In diabetes shorter telomere length is observed compared to age-matched non-diabetes controls. We have reported that shortened telomeres can also be observed in cultured cells under diabetes modelled conditions of high glucose and oxidant stress. The aim of this study was to investigate the cellular mechanism(s) of the accelerated telomere length loss under diabetes metabolic conditions in-vitro and potential telomere protective mechanism(s) of fenofibrate.

Primary cultures of human dermal fibroblasts (CRL-2097) were serially passaged and treated with elevated D-glucose (25mM) compared with 5.5mM, and across 7 days with AGEs-BSA or control-BSA prepared in house, glucosamine, or hydrogen peroxide (H₂0₂). A high-throughput qPCR assay, was used to measure relative telomere length (T) by comparing it to a single copy gene (S)¹, which was then normalised against a human standard. In parallel samples mRNA gene expression levels of Trf-1 and Trf-2, regulators of telomere stability were measured by qRT PCR.

Cells cultured in 25mM D-glucose lost their T/S ratio 4% faster compared to 5.5mM D-glucose concentration. AGEs-BSA (3.8μM) did not affect T/S ratio, whereas H₂0₂ (25 μM) and glucosamine (5mM) reduced T/S ratio (each >12%) after 7 days’ treatment (each P<0.05 vs untreated control). In subsequent studies, co-treatment with fenofibrate (100μM) significantly attenuated by ~50% the significant reduction in T/S caused by H₂0₂ (25μM).  The mRNA levels of Trf-1, and Trf-2 were induced in H₂0₂ treated cells (62 fold and 11 fold respectively vs non-treated cells; each P<0.01) after 7 days treatment but not in glucosamine treated cells. Fenofibrate addition prevented H₂0₂ (25μM) inductions of Trf-1, and -2 gene expression (P<0.05 compared to H₂0₂ added alone).

These findings demonstrate that a telomere shortening mechanism in the diabetic metabolic environment is associated with the overexpression of Trf-1 and -2 genes and potential protective effects of fenofibrate on telomeres may be utilising this mechanism.