Abstract
Numerous changes occur during pregnancy to accommodate the demands for fetal growth and development, including alterations in glucose, lipid and bile acid metabolism. Gestational diabetes mellitus (GDM) is a pathological condition that is becoming increasingly prevalent every year, increasing in frequency worldwide and affecting people of all backgrounds. There is limited understanding of the pathophysiology and progression of GDM, and improved treatments are needed.This thesis hypothesises that the metabolites progesterone sulphates and bile acids influence glucose metabolism, thereby having a role in the development of GDM. Serum samples from four cohorts of women were used to assess this. Three cohorts (Cohorts 1, 2, 4) were derived from the third trimester and were either GDM or non-GDM, with cohort 4 also being separated by ethnicity (European or South Asian) and BMI (normal and obese). Cohort 3 comprised serum samples obtained from women in the first trimester who either went onto develop GDM or have uncomplicated pregnancies. Cohort 3 was also divided into low (≤25 kg/m2) and high (≥35 kg/m2) BMI. Additional experiments using in vitro studies of islets obtained from mouse and humans were performed to assess how glucose stimulated insulin secretion (GSIS) is affected by metabolites that were altered in GDM, and calcium signalling experiments further evaluated mechanisms of action.
Compared to non-GDM women, some progesterone sulphates were lowered in women diagnosed with GDM in the third trimester. Epiallopregnanolone sulphate (PM5S) was also reduced in the first trimester of women that subsequently developed GDM in the third trimester. In vitro islet experiments demonstrated that PM5S increases GSIS in mouse and human islets via transient receptor potential cation channel subfamily melastatin member 3 (TRPM3), an ion channel which allows influx of calcium ions into cells. This was further corroborated when HEK293 cells transfected with TRPM3 displayed concentration dependent increase in calcium concentration with PM5S. These findings demonstrate a link between progesterone sulphates and the development of GDM.
Using cohort 4, we assessed serum bile acid concentrations in GDM. Obese GDM European women displayed the most significant changes, showing an increase in primary, secondary, conjugated, unconjugated and 12α-hydroxylated bile acids. In contrast, obese GDM south Asian women have reduced serum concentrations of secondary bile acids. Furthermore our in vitro data demonstrate that TCA and TCDCA induce increased GSIS in mouse and human islets, although the mechanism of action remains inconclusive. Our data suggests that bile acids have a role in glucose metabolism and consequently the progression of GDM.
| Date of Award | 1 Jan 2022 |
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| Original language | English |
| Awarding Institution |
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| Supervisor | Catherine Williamson (Supervisor), James Bowe (Supervisor) & Gavin Bewick (Supervisor) |