MafA expression and insulin promoter activity are induced by nicotinamide and related compounds in INS-1 pancreatic β-cells

Diana Z. Ye, Mei Hui Tai, Katrina D. Linning, Csaba Szabo, L. Karl Olson

Research output: Contribution to journalArticle

28 Citations (Scopus)

Abstract

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

Original languageEnglish (US)
Pages (from-to)742-750
Number of pages9
JournalDiabetes
Volume55
Issue number3
DOIs
StatePublished - Mar 2006
Externally publishedYes

Fingerprint

Niacinamide
Insulin
Glucose
Thioctic Acid
Messenger RNA
Protein Stability
Quercetin
RNA Stability
Acetylcysteine
Poly(ADP-ribose) Polymerase Inhibitors
Reporter Genes
Genes
Regeneration
Proteins
Stem Cells
Antioxidants
Binding Sites
Phenotype
Mutation
pancreatic and duodenal homeobox 1 protein

ASJC Scopus subject areas

  • Internal Medicine
  • Endocrinology, Diabetes and Metabolism

Cite this

MafA expression and insulin promoter activity are induced by nicotinamide and related compounds in INS-1 pancreatic β-cells. / Ye, Diana Z.; Tai, Mei Hui; Linning, Katrina D.; Szabo, Csaba; Olson, L. Karl.

In: Diabetes, Vol. 55, No. 3, 03.2006, p. 742-750.

Research output: Contribution to journalArticle

Ye, Diana Z. ; Tai, Mei Hui ; Linning, Katrina D. ; Szabo, Csaba ; Olson, L. Karl. / MafA expression and insulin promoter activity are induced by nicotinamide and related compounds in INS-1 pancreatic β-cells. In: Diabetes. 2006 ; Vol. 55, No. 3. pp. 742-750.
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