The role of fatty acid signalling in Islet Beta-cell adaptation to normal pregnancy

Hyperinsulinaemia has an important role in normal pregnancy by mediating the process of facilitated anabolism in early pregnancy and compensating for insulin resistance in late pregnancy. However, the mechanisms affecting islet {u03B2}-cells that underlie the hyperinsulinaemia of late pregnancy remain poorly understood. There is very good evidence that lactogenic hormones are involved, but the role of lipid signalling processes has been minimally investigated. As (i) pregnancy is associated with a physiological hyperlipidaemia and (ii) enhanced fatty acid augmentation of glucose-stimulated insulin secretion (GSIS) has been implicated in islet {u03B2}-cell compensation for insulin resistance in non-pregnancy models, the main aim of this thesis was to examine the potential role of lipid signalling in islet adaptation to normal pregnancy. The first major aim was to determine the effects of fatty acids on insulin secretion in isolated islets of virgin, Day 11 (D11) and Day 19 (D19) pregnant rats. Insulin secretion in response to glucose alone was increased as expected in islets of pregnant compared to virgin rats. This increased GSIS was further accentuated by fatty acids such that the absolute increase in GSIS induced by fatty acids was greater in D19 pregnant compared to virgin rat islets. The proportional increase in GSIS by fatty acids, however, was unchanged by pregnancy. Fatty acid augmentation of GSIS in non-pregnancy models occurs partly by the production of intracellular lipid signalling molecules via glucose-responsive glycerolipid/free fatty acid (GL/FFA) cycling. The second major aim, therefore, was to determine the effects of pregnancy on intracellular fatty acid metabolism, in particular, the activity of the GL/FFA cycle. Islets of both mid and late pregnant rats showed reduced rates of fatty acid oxidation which would favour the build-up of long chain acyl-CoA for GL/FFA cycling. Glucose-responsive fatty acid esterification processes into complex lipids was increased in D19 pregnant islets compared to virgin islets but this was not associated with increased lipolysis rates. The net result in pregnant islets would be greater accumulation of lipid signalling molecules from the esterification arm of the GL/FFA cycle, which would favour enhanced fatty acid augmentation of insulin secretion. The third major aim was to determine the effects of pregnancy on mRNA expression of key {u03B2}-cell genes including transcription factors and enzymes involved in {u03B2}-cell lipid metabolism. Additional genes assessed related to glucose metabolism and {u03B2}-cell receptor signalling pathways. Of these genes, only pyruvate carboxylase (PC) and peroxisome proliferator-activated {u03D2} coactivator I-a (PGCI-a) expression was significantly altered in late pregnant compared to virgin islets. Reduced expression of PC may relate to reduced glucose supply to islet {u03B2}-cells in late pregnancy. PGC1-a is a key factor involved in regulation of energy metabolism, such that its mRNA reduction in islets in pregnancy is likely to have an important adaptive role. From these studies, it is concluded that the increased lipid supply to islets found in pregnancy contributes, together with hormonal factors, to islet {u03B2}-cell adaptation to pregnancy. Altered intracellular fatty acid partitioning in late pregnancy is likely to be involved in the mechanisms