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

Abstract

Nicotinamide has been reported to induce differentiation of precursor/stem cells toward a ␤-cell phenotype, increase islet regeneration, and enhance insulin biosynthesis. Exposure of INS-1 ␤-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/LMaf (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. Diabetes 55: [742][743][744][745][746][747][748][749][750] 2006 A cute elevations in glucose concentration regulate pancreatic ␤-cell function, including stimulation of insulin secretion and biosynthesis. In contrast, chronic exposure of ␤-cells to elevated glucose diminishes cell function by altering ␤-cell gene expression (1) through a poorly understood process termed glucose toxicity. One of the associated outcomes of glucose toxicity on ␤-cells is a reduction in insulin gene expression (1-6) that results from decreased insulin promoter activity (2-4,7-9). The decline in insulin promoter activity correlates to a reduction in expression and/or binding of ␤-cell-enriched transcription factors, including pancreatic duodenal homeobox factor 1 (PDX-1) (1,4 -6,8,10) and mammalian homologue of avian MafA/L-Maf (MafA; also known as RIPE3b1 or C1 activator) (3,4,7, 9,11). The biochemical mechanisms whereby elevated glucose reduced PDX-1 and MafA binding activity are unknown; however, a number of studies support the possible involvement of oxidative stress (6,(11)(12)(13)(14).Nicotinamide has historically been used to augment pancreatic ␤-cell differentiation and protect islet cells from toxic insults. Treatment of cultured fetal human or porcine islet-like cell clusters, pancreatic precursor/stem cells, or embryonic stem cells with nicotinamide enhances the differentiation of ␤-cells, and this is characterized by increased insulin mRNA levels, biosynthes...

Effect of nicotinamide on early graft failure following intraportal islet transplantation

“…nicotinamide promotes islet regeneration (Yonemura et al, 1984), induces differentiation (Hellerstrom 1984;Sandler and Andersson 1988), and enhances insulin biosynthesis (Ye et al, 2006). Based on these properties, we suggest that nicotinamide may serve several therapeutic roles in the early post-transplantation period, to prevent IBMIR and promote graft survival after intraportal islet infusion.…”

Sumoylation Regulates the Transcriptional Activity of MafA in Pancreatic β Cells

“…Transient exposure of ␤ cells to high glucose has been reported to both increase and decrease MafA mRNA and protein (11,12), whereas chronic exposure to high glucose or lipids has been reported to decrease MafA protein with or without a loss of MafA mRNA (13,14). Glucose and oxidative stress are reported to regulate mafA expression at the transcriptional level through FoxO1 (15).…”

Differentiation of nestin-positive cells derived from bone marrow into pancreatic endocrine and ductal cells in vitro

“…In the second step, retinoic acid (RA) was used to promote pancreatic differentiation, consistent with the previous observation that RA is required for early pancreas development in human and mice (Ostrom et al 2008). In the last step, we used nicotinamide, which has been reported to induce differentiation/maturation of precursor/stem cells toward a b-cell phenotype and enhance insulin biosynthesis (Ye et al 2006).…”