Coordinated changes in hepatic amino acid metabolism and endocrine signals support hepatic glucose production during fetal hypoglycemia

Abstract

Houin SS, Rozance PJ, Brown LD, Hay WW Jr, Wilkening RB, Thorn SR. Coordinated changes in hepatic amino acid metabolism and endocrine signals support hepatic glucose production during fetal hypoglycemia. Am J Physiol Endocrinol Metab 308: E306 -E314, 2015. First published December 17, 2014 doi:10.1152/ajpendo.00396.2014.-Reduced fetal glucose supply, induced experimentally or as a result of placental insufficiency, produces an early activation of fetal glucose production. The mechanisms and substrates used to fuel this increased glucose production rate remain unknown. We hypothesized that in response to hypoglycemia, induced experimentally with maternal insulin infusion, the fetal liver would increase uptake of lactate and amino acids (AA), which would combine with hormonal signals to support hepatic glucose production. To test this hypothesis, metabolic studies were done in six late gestation fetal sheep to measure hepatic glucose and substrate flux before (basal) and after [days (d)1 and 4] the start of hypoglycemia. Maternal and fetal glucose concentrations decreased by 50% on d1 and d4 (P Ͻ 0.05). The liver transitioned from net glucose uptake (basal, 5.1 Ϯ 1.5 mol/min) to output by d4 (2.8 Ϯ 1.4 mol/min; P Ͻ 0.05 vs. basal). The [U-13 C]glucose tracer molar percent excess ratio across the liver decreased over the same period (basal: 0.98 Ϯ 0.01, vs. d4: 0.89 Ϯ 0.01, P Ͻ 0.05). Total hepatic AA uptake, but not lactate or pyruvate uptake, increased by threefold on d1 (P Ͻ 0.05) and remained elevated throughout the study. This AA uptake was driven largely by decreased glutamate output and increased glycine uptake. Fetal plasma concentrations of insulin were 50% lower, while cortisol and glucagon concentrations increased 56 and 86% during hypoglycemia (P Ͻ 0.05 for basal vs. d4). Thus increased hepatic AA uptake, rather than pyruvate or lactate uptake, and decreased fetal plasma insulin and increased cortisol and glucagon concentrations occur simultaneously with increased fetal hepatic glucose output in response to fetal hypoglycemia.

Chronic anemic hypoxemia increases plasma glucagon and hepatic PCK1 mRNA in late-gestation fetal sheep

“…These results show that fetal anemic hypoxemia is sufficient to stimulate and sustain increases in factors that are associated with activation of both gluconeogenesis and glycogenolysis. Furthermore, these results demonstrate that fetal hypoglycemia (a hallmark of PI-IUGR) is not necessary for this response, even though it can, by itself, lead to fetal HGP (21). Supporting this conclusion is our finding that exposure to either 3% oxygen or glucogenic activators (cAMP ϩ dexamethasone) increases expression of PCK1 and PGC1A in isolated fetal hepatocytes.…”

Role of placental insufficiency and intrauterine growth restriction on the activation of fetal hepatic glucose production

“…It is delivered to the fetus by facilitated diffusion across the placenta according to its maternal-fetal concentration gradient (Hay et al, 1990), eliminating the need for endogenous hepatic glucose production (HGP) by the fetus (Hay et al, 1984). Indeed, studies using catheters across the liver in normal fetal sheep have shown that there is net hepatic glucose uptake, rather than hepatic glucose output (Houin et al, 2015, Teng et al, 2002, Timmerman et al, 2000). The absence of fetal hepatic glucose output is advantageous for the fetus as it helps maintain the maternal-fetal glucose concentration gradient and transfer of maternally derived glucose to the fetus (Thureen et al, 1992).…”

“…Similar to the IUGR fetus, the hypoglycemic fetus increases fetal HGP and hepatic gluconeogenic gene activation (DiGiacomo and Hay, 1989, DiGiacomo and Hay, 1990, Fowden and Forhead, 2012, Hay et al, 1981, Narkewicz et al, 1993, Rozance et al, 2008, Thorn et al, 2012). Acute hypoglycemia can also activate HGP, as HGP has been directly measured using hepatic catheterization as evidenced by net hepatic glucose output, rather than uptake, following hypoglycemia for 4 d (Houin et al, 2015). …”

Endocrine And Metabolic Adaptations Of Calves To Extra-Uterine Life

“…Thus it seems that mobilization of glycogen is a key mechanism that contributes to the short-term fetal glucose regulation. On the other hand, gluconeogenesis, regulated by glucagon, does not play a signifi cant part in fetal glucose homeostasis, although such a mechanism would be possible due to the large increase in amino acid catabolism observed during prolonged fasting [100].…”