Abstract
This thesis focuses on metformin – a drug commonly used in type 2 diabetes. Despite being a sexagenarian, metformin continues to intrigue researchers. This is due, in part, to: the variability in response to and tolerance of metformin; the uncertainty regarding its mechanism of action; and the potential for re-purposing metformin out-with diabetes. While metformin is the common theme, this thesis details three distinct clinical studies, each intended to further the understanding of the variability in response to and tolerance of metformin.Firstly, an open label pharmacokinetic study of the potential mechanisms of metformin intolerance, including: altered uptake; increased lactate production; and alterations in serotonin uptake or bile acid pool, demonstrated that despite evidence of severe intolerance in our cohort, there was no significant difference in the pharmacokinetics of metformin, nor in systemic lactate, serotonin or bile acids. These results suggest that intolerance may be attributable to local factors within the lumen or enterocyte.
Secondly, a recruit-by-genotype, double-blind, randomised, placebo-controlled, crossover study to determine the impact of OCT1 genotype and the use of OCT1 inhibiting drugs on metformin intolerance, has identified a significant gene*drug interaction between OCT1, metformin and omeprazole. The study data show that individuals with OCT1 wild type have improved tolerance of metformin whilst taking omeprazole, compared to placebo. However, this benefit is lost in those with reduced OCT1 function.
Finally, to further investigate a GWAS-identified SNP associated with metformin response, an open label, crossover study of individuals with Ataxia-Telangiectasia (A-T) and healthy controls, employed dual-tracer mixed meal tests to assess their response to metformin and pioglitazone. Although unable to validate the GWAS result, the study data show that pioglitazone improves the insulin resistance and adipocyte dysfunction associated with A-T, and suggests that pioglitazone, rather than metformin, should be considered in the management of diabetes associated with A-T.
| Date of Award | 2019 |
|---|---|
| Original language | English |
| Supervisor | Ewan Pearson (Supervisor) & Rory McCrimmon (Supervisor) |