Biomarkers associated with glycaemic control, comorbidity and response to GLP-1 analogue therapy

Abstract

Glycaemic dysregulation drives type II diabetes (T2D) pathogenesis, perpetuating multimorbidity that is thought to be linked to mood and cognitive decline. Glucagonlike peptide-1 receptor agonists (GLP-1Ras) are an effective insulin sensitising and weight loss medication. Preclinical studies have shown them to have positive effects on cognition. Whether such effects are seen in humans is unknown. The aims of this PhD were to investigate potential disease mechanisms and assess current and novel biomarker panels, clinically, that relate to T2D, cognitive decline and GLP-1Ra response. qPCR arrays using 3 in-vivo models showed leptin and insulin related genes were differentially affected by treatment duration in brain, and these changes may be evident peripherally. Clinically, ECR records of 500 T2D patents indicated diabetes is poorly managed, and that cardiovascular disease (CVD) and hyperlipidaemia management appear to be prioritised. Current biochemical measures of diabetes (HbA1c, BMI and plasma lipid profile) did not correlate strongly with any aspect of T2D, while C-peptide, currently not routinely measured, may be a valuable addition to the clinic. Multiplex proteomics of 374 T2D participants and 20 controls, screened 368 proteins across 12 variables; previously shown to be central in T2D. Unique protein panels were identified for each variable, and vascular endothelial dysfunction was a commonalty between all. Genetic supplementation of the proteomic markers was also achieved via SNP genotyping of 20 insulin and leptinrelated genes. One hundred and five SNPs differentiated T2D and controls and 25 were indicative of GLP-1Ra response. GLP-1Ra non-responders were found to have the greatest level of comorbidity and highest scores on the Beck depression and anxiety inventories. This translated to lower cognitive domain scores in, memory and perception. These data have identified prescribing and comorbidity patterns in a Northern Irish T2D population, and demonstrated that current measures do not adequately correlate with disease progression or comorbidity onset. Novel markers identified may allow for higher predictive capability, and may reduce the impact of cognitive decline in T2D.

Date of Award	May 2018
Original language	English
Sponsors	Department of Employment and Learning
Supervisor	Paula McClean (Supervisor) & Catriona Kelly (Supervisor)