The objective of this thesis was to further the understanding of the effect of diet, insulin and exercise on the regulation of carbohydrate metabolism in health and type 1 diabetes. Three studies were undertaken in both non-diabetic healthy volunteers and patients with type 1 diabetes. The first study determined the influence of high fat diet on biochemical and molecular regulators of whole body and muscle metabolism in healthy volunteers. The second study examined the influence of insulin on whole body and muscle metabolism in patients with type 1 diabetes during moderate exercise. The final study compared the influence of insulin and a high carbohydrate diet on liver glycogen concentrations and substrate oxidation during exercise between patients with type 1 diabetes and healthy volunteers. The main results were, a) 6 days of high fat/low carbohydrate dietary intake did not induce whole-body insulin resistance but caused a shift in intramuscular glucose metabolism from oxidation to glycogen storage when compared to a normal balanced diet. Insulin-stimulated carbohydrate oxidation and muscle PDCa activity were blunted after the high fat diet and this was associated with an up regulation of muscle PDK4 mRNA and protein expression, b) Exercise under hyperinsulinaemic conditions in patients with type 1 diabetes did not spare muscle glycogen utilisation at a time of high exogenous glucose utilization and oxidation, and finally c) Changes in liver glycogen concentration and substrate oxidation during exercise occurred at comparable rates in patients with type 1 diabetes and in healthy controls despite the presence of relative hyperinsulinaemia in the former compared to the latter group. The key conclusions are, 1) in healthy humans short-term high fat feeding does not induce whole body insulin resistance but impairs basal and insulin-stimulated carbohydrate oxidation, most likely as a result of fat-induced upregulation of muscle PDK4 protein expression. The precise signaling mechanisms involved in the chronic regulation of PDK4 need to be determined. 2) Contrary to previous observation in non-diabetic individuals, it appears that hyperinsulinaemic conditions in patients with type 1 diabetes do not suppress the exercise-induced changes in muscle and liver glycogen stores. The underlying physiological mechanism(s) behind this apparently divergent response remains to be elucidated.
| Identifer | oai:union.ndltd.org:bl.uk/oai:ethos.bl.uk:559501 |
| Date | January 2007 |
| Creators | Chokkalingam, Kamalakkannan |
| Publisher | University of Nottingham |
| Source Sets | Ethos UK |
| Detected Language | English |
| Type | Electronic Thesis or Dissertation |
| Source | http://eprints.nottingham.ac.uk/10441/ |
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