IKKβ inhibition prevents fat-induced beta cell dysfunction in vitro and in vivo in rodents.

Autor: Ivovic A; Department of Physiology, Faculty of Medicine, University of Toronto, Toronto, ON, Canada, M5S 1A8., Oprescu AI; Institute of Medical Science, Faculty of Medicine, University of Toronto, Toronto, ON, Canada., Koulajian K; Department of Physiology, Faculty of Medicine, University of Toronto, Toronto, ON, Canada, M5S 1A8., Mori Y; Division of Diabetes, Metabolism, and Endocrinology, Showa University School of Medicine, Shinagawa, Tokyo, Japan., Eversley JA; Department of Physiology, Faculty of Medicine, University of Toronto, Toronto, ON, Canada, M5S 1A8., Zhang L; Division of Cellular and Molecular Biology, Toronto General Research Institute, University Health Network, Toronto, ON, Canada., Nino-Fong R; Department of Biomedical Sciences, Ross University School of Veterinary Medicine, Basseterre, St Kitts and Nevis., Lewis GF; Department of Physiology, Faculty of Medicine, University of Toronto, Toronto, ON, Canada, M5S 1A8.; Department of Medicine, Faculty of Medicine, University of Toronto, Toronto, ON, Canada.; Banting and Best Diabetes Centre, University of Toronto, Toronto, ON, Canada., Donath MY; Department of Endocrinology, Diabetes, and Metabolism, University Hospital Basel, Basel, Switzerland., Karin M; Department of Pharmacology, University of California, San Diego, School of Medicine, La Jolla, CA, USA., Wheeler MB; Department of Physiology, Faculty of Medicine, University of Toronto, Toronto, ON, Canada, M5S 1A8., Ehses J; Department of Surgery, Faculty of Medicine, University of British Columbia, Vancouver, BC, Canada.; Child and Family Research Institute, Vancouver, BC, Canada., Volchuk A; Keenan Research Centre for Biomedical Science, St Michael's Hospital, Toronto, ON, Canada., Chan CB; Department of Agriculture, Food and Nutritional Sciences, Faculty of Agricultural, Life and Environmental Sciences, University of Alberta, Edmonton, AB, Canada.; Department of Physiology, Faculty of Medicine and Dentistry, University of Alberta, Edmonton, AB, Canada., Giacca A; Department of Physiology, Faculty of Medicine, University of Toronto, Toronto, ON, Canada, M5S 1A8. adria.giacca@utoronto.ca.; Institute of Medical Science, Faculty of Medicine, University of Toronto, Toronto, ON, Canada. adria.giacca@utoronto.ca.; Department of Medicine, Faculty of Medicine, University of Toronto, Toronto, ON, Canada. adria.giacca@utoronto.ca.; Banting and Best Diabetes Centre, University of Toronto, Toronto, ON, Canada. adria.giacca@utoronto.ca.
Jazyk: angličtina
Zdroj: Diabetologia [Diabetologia] 2017 Oct; Vol. 60 (10), pp. 2021-2032. Date of Electronic Publication: 2017 Jul 20.
DOI: 10.1007/s00125-017-4345-9
Abstrakt: Aims/hypothesis: We have previously shown that oxidative stress plays a causal role in beta cell dysfunction induced by fat. Here, we address whether the proinflammatory kinase inhibitor of (nuclear factor) κB kinase β (IKKβ), which is activated by oxidative stress, is also implicated.
Methods: Fat (oleate or olive oil) was infused intravenously in Wistar rats for 48 h with or without the IKKβ inhibitor salicylate. Thereafter, beta cell function was evaluated in vivo using hyperglycaemic clamps or ex vivo in islets isolated from fat-treated rats. We also exposed rat islets to oleate in culture, with or without salicylate and 4(2'-aminoethyl)amino-1,8-dimethylimidazo(1,2-a)quinoxaline; BMS-345541 (BMS, another inhibitor of IKKβ) and evaluated beta cell function in vitro. Furthermore, oleate was infused in mice treated with BMS and in beta cell-specific Ikkb-null mice.
Results: 48 h infusion of fat impaired beta-cell function in vivo, assessed using the disposition index (DI), in rats (saline: 1.41 ± 0.13; oleate: 0.95 ± 0.11; olive oil [OLO]: 0.87 ± 0.15; p < 0.01 for both fats vs saline) and in mice (saline: 2.51 ± 0.39; oleate: 1.20 ± 0.19; p < 0.01 vs saline) and ex vivo (i.e., insulin secretion, units are pmol insulin islet -1  h -1 ) in rat islets (saline: 1.51 ± 0.13; oleate: 1.03 ± 0.10; OLO: 0.91 ± 0.13; p < 0.001 for both fats vs saline) and the dysfunction was prevented by co-infusion of salicylate in rats (oleate + salicylate: 1.30 ± 0.09; OLO + salicylate: 1.33 ± 0.23) or BMS in mice (oleate + BMS: 2.25 ± 0.42) in vivo and by salicylate in rat islets ex vivo (oleate + salicylate: 1.74 ± 0.31; OLO + salicylate: 1.54 ± 0.29). In cultured islets, 48 h exposure to oleate impaired beta-cell function ([in pmol insulin islet -1  h -1 ] control: 0.66 ± 0.12; oleate: 0.23 ± 0.03; p < 0.01 vs saline), an effect prevented by both inhibitors (oleate + salicylate: 0.98 ± 0.08; oleate + BMS: 0.50 ± 0.02). Genetic inhibition of IKKβ also prevented fat-induced beta-cell dysfunction ex vivo ([in pmol insulin islet -1  h -1 ] control saline: 0.16 ± 0.02; control oleate: 0.10 ± 0.02; knockout oleate: 0.17 ± 0.04; p < 0.05 control saline vs. control oleate) and in vivo (DI: control saline: 3.86 ± 0.40; control oleate: 1.95 ± 0.29; knockout oleate: 2.96 ± 0.24; p < 0.01 control saline vs control oleate).
Conclusions/interpretation: Our results demonstrate a causal role for IKKβ in fat-induced beta cell dysfunction in vitro, ex vivo and in vivo.
Databáze: MEDLINE
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