High glucose potentiates palmitate-induced NO-mediated cytotoxicity through generation of superoxide in clonal beta-cell HIT-T15.
Prolonged exposure to free fatty acids induces beta-cell cytotoxicity. We investigated whether this fatty-acid-induced cytotoxicity is affected by high glucose levels. In clonal beta-cell HIT-T15, palmitate-induced cytotoxicity was potentiated depending on elevated glucose concentrations due to increased apoptosis without cytotoxic effects of high glucose per se. This palmitate cytotoxicity was blocked by NO synthase inhibitors, and palmitate actually increased cellular NO production. The potentiation of palmitate cytotoxicity under high glucose was reversed by decreasing superoxide production, suggesting that superoxide overproduction under high glucose enhances NO-mediated cytotoxicity in beta-cells, which may explain the mechanism of synergistic deterioration of pancreatic beta-cells by free fatty acids and high glucose.
Okuyama
Ryo
R
Pharmacology and Molecular Biology Research Laboratories, Sankyo Co. Ltd., 2-58 Hiromachi-1-chome, Shinagawa-ku, 140-8710, Tokyo, Japan. ryooku@shima.sankyo.co.jp
Fujiwara
Toshihiko
T
Ohsumi
Jun
J
D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D002460:Cell Line; D002470:Cell Survival / Q000187:drug effects; D002999:Clone Cells; D006224:Cricetinae; D004305:Dose-Response Relationship, Drug; D004791:Enzyme Inhibitors / Q000494:pharmacology; D005230:Fatty Acids, Nonesterified / Q000378:metabolism / Q000494:pharmacology; D005944:Glucosamine / Q000378:metabolism; D005947:Glucose / Q000494:pharmacology / Q000502:physiology*; D007211:Indoles / Q000494:pharmacology; D007515:Islets of Langerhans / Q000166:cytology / Q000187:drug effects* / Q000378:metabolism*; D008301:Maleimides / Q000494:pharmacology; D009569:Nitric Oxide / Q000378:metabolism; D019308:Palmitic Acid / Q000494:pharmacology*; D013481:Superoxides / Q000378:metabolism*; D013997:Time Factors
D004791:Enzyme Inhibitors; D005230:Fatty Acids, Nonesterified; D007211:Indoles; D008301:Maleimides; D013481:Superoxides; D019308:Palmitic Acid; D009569:Nitric Oxide; D005947:Glucose; C088060:bisindolylmaleimide; D005944:Glucosamine