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Title: Factors responsible for the development of diabetes in adults with cystic fibrosis
Author: Nazareth, Dilip Stephen
ISNI:       0000 0004 7428 5803
Awarding Body: University of Liverpool
Current Institution: University of Liverpool
Date of Award: 2018
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As survival in Cystic Fibrosis (CF) has improved dramatically, Cystic Fibrosis Related Diabetes (CFRD) has now come to the forefront, with an increasing prevalence. CFRD is associated with worse pulmonary function, under nutrition and an increase in early mortality. The pathophysiology of CFRD is complex and not fully understood, with CFRD unlike other types of diabetes. In CF, gastric emptying and motility are likely to be altered, changing the way in which nutrients are presented to the gut compared to normal individuals. Then, the relative progressive insulinopaenia that occurs in CF may result in diurnal changes in glucose and other nutrient handling, and abnormalities in the small intestine may alter incretin secretion and associated pancreatic enzymes. The aim of this thesis was to enhance understanding of the physiology and regulation of gastric emptying, glucose handling and pancreatic hormones in CF individuals. A series of experiments involving 10 healthy volunteers and 20 CF patients are presented in this thesis. Firstly, gastric emptying was measured using a novel easy technique and the responses compared to healthy control subjects, throughout the day. Secondly, glucose handling and secretory patterns of insulin, c-peptide, glucagon, incretin hormones (GLP1 and GIP) and pancreatic polypeptide (PYY) throughout the day were compared. The main conclusions that can be drawn from this thesis are: (1) There is delayed gastric emptying throughout the day in CF subjects (2) The novel and inexpensive bedside technique used in this study, provides a simple method of assessing gastric emptying (3) The mixed meal is more physiological in CF (4) In CF subjects without frank diabetes, there is deficient glucose handling with differences in the afternoon and testing in the evening deserving more attention (5) The quantity of insulin secreted is similar in CF and healthy subjects with an insulin lag in CF subjects and glucagon does not appear to contribute to elevated blood sugars (6) Insulin sensitivity is highest in the afternoon and appears to play a significant part in improving glucose handling in the afternoon (7) b cells take longer in in the evening to produce insulin, a concept I refer to as 'pancreatic fatigue' (8) There is no difference in GLP1 or GIP secretion following a mixed-meal, but GIP hypersecretion exists early in the response to the OGTT in the CF group (9) CF subjects have lower PYY levels likely to be secondary to existing pancreatic insufficiency. Areas of potential future research based on this thesis are also outlined.
Supervisor: Walshaw, Martin Sponsor: Not available
Qualification Name: Thesis (M.D.) Qualification Level: Doctoral