Phenotypic and Genotypic Determinants of Drug Response to Anti-Hyperglycaemic Drugs in White Europeans and Asian Indians

  • Sushrima Gan

Student thesis: Doctoral ThesisDoctor of Philosophy

Abstract

Type 2 diabetes (T2D) is a complex disease characterized by insulin deficiency, due to pancreatic beta cell dysfunction, and insulin resistance (IR) leading to hyperglycemia. The management of hyperglycemia in T2D has become extraordinarily complex with a large number of medicine regimes being available which creates a major challenge in determining the best approach to achieve and maintain the appropriate level of glycaemic control. Response to anti-hyperglycaemic agents is conditional on phenotypic and pharmacogenetic effects. It is important to determine the contributing factors affecting response to carry out treatment. In this thesis, we have focused on two ethnics groups- white Europeans and Asian Indians to study the phenotypic and genotypic determinants of response to oral anti-hyperglycemic agents. This thesis focuses on the anthropometric and clinical determinants of glycaemic response to treatment with DPP-4I, SU and TZD in T2D individuals from Tayside and Fife, Scotland, Madras Diabetes Research Foundation (MDRF), India and UKBB populations. We assessed whether anthropometric, clinical and biochemical factors including markers of insulin resistance and insulin secretion are associated with 6-month glycaemic response to DPP-4i, SU and TZD in White Europeans and Asian Indians. In the first half we conducted a meta-analysis on three newer anti-hyperglycaemic agents and showed that Asians responded better to the drugs compared to whites. It is interesting to note that with our data in the combined analyses Asian Indians responded better to all three drugs studied in this thesis. In my study, c-peptide and triglycerides were not associated with response for DPP-4I and HDL-c was not associated with glycaemic response for both the cohorts in our study. The sub-group analysis in the Asian Indian population showed that higher HOMA B is associated with better response. Also, clinical markers of lower beta cell response like longer duration of diabetes were associated with reduced response in the Asian Indian population. I have demonstrated obese women respond very well to TZD whereas slim men respond well to SUs in both Tayside and Fife population (White European) and MDRF population (Asian Indian). Most diabetes intervention trials are undertaken in the West and very few are focused on India. The pronounced difference in response between the two populations mandates ethnicity specific trials to be undertaken in order to move a step forward in the targeted therapy approach.
Date of Award2022
Original languageEnglish
SupervisorEwan Pearson (Supervisor) & Alexander Doney (Supervisor)

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