Mechanisms of insulin action and identification of defects leading to insulin resistance in maternal obesity and gestational diabetes
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2011
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Melbourne Authors
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Medicine, Dentistry & Health Sciences, Obstetrics and Gynaecology (RWH)
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PhD thesis
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Colomiere, M. (2011). Mechanisms of insulin action and identification of defects leading to insulin resistance in maternal obesity and gestational diabetes. PhD thesis, Medicine, Dentistry & Health Sciences, Obstetrics and Gynaecology (RWH), The University of Melbourne.
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© 2011 Dr. Michelle Colomiere
Abstract
Obesity and type two diabetes mellitus (type II DM) significantly impact not only on the health and wellbeing of individuals, but also the healthcare system. Of particular concern is the alarming increase in childhood obesity and the associated increased risk of type II DM. Abnormalities in maternal metabolism, such as maternal obesity and gestational diabetes mellitus (GDM) may cause fetal metabolic re-programming, thus leading to long term consequences such as childhood obesity and the development of type II DM. As a consequence, understanding the changes involved in the intrauterine environment, governed by interactions with hormones, genetics, nutrition, and environmental factors, is essential in order to further our understanding of pregnancy related diseases and how they contribute to fetal growth.
Insulin resistance develops during pregnancy as maternal metabolism is directed towards supplying adequate nutrients to the growing fetus. Low grade inflammation is associated with insulin resistance in pregnancy. Similarly, outside of pregnancy cytokines play a central role in the development of insulin resistance. Given that inflammation is said contribute to the insulin resistance in pregnancy, investigations into both inflammation and glucose metabolism were warranted. Studies have suggested the secretion of placental hormones may negatively regulate glucose metabolism and induce low grade inflammation during pregnancy. The placenta has an extraordinary capacity to synthesise hormones such as progesterone and human placental lactogen (hPL). During pregnancy, these hormones exert endocrine, paracrine and/or autocrine actions which may have immediate effects on placental function and peripheral tissues.
Through the use of ex situ tissue explant cultures, the effects of progesterone and hPL on glucose metabolism and inflammation were investigated. Progesterone had no affect on the transduction of the insulin signalling pathway nor did it significantly affect glucose uptake in placenta (collected via Caesaren Section), adipose tissue or skeletal muscle. Additionally, progesterone had no effect on low grade inflammation in maternal or fetal tissues. In contrast, hPL inhibited glucose uptake and induced IL-6 and IL-8 release in both placenta and adipose tissue from NGT pregnant women, although it displayed no affect on skeletal muscle. Inhibition of glucose uptake induced by hPL was shown to work via activation of the prolactin receptor, while hPL-induced inflammation was inhibited by NF-kB. Overall, the data presented supports a role for hPL in regulation of glucose metabolism and inflammation in pregnancy, however no relationship exists between the two, but work via independent mechanisms.
In summary, the data presented in this thesis demonstrate changes in glucose homeostasis observed in obese NGT and GDM mothers, are regulated by dysregulation of the insulin signalling pathway in both maternal and fetal tissues. Consequently, the intrauterine environment is vulnerable to fluctuations in maternal glucose homeostasis and may be a mechanism which underlies fetal re-programming. Finally this thesis demonstrates a role for hPL in the pathophysiology of insulin-resistance in pregnancy through its ability to interfere with both glucose uptake and induce low grade inflammation, however via independent mechanisms. This data adds insight into the cellular mechanisms which underlie pregnancy associated insulin resistant pathologies; however further expanding our knowledge is essential in the hope that one day, clinicians can ultimately better control glucose metabolism in pregnant women to provide better long term outcomes for mothers and offspring.
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gestational diabetes