The effects of hypoxia on gestational diabetes mellitus in mice

Abstract

Hypoxia and oxygen sensing are mechanisms which play important roles in many physiological processes like the generation of new blood vessels, production of red blood cells, fetal development as well as in pathophysiological processes like chronic renal failure and cancer. Especially since the Nobel Prize in Physiology or Medicine 2019 was awarded to William G. Kaelin, Gregg L. Semenza and Peter J. Ratcliffe working on this specific topic a broader range of people became aware of its importance. (The Nobel Prize in Physiology or Medicine 2019 — Press release n.d.). In terms of pregnancy hypoxia is the most important determining factor when it comes to duration of gestation and the second most important in birth weight (Krampl 2002)(Jensen and Moore 1997). It is estimated that for every 1000m above sea level the average fetal birth weight decreases by 100g (Soria et al. 2013). Gestational diabetes mellitus (GDM) is defined as a state hyperglycaemia of any degree which is first recognized in pregnant women. (Menke, Casagrande, and Cowie 2018). It has a worldwide prevalence ranging from 6.1 to 30% and has lots of short- and long-term consequences like fetal overgrowth and a higher risk of getting the metabolic syndrome in later life of the child. Because of the observed opposing effects of hypoxia and GDM during pregnancy, we investigated whether hypoxia will ameliorate the GDM symptoms in pregnant mice with insulin resistance. To study the effects of hypoxia on GDM in mice, obesity was induced by feeding 4-months-old C57BL/6N dams with an obesogenic diet for 7 weeks before and throughout pregnancy. Mice fed a normal chow (NC) served as control. Animals were bred following an established protocol and were marked at day E 0.5 after mating which was considered as the beginning of pregnancy. The groups were housed either in normoxic conditions (O2 ≈ 21 %) or in normobaric hypoxia (O2 = 15 %, this corresponds to oxygen tension at 2700m altitude) during gestation; mice were sacrificed at E 9.5 (mid pregnancy) as well as in a second experiment with the same setup at E 17.5 (end pregnancy). General measurements of the dams like weight gain or embryo number were taken as well as metabolites from the lipid and glucose metabolism. On expression level was also checked for genes which play a role in hypoxia response or glucose metabolism. Central findings of the present studies were that the obesogenic diet affected the mice which could be shown through many altered parameters in mid- and in late-pregnancy like elevated serum cholesterol levels or liver triglyceride levels as well as increased insulin resistance. Concerning the effect of hypoxia on obesogenic mice a clear compensating effect of the altered parameters in the H/OD group could not be shown in mid- as well as in late-pregnancy. Due to mating problems with the mice during this study in late-pregnancy the group sizes and other parameters were not as consistent as anticipated, this makes comparison and interpretation of the present results more difficult. Part of the experiments should be repeated and further research needs to be done in order to get a better insight in the underlying mechanisms.