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MafA Expression and Insulin Promoter Activity Are Induced by Nicotinamide and Related Compounds in INS-1 Pancreatic ß-Cells

¹ Department of Pharmacology and Toxicology, Michigan State University, East Lansing, Michigan
² Department of Physiology, Michigan State University, East Lansing, Michigan
³ Inotek, Beverly, Massachusetts
⁴ Department of Human Physiology and Experimental Research, Semmelweis University Medical School, Budapest, Hungary

Address correspondence and reprint requests to L. Karl Olson, PhD, Michigan State University, Department of Physiology, 3176 BiomedicalPhysical Sciences Bldg., East Lansing, MI 48824. E-mail: olsonla{at}msu.edu

Abbreviations: BETA2, ß-cell E-box trans-activator 2; CAT, chloramphenicol acetyltransferase; DCF, dichlorofluorescein; H₂DCF, dihydrodichlorofluorescein; MafA, mammalian homologue of avian MafA/L-Maf; NAC, N-acetylcysteine; PARP, poly(ADP-ribose) polymerase; PDX-1, pancreatic duodenal homeobox factor 1; ROS, reactive oxygen species

Nicotinamide has been reported to induce differentiation of precursor/stem cells toward a ß-cell phenotype, increase islet regeneration, and enhance insulin biosynthesis. Exposure of INS-1 ß-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.

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