Diabetes mellitus is a disease usually associated with insulin deprivation, insulin resistance and disordered insulin secretion. Conventional treatments can only control disease progression but do not have the ability to cure diabetes. Cell therapy has provided us with an alternative and better way to fight the disease. However, extreme shortage of islet cell surrogates is one of the obstacles that have been hampering the application of the technology. Congenital hyperinsulinism (CHI), a potentially fatal disease that has been characterised as "inappropriate release of insulin for the level of glycaemia", has offered us a unique model for studying pancreatic islet cell development and maintenance. In this thesis, I aimed to investigate morphological and physiological alterations associated with CHI pathogenesis so that novel diagnostic tools and therapeutic options for CHI treatment could be developed.By studying the architecture of the islets from CHI patients as well as a mouse model of CHI (SUR1-KO), I discovered that CHI was associated with morphological changes in islet structure and delay in islet cell maturation. This provided us with valuable information to advance our knowledge on CHI pathogenesis and in the diagnosis. Also, significantly elevated serum GLP-1:GIP ratio was noticed in atypical CHI patients, which suggests that serum incretin ratio could also assist the diagnosis and differentiation of atypical CHI.Currently, treatment options available for CHI are limited due to adverse effects and limited efficacy. As a result, pancreatectomy is normally required in severe cases. Therefore, I intended to explore new treatment options for CHI. Currently available somatostatin receptor (SSTR) agonists mainly target SSTR2 and are widely used in CHI treatment to inhibit insulin release. However, there are concerns regarding techyphylaxis and the loss of natural counterregulatory response. Through immunohistochemical staining, I found that the loss of SSTR2 expression was evident in diffuse and atypical patients which could explain the sudden decrease in responsiveness to medication. After pancreatectomy and withdrawal of the SST analogue octreotide, SSTR2 expression recovered. SSTR2 expression was present in alpha-cells in almost all the patients, which questioned the usefulness of SSTR2-targeting SST analogues. Fortunately, SST analogue SOM230, which mainly targets SSTR1, 3 and 5, was found to be able to inhibit insulin release at a similar level to that of octreotide, indicating its potential in CHI treatment. Another medicine I investigated was GABAB receptor agonist baclofen. However, it could only suppress insulin secretion if there was a large enough elevation of insulin release which does not happen often in CHI.In the present thesis, I have investigated morphological and physiological changes associated with CHI and evaluated the potential of new medical treatment options for CHI, which has implications in CHI management and our understanding on postnatal pancreatic development and maintenance.
|Date of Award||1 Aug 2014|
- The University of Manchester
|Supervisor||Mark Dunne (Supervisor) & Alison Gurney (Supervisor)|