Whole Body De Novo Amino Acid Synthesis in Type I (Insulin-dependent) Diabetes Studied With Stable Isotope-labeled Leucine, Alanine, and Glycine

Dynamic aspects of whole body alanine and glycine metabolism have been explored in insulin-dependent (type I) diabetic subjects. Using a primed, continuous intravenous (i.v.) infusion of [²H₃]alanine and [¹⁵N] glycine given simultaneously with [1-¹³C] leucine, whole body alanine and glycine fluxes and their rates of de novo synthesis were measured in 6 diabetic young men. Subjects were studied in the postabsorptive state, after blood glucose was clamped overnight at 15.2 ± 0.3 mM, and then, on the following night, at 5.9 ± 0.2 mM (insulin infusion rates of 0.24 ± 0.09 and 1.65 ± 0.20 U/h, respectively). In the normoglycemic state, leucine, alanine, and glycine fluxes averaged 88 ± 4, 378 ± 39, and 155 ± 8 μmol · kg⁻¹ · h⁻¹ respectively. Based on the leucine flux, alanine and glycine de novo synthesis rates were 264 ± 36 and 67 ± 8 ftmol · kg⁻¹ · h⁻¹. In the hyperglycemic state, leucine flux increased 23% (P < 0.01), alanine flux rose slightly (+ 5%) but significantly (P < 0.05), while alanine de novo synthesis and glycine flux remained unchanged and glycine de novo synthesis decreased by 33% (P < 0.001). These results show that small alterations in peripheral alanine inflow in the hyperglycemic state reflect increased proteolysis and suggest that increased circulating plasma glucose does not contribute to de novo alanine synthesis in the absence of adequate insulin effect and/or augmented glucose tissue uptake. These observations also reveal the importance of insulin in the maintenance of whole body leucine economy, since a lower rate of insulin administration was associated with an increased rate of leucine oxidation.