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Title: Insulin secretion : regulation of paracrine interrelation
Author: Tan, Kim Sze
ISNI:       0000 0001 3497 5795
Awarding Body: University of Surrey
Current Institution: University of Surrey
Date of Award: 1982
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In the present study, a transplantable rat insulinoma was characterised and its functional properties investigated. Immunocytochemical staining and radioimmunoassay techniques confirmed the presence of insulin and somatostatin in the tumour, but an absence of glucagon. The molecular heterogeneity of insulin and somatostatin in the insulinoma was also investigated by gel filtration and HPLC techniques. The metabolic effects of the insulinoma in response to various stimuli and inhibitors of insulin release were studied. Plasma insulin and glucose responses to glucose, arginine, glibenclamide and exogenous insulin were impaired in the tumour bearing rats, and diurnal variations of glucose homeostasis were abolished. Data from the metabolic studies indicate the suitability of the rat insulinoma as a model for studies on the spontaneous insulinoma in man. Although surgical resection of the insulinoma resulted in a marked reversal of the metabolic abnormalities, tumour recurrence was nevertheless observed in all rats. Methotrexate and alloxan failed to alleviate the hypoglycaemia in contrast to streptozotocin. The divergent responses of alloxan and streptozotocin may be related to the tumour defect. The role of glucagon in normal physiology was re-examined. Neutralisation of endogenous glucagon by glucagon-specific antibodies was used as a tool in unravelling glucagon's role in glucose homeostasis. Glucagon did not prove to be important for the maintenance of basal blood glucose in the rat. Furthermore, its insulinotrophic effect was substantiated. Arginine stimulated insulin release was inhibited by glucagon antibodies in in vivo experiments and in isolated islets of Langerhans, suggesting an essential role for glucagon in mediating the insulinotrophic effect of arginine. In contrast, glucose stimulated insulin release was not inhibited by glucagon antibodies indicating that different mechanisms are involved in the stimulation of insulin secretion by arginine and glucose. In agreement with the in vivo data, glucose and arginine failed to stimulate insulin release in the in vitro insulinoma cell suspension, whilst glucagon evoked a marked response. It is suggested that the impaired response of glucose may be related to the tumour defect, but that failure of arginine to stimulate insulin secretion in vivo and in vitro was due to the absence of A-cells in the tumour. These observations provide further evidence for the role of glucagon in insulin secretion. The absence of A-cells in the insulinoma suggests that it might be a suitable model for studying B- and D-cell inter-relationships in an A-cell free environment.
Supervisor: Not available Sponsor: Not available
Qualification Name: Thesis (Ph.D.) Qualification Level: Doctoral
EThOS ID:  DOI: Not available
Keywords: Biochemistry