Abstract
Type 2 diabetes mellitus (T2DM) is a metabolic disorder with underlying pathologies of progressive insulin resistance and beta-cell dysfunction formed by complex interactions between genetic and environmental factors of which obesity is the major contributor. Incretins are degraded by dipeptidyl-peptidase-4 (DPP-4) resulting in loss of insulinotropic action. It is proposed DPP-4 plays a role in the progression of diabetes, influencing treatment. This study combines in vitro, pre-clinical and clinical studies to examine distribution of DPP-4 in murine models of dietary induced insulin resistance, genetic models of impaired glucose tolerance and in type 1 and 2 diabetic patients. The effects of various antidiabetic drugs on DPP-4 activity was also determined.DPP-4 was detectible in models of insulin resistance, IGT and T2DM. Plasma DPP-4 was increased in IGT and insulin resistant mice but decreased in type 2 diabetic mice. Tissue specific modulation of DPP-4 was noted in all groups. Gene expression studies revealed down-regulation of DPP-4 in the pancreas of IGT mice and up-regulation in pancreas of diabetic mice. Small intestine exhibited down-regulation in insulin resistant mice and upregulation in type 2 diabetic mice. Recent diabetic therapeutics focus on DPP-4 inhibition to increase GIP/GLP-1, improving metabolic control; so this thesis has investigated plasma DPP-4 enzyme activity in diabetes over 24 months. Type 1 diabetic subjects were treated with insulin; type 2 treated by diet, metformin, sulphonylurea and/or TZD. DPP-4 activity was reduced in type 1 & 2 diabetes compared to controls. In type 1, DPP-4 activity fluctuated with changes observed at 0 and 6 months whereas in type 2 cohort DPP-4 was decreased at 0, 6 and 12 months compared to controls. GLP-1 levels were also found to be decreased in circulation of type 1 and increased in type 2 subjects compared to healthy controls. Plasma incubation with metformin resulted in significant inhibition of DPP-4 at all concentrations. Metformin treated insulin resistant mice showed no change in pancreatic DPP-4 enzyme activity, but interestingly, the gene was up-regulated along with GLP-1 receptor compared to lean and high-fat saline controls, suggesting modulation of multiple components of the incretin axis with enhancement of GLP-1r expression and related insulinotropic islet receptors. These studies demonstrate tissue specific modulation of DPP-4 in the progression of diabetes. Various other drugs modulate DPP-4 supporting the concept that diabetic treatments not only potentiate insulin release directly but also play a vital role in the moderation of DPP-4 activity thereby increasing GLP-1 action and promoting insulin release.
Thesis is embargoed until 31st October 2016
| Date of Award | Oct 2014 |
|---|---|
| Original language | English |
| Sponsors | Department for Employment and Learning, Northern Ireland |
| Supervisor | Aine McKillop (Supervisor) & Yasser Abdel-Wahab (Supervisor) |
Cite this
- Standard