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Title: Programming of the hypothalamic-pituitary-adrenal axis during fetal life
Author: Reynolds, Rebecca M.
Awarding Body: University of Edinburgh
Current Institution: University of Edinburgh
Date of Award: 2002
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The aim of this thesis was to study the HPA axis in detail, examining aspects of both activity of the axis and cortisol action, in order to determine variations that could explain the link between low birthweight and subsequent development of cardiovascular risk factors. The principal findings were that men aged 66-77 years, who were of low birthweight and/or with the Metabolic Syndrome, have activation of the HPA axis with increased cortisol response to ACTH1-24 and increased urinary cortisol metabolite excretion. In contrast to rats programmed by dexamethasone administration during pregnancy, there was no evidence of altered central feedback sensitivity to low dose dexamethasone. However, dexamethasone may not cross the blood-brain barrier at low doses in man, so that this only tests the pituitary component of the negative feedback loop. Alternatively, rather than impaired central negative feedback, the activation of the HPA axis could be due to increased forward drive to ACTH and cortisol secretion from higher centres. Consistent with this hypothesis there was lack of habituation to the stress of repeated venepuncture in diabetic subjects. In contrast to the central GR changes, peripheral (liver) GR expression is increased in the rodent model. Tissue-specific differences in GR levels are a potential mechanism whereby subtle abnormalities in cortisol action could contribute to variations in insulin sensitivity in the population. Using competitive quantitative RT-PCR, GR mRNA levels were determined in total RNA extracted from skeletal muscle biopsies from 23 men in Uppsala, Sweden who had been studied at age 70 years with an oral glucose tolerance test and a euglycaemic hyperinsulinaemic clamp. Increased GR expression was associated with resistance to insulin-mediated glucose uptake, independent of obesity.
Supervisor: Not available Sponsor: Not available
Qualification Name: Thesis (Ph.D.) Qualification Level: Doctoral
EThOS ID:  DOI: Not available