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

Abstract

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

“…All mouse samples (milk and brain tissue) were left-over samples from a previous study, which was conducted following institutional guidelines for the care and use of laboratory animals at the University of Groningen [ 3 ]. All animal procedures related to the purpose of the research were approved by the local Animal Welfare Body under an Ethical license provided by the national competent authority (Centrale Commissie Dierproeven, CCD, #AVD1050020185445), securing full compliance with the European Directive 2010/63/EU for the use of animals for scientific purposes.…”

“…Breast milk is considered an optimal feeding source for newborns and contains various nutrients and biological active factors important for growth and development [ [1] , [2] ]. Human milk oligosaccharides (hMOS) are human milk's most abundant bioactive factors, with concentrations of more than 20 g/L in colostrum and around 7–15 g/L in mature milk [ 3 ]. The structures of hMOS are complex and more than 160 hMOS have been structurally characterized [ [4] , [5] , [6] ].…”

“…We further propose that altered Sia levels in milk may influence brain Sia levels. In the current study, we made use of a lean GDM mouse model that combines multiple low-dose streptozotocin (STZ) injections prior to pregnancy with short-term, high-fat (HF)-feeding as previously described [ 3 ]. Other lean mouse models use STZ injections during pregnancy [ 32 ].…”

“…Other lean mouse models use STZ injections during pregnancy [ 32 ]. This approach results in insulin-sensitive, lean GDM dams [ 3 ]. In this study, we aimed to (i) characterize quantitative profiles of mMOS and Sia concentrations in mouse milk and the offspring brain; (ii) identify whether maternal HIP (PDM/GDM) affects the bioactive components in mouse milk (oligosaccharides and Sia) and whether that influences Sia content in the brain of offspring.…”

Xylooligosaccharides ameliorate insulin resistance by increasing Akkermansia muciniphila and improving intestinal barrier dysfunction in gestational diabetes mellitus mice

“…The BW and fasting blood glucose levels were determined again. Then, the pregnant mice in the 3rd and 4th groups were intraperitoneally injected with low dosage (30 mg per kg BW) of streptozotocin (STZ) once a day for a continuous 3 days to induce the GDM pathogenesis, 17,18 while those in the 2nd group were intraperitoneally injected with normal saline (NS). The BW and random blood glucose (RBG) of all mice were then measured (Day 3).…”