MafA expression and insulin promoter activity are induced by nicotinamide and related compounds in INS-1 pancreatic beta-cells.
Nicotinamide has been reported to induce differentiation of precursor/stem cells toward a beta-cell phenotype, increase islet regeneration, and enhance insulin biosynthesis. Exposure of INS-1 beta-cells to elevated glucose leads to reduced insulin gene transcription, and this is associated with diminished binding of pancreatic duodenal homeobox factor 1 (PDX-1) and mammalian homologue of avian MafA/l-Maf (MafA). Nicotinamide and other low-potency poly(ADP-ribose) polymerase (PARP) inhibitors were thus tested for their ability to restore insulin promoter activity. The low-potency PARP inhibitors nicotinamide, 3-aminobenzamide, or PD128763 increased expression of a human insulin reporter gene suppressed by elevated glucose. In contrast, the potent PARP-1 inhibitors PJ34 or INO-1001 had no effect on promoter activity. Antioxidants, including N-acetylcysteine, lipoic acid, or quercetin, only minimally induced the insulin promoter. Site-directed mutations of the human insulin promoter mapped the low-potency PARP inhibitor response to the C1 element, which serves as a MafA binding site. INS-1 cells exposed to elevated glucose had markedly reduced MafA protein and mRNA levels. Low-potency PARP inhibitors restored MafA mRNA and protein levels, but they had no affect on PDX-1 protein levels or binding activity. Increased MafA expression by low-potency PARP inhibitors was independent of increased MafA protein or mRNA stability. These data suggest that low-potency PARP inhibitors increase insulin biosynthesis, in part, through a mechanism involving increased MafA gene transcription.
Ye
Diana Z
DZ
Michigan State University, Department of Pharmacology and Toxicology, East Lansing, MI, USA.
Tai
Mei-Hui
MH
Linning
Katrina D
KD
Szabo
Csaba
C
Olson
L Karl
LK
D000975:Antioxidants / Q000494:pharmacology; D001549:Benzamides / Q000494:pharmacology*; D002478:Cells, Cultured; D004791:Enzyme Inhibitors / Q000494:pharmacology; D018398:Homeodomain Proteins / Q000378:metabolism; D007328:Insulin / Q000235:genetics*; D050417:Insulin-Secreting Cells / Q000378:metabolism*; D007546:Isoquinolines / Q000494:pharmacology*; D051473:Maf Transcription Factors, Large / Q000235:genetics* / Q000378:metabolism; D009243:NAD / Q000378:metabolism; D009536:Niacinamide / Q000494:pharmacology*; D000067856:Poly(ADP-ribose) Polymerase Inhibitors; D011401:Promoter Regions, Genetic; D012333:RNA, Messenger / Q000032:analysis; D015534:Trans-Activators / Q000378:metabolism
D000975:Antioxidants; D001549:Benzamides; D004791:Enzyme Inhibitors; D018398:Homeodomain Proteins; D007328:Insulin; D007546:Isoquinolines; C485159:MAFA protein, human; D051473:Maf Transcription Factors, Large; D000067856:Poly(ADP-ribose) Polymerase Inhibitors; D012333:RNA, Messenger; D015534:Trans-Activators; C084010:pancreatic and duodenal homeobox 1 protein; D009243:NAD; C068870:3,4-dihydro-5-methyl-1(2H)-isoquinolinone; D009536:Niacinamide; C025160:3-aminobenzamide