Leucine metabolism in chronically hypoglycemic hypoinsulinemic growth-restricted fetal sheep

We measured leucine flux rates during infusions of L-[1-C-14]- and L-[1-C-13]leucine in fetal sheep exposed to maternal insulin-induced hypoglycemia over the last 8 wk (40%) of gestation to determine effects of chronic glucose deficiency and hypoglycemia on fetal leucine metabolism. Compared with control fetuses (C, n = 5), hypoglycemic fetuses (HG, n = 8) weighed less (C, 3.43 +/- 0.07 kg; HG, 2.32 +/- 0.24 kg), had lower plasma glucose (C, 1.04 +/- 0.02 mM; HG, 0.59 +/- 0.01 mM), insulin (C, 48 +/- 6 pM; HG, 12 +/- 6 pM), and leucine concentrations (C, 195.6 +/- 8.3 mu M; HG, 140.8 +/- 15.0 mu M), lower rates of net leucine uptake (C, 4.2 +/- 0.6 mu mol . min(-1) . kg(-1); HG, 2.1 +/- 0.4 mu mol . min(-1) . kg(-1)) and leucine flux into protein accretion (C, 2.8 +/- 0.2 mu mol . min(-1) . kg(-1); HG, 0.6 +/- 0.1 mu mol . min(-1) . kg(-1)), and an increased rate of leucine release from protein breakdown (C, 1.1 +/- 0.1 mu mol . min(-)1 . kg(-1); HG, 3.3 +/- 0.2 mu mol . min(-1) . kg(-1)) (P < 0.05 for all). Plasma leucine disposal, flux into protein synthesis, and oxidation were not different between groups. We conclude that adaptations of fetal leucine metabolism to long-term hypoglycemia and decreased glucose supply represent diminished leucine uptake and increased leucine release from protein breakdown, which are associated with decreased incorporation of leucine into protein accretion and a slower rate of fetal growth.