title: Protective effect of nicotinamide on high glucose/palmitate-induced glucolipotoxicity to INS-1 beta cells is attributed to its inhibitory activity to sirtuins.
abstract: This study was initiated to determine whether the protective effect of nicotinamide (NAM) on high glucose/palmitate (HG/PA)-induced INS-1 beta cell death was due to its role as an anti-oxidant, nicotinamide dinucleotide (NAD+) precursor, or inhibitor of NAD+-consuming enzymes such as poly (ADP-ribose) polymerase (PARP) or sirtuins. All anti-oxidants tested were not protective against HG/PA-induced INS-1 cell death. Direct supplementation of NAD+ or indirect supplementation through NAD+ salvage or de novo pathway did not protect the death. Knockdown of the NAD+ salvage pathway enzymes such as nicotinamide phosphoribosyl transferase (NAMPT) or nicotinamide mononucleotide adenyltransferase (NMNAT) did not augment death. On the other hand, pharmacological inhibition or knockdown of PARP did not affect death. However, sirtinol as an inhibitor of NAD-dependant deacetylase or knockdown of SIRT3 or SIRT4 significantly reduced the HG/PA-induced death. These data suggest that protective effect of NAM on beta cell glucolipotoxicity is attributed to its inhibitory activity on sirtuins.
authors.affiliation: Institute for Medical Sciences, Ajou University School of Medicine, Suwon, Republic of Korea.
authors.forename: Soo-Jin
authors.initials: SJ
authors.lastname: Lee
authors.forename: Sung-E
authors.initials: SE
authors.lastname: Choi
authors.forename: Ik-Rak
authors.initials: IR
authors.lastname: Jung
authors.forename: Kwan-Woo
authors.initials: KW
authors.lastname: Lee
authors.forename: Yup
authors.initials: Y
authors.lastname: Kang
mesh_terms: D000111:Acetylcysteine / Q000494:pharmacology; D000818:Animals; D000975:Antioxidants / Q000494:pharmacology*; D016923:Cell Death / Q000187:drug effects; D045744:Cell Line, Tumor; D002470:Cell Survival / Q000187:drug effects; D036388:Ephrin-B2 / Q000378:metabolism; D055785:Gene Knockdown Techniques; D005947:Glucose / Q000378:metabolism* / Q000633:toxicity; D005978:Glutathione / Q000494:pharmacology; D050417:Insulin-Secreting Cells / Q000166:cytology / Q000187:drug effects*; D048670:MAP Kinase Kinase 4 / Q000378:metabolism; D009243:NAD / Q000378:metabolism / Q000494:pharmacology; D009536:Niacinamide / Q000494:pharmacology*; D010168:Palmitates / Q000378:metabolism* / Q000633:toxicity; D010766:Phosphorylation; D011064:Poly Adenosine Diphosphate Ribose / Q000037:antagonists & inhibitors; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D051381:Rats; D056566:Sirtuin 3 / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism; D037761:Sirtuins / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000378:metabolism; D051742:Transcription Factor CHOP / Q000378:metabolism
chemical_list: D000975:Antioxidants; D036388:Ephrin-B2; D010168:Palmitates; D009243:NAD; D051742:Transcription Factor CHOP; D009536:Niacinamide; D011064:Poly Adenosine Diphosphate Ribose; D051057:Proto-Oncogene Proteins c-akt; D048670:MAP Kinase Kinase 4; C530376:SIRT5 protein, rat; D056566:Sirtuin 3; D037761:Sirtuins; D005978:Glutathione; D005947:Glucose; D000111:Acetylcysteine