1) x min(-1)) (both P = 0.001) was increased while its oxidation (2.84 +/- 0.27 vs. 1.84 +/- 0.15 micromol x kg(-1) x min(-1), P = 0.03) and forearm release (0.77 +/- 0.05 vs. 0.62 +/- 0.09 micromol x kg(-1) x min(-1), P < 0.008) were both reduced. Our results thus demonstrate that there are substantial alterations of glutamine and alanine metabolism in NIDDM. Conversion of both amino acids to glucose and the proportion of their turnover used for gluconeogenesis are increased; release of both amino acids from tissues other than skeletal muscle seems to be increased. Finally, the reduction in glutamine oxidation, possibly the result of competition with glucose and free fatty acids as fuels, makes more glutamine available for gluconeogenesis without a change in its turnover.

There is evidence that glutamine may act as a regulator of protein, free fatty acid, and glycogen metabolism. To test the hypothesis that glutamine may act as a physiological regulator of gluconeogenesis, we infused 16 normal postabsorptive volunteers with glutamine at a rate (11.4 micromol kg(-1) x min(-1)) estimated to approximate its appearance in plasma after a protein meal and assessed changes in production of glucose from glutamine, systemic glucose appearance and disposal, and uptake and release of glucose, glutamine, and alanine by forearm skeletal muscle. Although infusion of glutamine increased plasma glutamine concentration and turnover only threefold (from 0.63 +/- 0.03 to 1.95 +/- 0.10 mmol/l and from 5.43 +/- 0.24 to 14.85 +/- 0.66 micromol x kg(-1) x min(-1), respectively; P < 0.001), formation of glucose from glutamine increased sevenfold from 0.55 +/- 0.03 to 3.74 +/- 0.28 micromol x kg(-1) x min(-1) (P < 0.001). Formation of glucose from alanine was also stimulated (0.52 +/- 0.05 vs. 0.75 +/- 0.04 micromol x kg(-1) x min(-1); P < 0.001) in the absence of a change in plasma alanine concentration. Furthermore, glutamine infusion decreased its own de novo synthesis (4.55 +/- 0.22 vs. 2.81 +/- 0.62 micromol x kg(-1) x min(-1);P < 0.02) while increasing that of alanine (2.82 +/- 0.32 vs. 3.56 +/- 0.32 micromol x kg(-1) x min(-1); P < 0.002). Systemic glucose appearance, systemic glucose disposal, and forearm balance of glucose and alanine were not altered. Because the stimulatory effects of glutamine on gluconeogenesis occurred in the absence of changes in plasma insulin and glucagon levels, these results provide evidence that, in humans, glutamine may act both as a substrate and as a regulator of gluconeogenesis as well as a modulator of its own metabolism.

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