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Shortening of telomere length by metabolic factors in diabetes: protective effects of fenofibrate.

Abstract

People with diabetes mellitus have shorter telomeres compared with non-diabetic subjects. The aim of this study was to investigate an in-vitro model of telomere shortening under diabetes metabolic conditions. The mechanisms of the accelerated telomere length attrition and the potential telomere protective action of fenofibrate with related cellular mechanisms were also examined. Human dermal fibroblasts were passaged and cultured in normal (5.5 mM) or high (25 mM) D-glucose, across 7 days with hydrogen peroxide (H2O2), glucosamine (GA), or glycated albumin (AGEs-BSA). Relative telomere length (RTL) was determined by qPCR. The expression of shelterin complex members which regulate telomere stability were measured by qRT-PCR and Western immunoblot. Culture in high glucose decreased RTL compared with normal glucose: H2O2 and GA lowered the RTL after 7 days (each P < 0.05 vs untreated control), whereas AGEs-BSA had no effect compared with control-BSA. At day 7 the mRNA levels of most shelterin complex members, were induced by H2O2 and to a lesser extent by GA. Trf1 and Trf2 protein were induced by H2O2. Co-treatment with fenofibrate (100 μM) significantly attenuated the reduction in RTL caused by H2O2 and GA and prevented Trf induction by H2O2. However knockdown of Trf1 and Trf2 expression using specific siRNA did not prevent H2O2 effects to lower RTL, thus implicating factors other than these Trfs alone in the fenofibrate protection against the H2O2 induction of RTL lowering. These in vitro findings demonstrate that diabetic conditions can induce telomere shortening and that fenofibrate has protective effects on telomere attrition, through as yet undefined mechanisms.

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  • Authors+Show Affiliations

    ,

    Greg Brown Diabetes and Endocrinology Research Laboratory, Sydney Medical School (Central), Charles Perkins Centre, The University of Sydney, Sydney, NSW, 2006, Australia. Department of Endocrinology, Royal Prince Alfred Hospital, Sydney, NSW, Australia.

    ,

    Greg Brown Diabetes and Endocrinology Research Laboratory, Sydney Medical School (Central), Charles Perkins Centre, The University of Sydney, Sydney, NSW, 2006, Australia. Department of Endocrinology, Royal Prince Alfred Hospital, Sydney, NSW, Australia. NSW Health Pathology, Sydney, Australia.

    ,

    Greg Brown Diabetes and Endocrinology Research Laboratory, Sydney Medical School (Central), Charles Perkins Centre, The University of Sydney, Sydney, NSW, 2006, Australia.

    Greg Brown Diabetes and Endocrinology Research Laboratory, Sydney Medical School (Central), Charles Perkins Centre, The University of Sydney, Sydney, NSW, 2006, Australia. stephen.twigg@sydney.edu.au. Department of Endocrinology, Royal Prince Alfred Hospital, Sydney, NSW, Australia. stephen.twigg@sydney.edu.au.

    Source

    Pub Type(s)

    Journal Article

    Language

    eng

    PubMed ID

    31203557

    Citation

    Sutanto, Surya Shin Ichi, et al. "Shortening of Telomere Length By Metabolic Factors in Diabetes: Protective Effects of Fenofibrate." Journal of Cell Communication and Signaling, 2019.
    Sutanto SSI, McLennan SV, Keech AC, et al. Shortening of telomere length by metabolic factors in diabetes: protective effects of fenofibrate. J Cell Commun Signal. 2019.
    Sutanto, S. S. I., McLennan, S. V., Keech, A. C., & Twigg, S. M. (2019). Shortening of telomere length by metabolic factors in diabetes: protective effects of fenofibrate. Journal of Cell Communication and Signaling, doi:10.1007/s12079-019-00521-x.
    Sutanto SSI, et al. Shortening of Telomere Length By Metabolic Factors in Diabetes: Protective Effects of Fenofibrate. J Cell Commun Signal. 2019 Jun 15; PubMed PMID: 31203557.
    * Article titles in AMA citation format should be in sentence-case
    TY - JOUR T1 - Shortening of telomere length by metabolic factors in diabetes: protective effects of fenofibrate. AU - Sutanto,Surya Shin Ichi, AU - McLennan,Susan Virginia, AU - Keech,Anthony C, AU - Twigg,Stephen Morris, Y1 - 2019/06/15/ PY - 2019/03/03/received PY - 2019/05/07/accepted PY - 2019/6/17/entrez PY - 2019/6/17/pubmed PY - 2019/6/17/medline KW - Diabetes KW - Glucosamine KW - Oxidative-stress KW - Premature-aging KW - Telomere JF - Journal of cell communication and signaling JO - J Cell Commun Signal N2 - People with diabetes mellitus have shorter telomeres compared with non-diabetic subjects. The aim of this study was to investigate an in-vitro model of telomere shortening under diabetes metabolic conditions. The mechanisms of the accelerated telomere length attrition and the potential telomere protective action of fenofibrate with related cellular mechanisms were also examined. Human dermal fibroblasts were passaged and cultured in normal (5.5 mM) or high (25 mM) D-glucose, across 7 days with hydrogen peroxide (H2O2), glucosamine (GA), or glycated albumin (AGEs-BSA). Relative telomere length (RTL) was determined by qPCR. The expression of shelterin complex members which regulate telomere stability were measured by qRT-PCR and Western immunoblot. Culture in high glucose decreased RTL compared with normal glucose: H2O2 and GA lowered the RTL after 7 days (each P < 0.05 vs untreated control), whereas AGEs-BSA had no effect compared with control-BSA. At day 7 the mRNA levels of most shelterin complex members, were induced by H2O2 and to a lesser extent by GA. Trf1 and Trf2 protein were induced by H2O2. Co-treatment with fenofibrate (100 μM) significantly attenuated the reduction in RTL caused by H2O2 and GA and prevented Trf induction by H2O2. However knockdown of Trf1 and Trf2 expression using specific siRNA did not prevent H2O2 effects to lower RTL, thus implicating factors other than these Trfs alone in the fenofibrate protection against the H2O2 induction of RTL lowering. These in vitro findings demonstrate that diabetic conditions can induce telomere shortening and that fenofibrate has protective effects on telomere attrition, through as yet undefined mechanisms. SN - 1873-9601 UR - https://www.unboundmedicine.com/medline/citation/31203557/Shortening_of_telomere_length_by_metabolic_factors_in_diabetes:_protective_effects_of_fenofibrate L2 - https://dx.doi.org/10.1007/s12079-019-00521-x DB - PRIME DP - Unbound Medicine ER -