Glutamine and Alanine Metabolism in NIDDM

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 µCi, 0.2 µCi/min), [U-¹⁴C]glutamine (20 µCi, 0.2 µCi/min), [3-¹³C]alanine (99% ¹³C, 2 mmol, 20 µmol/min), [ring-²H₅]phenylalanine (99% ²H, 2 µmol/kg, 0.03 µmol · kg^-1 · min^-1), and limb balance techniques. Alanine turnover (4.54 ± 0.24 vs. 5.64 ± 0.33 µmol · kg^-1 · min^-1), de novo, synthesis (3.00 ± 0.25 vs. 4.01 ± 0.33 µmol · kg^-1 · min^-1) were increased in NIDDM subjects (all P < 0.001), while its forearm release (0.45 ± 0.04 vs. 0.39 ± 0.04 µmol · kg^-1 · min^-1) was unaltered. Although glutamine turnover (4.81 ± 0.23 vs. 4.40 ± 0.31 µmol · kg^-1 · min^-1) was unaltered in NIDDM, its conversion to glucose (0.57 ± 0.04 vs. 1.08 ± 0.10 µmol · kg^-1 · min^-1) and to alanine (0.10 ± 0.01 vs. 0.34 ± 0.04 µmol · kg^-1 · min^-1) (both P = 0.001) was increased while its oxidation (2.84 ± 0.27 vs. 1.84 ± 0.15 µmol kg^-1 · min^-1 P = 0.03) and forearm release (0.77 ± 0.05 vs. 0.62 ± 0.09 µmol · kg^-1 · 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.