Use this URL to cite or link to this record in EThOS: http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.643250
Title: Mechanisms of insulin resistance in prenatally programmed rats
Author: Cleasby, Mark E.
Awarding Body: University of Edinburgh
Current Institution: University of Edinburgh
Date of Award: 2002
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Abstract:
This thesis addresses the question of whether programming of insulin resistance extends to skeletal muscle and adipose tissue, and whether altered expression of GR in insulin target tissues is important in determining the programmed insulin resistance. GR was elevated by prenatal treatment with dex in retroperitoneal (RP) fat, and reduced in soleus muscle, while its expression was unchanged in two other muscles and subcutaneous fat. In RP fat, this was accompanied a reduction in lipoprotein lipase mRNA and a shift from PPARg1 to PPARg2 expression, while leptin and resistin mRNA levels were unchanged. In quadriceps muscle, glycogen storage was reduced, associated with a downward trend in expression of the insulin-regulated glucose transporter. In summary, tissue-specific programming of GR in muscle and fat is associated with impaired lipolytic activity and a shift in PPARg expression in visceral fat, and evidence of attenuated glucose uptake into skeletal muscle. These findings are consistent with the presence of insulin resistance in muscle and visceral adipose tissue as a result of prenatal dex. To test whether changes in GR expression were secondary to hypercorticosteronaemia or insulin resistance, the [corticosterone] (cort) was varied in adult offspring, or rats were treated with insulin-sensitising drugs. No effect of varying [cort] was found in muscles or fat depots, while liver GR was increased by both adrenalectomy and supraphysiological cort. Metformin reduced GR, especially in the liver and muscle of dex-treated rats, but rosiglitazone reduced GR only in the liver and independently of prenatal treatment. The implications are that programming of GR in insulin target tissues is independent of circulating hypercorticosteronaemia and insulin resistance per se. Moreover, it seems that the mechanism of action of metformin may be in part glucocorticoid-mediated.
Supervisor: Not available Sponsor: Not available
Qualification Name: Thesis (Ph.D.) Qualification Level: Doctoral
EThOS ID: uk.bl.ethos.643250  DOI: Not available
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