Hepatic glucose-6-phosphatase (G6Pase) catalyses the final step in blood glucose production by the liver. It is a multicomponent system: the catalytic subunit is on the luminal surface of the endoplasmic reticulum membrane; there are transport proteins for glucose-6-phosphate, inorganic phosphate and glucose across the ER membrane; and there is a calcium-binding stabilising protein associated to the catalytic subunit. In fasted and diabetic humans (and rat models) kinetic analysis has shown that the capacity of the glucose-6-phosphate transport protein is the rate-limiting step in G6Pase activity, making this protein vital in controlling hepatic glucose output. However, deficiency of any part of this system will lead to hypoglycaemia and other possible metabolic upsets (type 1 glycogen storage diseases). The structure and known regulation of the G6Pase system are reviewed in the introduction to this thesis. The aims of the work presented here are to investigate the human glucose-6-phosphatase system by studying adult patients newly diagnosed with abnormalities of the G6Pase system, and tissues not previously proven to contain G6Pase in healthy adults thereby improving understanding of the enzyme, its regulation and physiological role and to look for a tissue more accesible than liver in which to study human G6Pase activity. A unique series of eight adult patients each with an abnormality of hepatic G6Pase (two with previously unrecorded defects) is presented and the features of these cases are discussed with reference to the existing literature on type 1 glycogen storage diseases. The cases demonstrate how difficult it can be to prove hypoglycaemia in adults; the diversity of presenting symptoms and signs; the use of a screening test (blood glucose response to a 1mg intramuscular dose of glucagon) for such patients; and the benefits of developing reliable assays for the protein components of the G6Pase system. This series of patients also give further clues to the physiological role of glucose-6-phosphatase in extra-hepatic tissues and the regulation of the hepatic G6Pase system. The diagnosis and subsequent follow-up of the above patients would have been eased by being able to study a more accessible tissue than liver. Intestinal mucosa and neutrophils have been described as abnormal in G6Pase deficiencies. Therefore G6Pase activity was sought in these tissues from normal adult humans.
| Identifer | oai:union.ndltd.org:bl.uk/oai:ethos.bl.uk:660481 |
| Date | January 1993 |
| Creators | Pears, John Stuart |
| Publisher | University of Edinburgh |
| Source Sets | Ethos UK |
| Detected Language | English |
| Type | Electronic Thesis or Dissertation |
| Source | http://hdl.handle.net/1842/20100 |
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