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Title: Investigations of pancreatic B-cell and gastrointestinal hormones in hyperinsulinaemic states
Author: Norris, Fiona Jane
ISNI:       0000 0001 3449 3251
Awarding Body: University of Surrey
Current Institution: University of Surrey
Date of Award: 1997
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The aim of this project was to investigate pancreatic B-cell, GIP and GLP-1(7-36)amide secretion and function in various hyperinsulinaemic, insulin-resistant states. A specific ELISA for insulin was developed as part of this, which was also used to investigate insulin production in a patient with a proinsulinoma tumour. A study on a group of obese and lean subjects examined the effects of modulating their circulating NEFA levels, with heparin and acipimox, on GLP-1(7-36)amide and other hormone secretion following oral glucose. Postprandial GLP-1(7-36)amide secretion was found to be inversely related to plasma NEFA levels. An attenuated GLP-1(7-36)amide response to glucose was observed in obese subjects relative to control subjects, even when their NEFA levels were suppressed to a similar degree. A second group of obese and lean subjects was investigated following a mixed test meal. The method of anthropometric measurement used to assess body fat distribution in the obese was found to influence the designation of subjects as having either an android or a gynoid fat distribution. This in turn affected the hormone and metabolite levels observed for each group. It was postulated that the android obese subjects exhibited increased des-31,32 proinsulin and decreased proinsulin relative to gynoid obese subjects. GIP hypersecretion was seen in the obese, being more marked in the gynoid obese, consistent with its role as an incretin producing increased proinsulin levels in this group. GLP-1(7-36)amide responses were similar between obese and control groups following the mixed test meal and not attenuated in obese subjects as in the first study in response to carbohydrate alone. This suggests that GLP-1(7-36)amide may be less important as a satiating factor in the normal physiological situation of mixed nutrient consumption. Responses to a mixed test meal were examined in groups of severely, moderately and normo-triglyceridaemic subjects They were also examined in another group of hyper-and normo-triglyceridaemic subjects in response to a sucrose load with and without the a-glucosidase inhibitor, acarbose. GIP hypersecretion was observed in hypertriglyceridaemic subjects; this was greater in those subjects with lower insulin levels, consistent with the hypothesis of feedback inhibition of insulin on fat stimulated-GIP secretion. Determining factors of GIP and GLP-1(7-36)amide circulating levels appeared to be the nutrient content of the meal, body fat distribution (GIP) and degree of hyperinsulinaemia (GIP). The studies suggested that GIP may play a minor part in the hyperinsulinaemia of obesity and hypertriglyceridaemia, but there was no evidence of a role for GLP-l(7-36)amide. An overactive enteroinsular axis did not appear to be involved in polycystic ovarian syndrome. The specific ELISA for insulin, developed during this project, proved useful in clarifying insulin production in obesity and in a patient with a proinsulinoma tumour, where proinsulin or des 31,32-proinsulin production was abnormal.
Supervisor: Not available Sponsor: Not available
Qualification Name: Thesis (Ph.D.) Qualification Level: Doctoral
EThOS ID:  DOI: Not available
Keywords: Pancreas; Insulin; Obesity