Fatty acid metabolism and adipocyte function in healthy and gestational diabetes mellitus pregnancy

Abstract

Gestational diabetes mellitus (GDM) is defined as a glucose intolerance of varying severity with first recognition during pregnancy. The prevalence of GDM is increasing worldwide, largely attributable to the dramatic rise in maternal obesity, resulting in several maternal and fetal complications. The maternal metabolic adaptation during pregnancy is challenged by maternal obesity, resulting in β cell dysfunction and exaggerated insulin resistance in women with GDM. However, the exact cellular mechanisms involved in the development of GDM are not yet completely understood. Increasing evidence from clinical and experimental studies has suggested that adipose tissue dysfunction could be one of the underlying mechanisms for the metabolic abnormalities observed in women with GDM. However, most of the published literature on this topic has been focused on plasma measures of adipocyte-derived adipokines and how they are linked to insulin resistance. Functional measures of adipocytes, such as adipocyte size, lipolysis, insulin sensitivity and direct measurement of adipocyte secretory function, have not been widely studied in GDM. Failure to efficiently increase the adipocyte cell number (hyperplasia) rather than increase size (hypertrophy) in order to store excess free fatty acids (FFA), and the subsequent failure to suppress adipocyte lipolysis when FFA demands are low, is believed to be a key mechanism in the development of type 2 diabetes in the non-pregnant. Similarly, this could be a major candidate pathway for pregnancy complicated by GDM, leading to the observed higher plasma FFA and higher plasma pro-inflammatory cytokine concentrations, which may result from exaggerated adipocyte insulin resistance and inflammation. Therefore, the hypothesis tested in this thesis was that GDM results from defective expansion of SAT adipocytes, resulting in adipocyte hypertrophy. Subsequently, there is increased adipocyte lipolysis and inflammatory adipokine secretion. The aim of this thesis was, firstly, to explore the epidemiological evidence for the role of maternal obesity in the development of GDM and other maternal and fetal complications, specifically in the highly diverse local Greater Glasgow and Clyde population. Data from the Scottish Morbidity Record 2 (SMR02) and the Scottish Care Information – Diabetes Mellitus (SCI-diabetes) databases for pregnant women between 2010 and 2015 was combined, and the prevalence of maternal obesity and GDM established among 38,178 births. The associated risks for several adverse pregnancy outcomes among women with maternal obesity and GDM in the Greater Glasgow and Clyde population were calculated. It was found that in the local population maternal obesity and GDM were at higher prevalence (22.3% and 2.2%, respectively) compared to recent historical studies, and are associated with an increase in the incidence of a range of adverse pregnancy outcomes. Furthermore, the resulting adverse maternal and fetal complications of both first trimester maternal obesity and GDM were likely to be a considerable burden on clinical resources. Assessment of the long-term implications of maternal and fetal complications secondary to GDM and maternal obesity was not included, and a prospective follow-up analysis of this cohort is recommended. The second aim of this thesis was to determine the evidence for the role of failure of adipocyte expansion in the development of underlying metabolic abnormalities in women with GDM. Several functional measures of adipocyte expansion were assessed, including adipocyte size, lipolytic function, adipokine secretion, and the expression of genes involved in adipocyte physiology and biochemistry. Subcutaneous adipose tissue (SAT) and visceral adipose tissue (VAT) biopsies from non-labouring women with GDM (n=22) and healthy (n=22) BMI-matched controls, undergoing elective caesarean s