Hyperglycaemia, pregnancy outcomes and maternal metabolic disease risk during pregnancy and lactation in a lean gestational diabetes mouse model.

Hyperglycaemia in pregnancy (HIP) is a pregnancy complication characterized by mild to moderate hyperglycaemia that negatively impacts short- and long-term health of mother and child. However, relationships between severity and timing of pregnancy hyperglycaemia and postpartum outcomes have not been systemically investigated. We investigated the impact of hyperglycaemia developing during pregnancy (gestational diabetes mellitus, GDM) or already present pre-mating (pre-gestational diabetes mellitus, PDM) on maternal health and pregnancy outcomes. GDM and PDM were induced in C57BL/6NTac mice by combined 60% high fat diet (HF) and low dose streptozotocin (STZ). Animals were screened for PDM prior to mating, and all underwent an oral glucose tolerance test on gestational day (GD)15. Tissues were collected at GD18 or at postnatal day (PN)15. Among HFSTZ-treated dams, 34% developed PDM and 66% developed GDM, characterized by impaired glucose-induced insulin release and inadequate suppression of endogenous glucose production. No increased adiposity or overt insulin resistance was observed. Furthermore, markers of non-alcoholic fatty liver disease (NAFLD) were significantly increased in PDM at GD18 and were positively correlated with basal glucose levels at GD18 in GDM dams. By PN15, NAFLD markers were also increased in GDM dams. Only PDM affected pregnancy outcomes such as litter size. Our findings indicate that GDM and PDM, resulting in disturbances of maternal glucose homeostasis, increase the risk of postpartum NAFLD development, related to the onset and severity of pregnancy hyperglycaemia. These findings signal a need for earlier monitoring of maternal glycaemia and more rigorous follow-up of maternal health after GDM and PDM pregnancy in humans. KEY POINTS: We studied the impact of high-fat diet/streptozotocin induced hyperglycaemia in pregnancy in mice and found that this impaired glucose tolerance and insulin release. Litter size and embryo survival were compromised by pre-gestational, but not by gestational, diabetes. Despite postpartum recovery from hyperglycaemia in a majority of dams, liver disease markers were further elevated by postnatal day 15. Maternal liver disease markers were associated with the severity of hyperglycaemia at gestational day 18. The association between hyperglycaemic exposure and non-alcoholic fatty liver disease signals a need for more rigorous monitoring and follow-up of maternal glycaemia and health in diabetic pregnancy in humans.

Characterization of milk oligosaccharide and sialic acid content and their influence on brain sialic acid in a lean mouse model for gestational diabetes.

Oligosaccharides and sialic acids (Sia) are bioactive components in milk that contribute to newborn development and health. Hyperglycemia in pregnancy (HIP) can have adverse effects on both mother and infant. HIP is associated with low-grade systemic inflammation. Inflammation influenced glycan composition, particularly of Sia-containing structures. We hypothesize that HIP and high-fat diet influence milk oligosaccharide composition, particularly sialylated oligosaccharides. Furthermore, we propose that milk Sia content influences pup brain Sia content. To test these hypotheses we (i) characterize mouse milk oligosaccharides and Sia concentrations in mouse milk of a GDM mouse model with dietary fat intake intervention; and (ii) determine Sia levels in offspring brains. The concentrations of oligosaccharides and Sia in mouse milk and offspring's brains were quantified using UPLC-FLD analysis. Analyses were performed on surplus samples from a previous study, where HIP was induced by combining high-fat diet (HF) feeding and low-dose streptozotocin injections in C57Bl/6NTac female mice. The previous study described the metabolic effects of HIP on dams and offspring. We detected 21 mouse milk oligosaccharides, including 9 neutral and 12 acidic structures using UPLC-MS. A total of 8 structures could be quantified using UPLC-FLD. Maternal HIP and HF diet during lactation influenced sialylated oligosaccharide concentrations in mouse milk and total and free sialic acid concentrations. Sia content in offspring brain was associated with total and free Neu5Gc in mouse milk of dams, but no correlations with HIP or maternal diet were observed.

Prenatal Amino Acid Supplementation to Improve Fetal Growth: A Systematic Review and Meta-Analysis.

Aberrant fetal growth remains a leading cause of perinatal morbidity and mortality and is associated with a risk of developing non-communicable diseases later in life. We performed a systematic review and meta-analysis combining human and animal studies to assess whether prenatal amino acid (AA) supplementation could be a promising approach to promote healthy fetal growth. PubMed, Embase and Cochrane libraries were searched to identify studies orally supplementing the following AA groups during gestation: (1) arginine family; (2) branched chain (BCAA); (3) methyl donors. Primary outcome was fetal/birth weight. 22 human and 89 animal studies were included in the systematic review. The arginine family, and especially arginine itself, was studied most. Our meta-analysis showed beneficial effects of arginine and (N-Carbamyl) glutamate (NCG), but not aspartic acid and citrulline on fetal/birth weight. However, no effects were reported when isonitrogenous control diet was included. BCAA and methyl donor supplementation did not affect fetal/birth weight. Arginine family supplementation, in particular arginine and NCG, improves fetal growth in complicated pregnancies. BCAA and methyl donor supplementation do not seem to be as promising to target fetal growth. Well controlled research in complicated pregnancies is needed before ruling out AA supplements or preferring arginine above other AAs.