Telomere Length Attrition in Diabetes: Exploring Associations and Cellular Mechanism

Abstract

Telomere is a repetitive DNA sequence at the end of eukaryotic chromosomes; it is involves in biological & physiological ageing. People with diabetes mellitus (DM) have shorter telomeres compared with those without. Fenofibrate may prevent diabetes vascular complications; whether fenofibrate has any effect on telomere length or its maintenance, has not been reported. This PhD study was designed to investigate accelerated telomere length attrition in DM & its association with DM complications, to define possible mechanism(s) of this phenomenon, and to examine methods to prevent the attrition due to DM and obesity. Relative telomere length (RTL) was measured by in-house qPCR assay. Results showed that in the type 1 and the type 2 DM pilot cross-sectional series, RTL was shorter compared with age-matched non-DM controls. It correlated inversely with DM duration & age, but did not consistently differ by complication status. In a large type 2 DM cohort (consisting of 5503 subjects), shorter RTL was found to associate with ageing, certain vascular risk factors & some prospective of DM complications. The in vivo animal model showed that RTL was regulated by high fat diet in some organs and fenofibrate affected RTL. The in vitro diabetes model identified potential causes of the accelerated RTL loss under diabetes conditions: high glucose, oxidative stress & the metabolic product of an overflow glucose pathway, glucosamine. Fenofibrate was found to have protective effects in vitro on RTL. This thesis has demonstrated RTL attrition in vivo in diabetes, which in vitro appears to be accelerated by certain metabolic conditions present in DM. It forms the basis for subsequent studies refining mechanism of telomere attrition in diabetes and methods to regulate and potentially prevent diabetes-related biological ageing. In contrast, due to small rates of change, RTL measures in white cells and tissues in diabetes, may have only limited individual clinical value.