We compared fetal glucose- and arginine-stimulated insulin secretion (delta I, pM) among four groups of pregnant sheep after 10-11 days of different maternal glycemic patterns: 1) control, euglycemic; 2) low-level basal plus "pulsatile" hyperglycemic (PHG group); 3) markedly hyperglycemic (HG) group); 4) markedly hypoglycemic (LG group). Mean delta I during a hyperglycemic clamp was greatest in the PHG group (190 +/- 28 pM, P < 0.01) and least in the HG (64 +/- 13 pM, P < 0.05) and LG groups (68 +/- 15 pM, P < 0.05) compared with the control group (126 +/- 18 pM). After an arginine bolus, insulin concentration was greater in the PHG group at two of four sampling times over 30 min compared with the control group and at all times compared with the HG and LG groups. The trend in mean delta I over the postarginine sampling period (PHG 1,092 +/- 114 pM; control 921 +/- 86 pM; HG897 +/- 117 pM; LG831 +/- 57 pM) was in the same direction as for glucose and was significant (P < 0.05). Thus glucose-stimulated fetal insulin secretion is regulated by the duration and pattern, as well as the magnitude, of maternal and fetal hyperglycemia; this regulation may also extend to insulin-secretion capacity.

To determine the gestational maturation of fetal insulin response to glucose and arginine and the effects of sustained hyperglycemia on these processes, we measured insulin secretion in different groups of fetal sheep at 75, 100, 122, and 137 days of gestation (50, 67, 81, and 91% of term gestation, respectively). The basal glucose concentration decreased progressively from 1.36 ± 0.16 mM at 75 days to 1.00 ± 0.07 mM at 137 days (p < 0.05). The fetal plasma insulin concentration did not change (54 ± 11 pM at 75 days, 68 ± 8 pM at 137 days), but there was a significant increase in the increment in plasma insulin concentration in response to a hyperglycemic clamp over this same period (ΔI pM/ΔG mM) from 20 ± 3 at 75 days to 105 ± 8 at 137 days (p < 0.001). The ΔI (pM) in response to arginine also increased from 129 ± 17 pM at 75 days to 635 ± 103 pM at 137 days (p < 0.001). Sustained hyperglycemia from 90 to 100 days reduced the ΔI (pM)/ΔG (mM) to glucose (13 ± 2, p < 0.01) and the ΔI pM to arginine (369 ± 86, p < 0.05) to values less than those found in euglycemic animals (ΔI/ΔG = 58 ± 4 to glucose, ΔI = 525 ± 71 to arginine). Thus, glucose and arginine stimulate insulin secretion at midgestation at 20% of the rate near term, and there is a consistently positive developmental pattern of insulin secretion to these secretagogues over the second half of gestation. Furthermore, chronic, high, relatively constant hyperglycemia blunts insulin secretion to glucose and arginine close to midgestation, similar to the effect seen near term. Such developmental and adaptive capacities may account for an important part of the variability in fetal glucose metabolism observed in animal models and human cases of diabetes during pregnancy.

To test the hypothesis that glucose supply to the uteroplacenta (UP) regulates UP glucose metabolism into oxidative and nonoxidative pathways, we studied eight late-gestation pregnant sheep at low (LG) and high (HG) maternal glucose concentrations (G(M)), using Fick principle and tracer glucose methodology. UP glucose consumption (UPGC) correlated directly with G(M) (r = 0.75, P = 0.0006), and UP glucose decarboxylation (r = 0.80, P = 0.0001), and lactate production (r = 0.90, P = 0.0001) rates were directly correlated with UPGC. The combined fractional production rate for lactate, fructose, and CO(2) from UPGC was the same in LG and HG periods. The fraction of UP oxygen consumption used for glucose oxidation increased by about 50% from LG to HG conditions; however, there was no change in UP oxygen consumption. Nearly half of UPGC was not accounted for by lactate, fructose, and CO(2) production, and about two-thirds of UP oxygen consumption was not accounted for by immediate oxidation of glucose carbon just taken up by the UP. These results indicate that glucose supply directly regulates UP glucose oxidative metabolism and that there is a reciprocal relationship between UP glucose oxidation and the oxidation of other substrates.

No abstract

We examined the rate of production of [14C]fructose and [14C]lactate from [U-14C]glucose by the placenta and the contribution of 14CO2 from fetal oxidation of these metabolic products to the calculation of glucose oxidation rate in fetal sheep. During fetal tracer infusions (n = 16), oxidation of fructose contributed 16 +/- 3% of total fetal CO2 production; oxidation of lactate accounted for 3.3 +/- 0.1%. Thus 80% of total fetal CO2 production resulted from direct oxidation of carbon atoms in glucose; the "direct" glucose oxidation fraction was 0.46 +/- 0.04. During maternal tracer infusion (n = 15), CO2 production from fructose was 21 +/- 3, 20 +/- 3, and 30 +/- 4% and from lactate was 16 +/- 3, 13 +/- 3, and 11 +/- 4% in hypo-, normo-, and hyperglycemic animals, respectively; the direct glucose oxidation fraction was 0.40 +/- 0.04, not different from the fraction obtained with the fetal tracer infusion. Fetal oxidation of substrates derived from glucose metabolism in the placenta contributes significantly to fetal CO2 production. Fetal oxidation of placental products of a metabolic substrate tracer should be considered in studies of fetal oxidative metabolism.