Treatment response in type 2 diabetes varies greatly: the same glucose lowering medication may have a marked effect in one individual but little effect in another. This is likely to have at least a partly biological basis (type 2 diabetes is a highly heterogeneous condition), raising the possibility of a personalised or 'stratified' approach to treatment where the therapy most likely to be effective for an individual is prescribed based on that person's clinical characteristics or biomarkers. One aspect of type 2 diabetes that varies greatly is beta cell insulin secretion. While many patients will be highly insulin resistant with relatively preserved insulin secretion, others are insulin sensitive with marked beta cell failure. It is plausible that these differences will be associated with variation in treatment response, particularly to treatments exerting their effect through beta cell dependant mechanisms. Insulin secretion is best assessed in clinical practice by measuring C-peptide, co-secreted in equimolar amounts to endogenous insulin. However the measurements commonly used in research are not practical for general clinical use. The aim of this thesis is to assess practical methods of measuring insulin secretion that could be incorporated into routine clinical practice and to examine the utility of these methods in diabetes treatment stratification. In Chapter 1 we review the current evidence on asseSSing insulin secretion and its potential use in diabetes treatment stratification. 3 In Chapters 2 and 3 we assess practical alternatives to the 'gold standard' mixed meal tolerance test stimulated C-peptide for assessing insulin secretion. We show that urine C-peptide creatinine ratio (UCPCR) and fasting C-peptide provide valid alternatives to stimulated blood tests for clinical practice, with high sensitivity and specificity for commonly used clinical thresholds. We demonstrate that a mixed meal test to assess insulin secretion can be undertaken with concurrent insulin given, retaining a high discriminative value for absolute insulin deficiency despite a marked reduction in hyperglycaemia. In Chapter 4 we demonstrate a strong inverse relationship between postprandial glucose rise and C-peptide, including fasting C-peptide and UCPCR. We demonstrate that those who have preserved insulin secretion have markedly reduced response to prandial (meal time) fast acting insulin. In Chapters 5 and 6 we explore problems of confounding by baseline glycaemia in studies of diabetes treatment stratification; we demonstrate that adjustment for baseline HbA 1 c in studies of stratification is both necessary and appropriate. In Chapter 7 we demonstrate in a large prospective cohort that markers of insulin deficiency, including low fasting C-peptide and positive GAD antibodies, are associated with reduced glycaemic response to GLP-1 agonist therapy in patients with a clinical diagnosis of type 2 diabetes. Participants who were Cpeptide negative and/or autoantibody positive had markedly reduced response to these therapies. An overview of the major finding of each chapter and their implications potential future research are discussed in Chapter 8.
| Identifer | oai:union.ndltd.org:bl.uk/oai:ethos.bl.uk:658026 |
| Date | January 2014 |
| Creators | Jones, Angus George |
| Publisher | Exeter and Plymouth Peninsula Medical School |
| Source Sets | Ethos UK |
| Detected Language | English |
| Type | Electronic Thesis or Dissertation |
Page generated in 0.0188 seconds