Selective and sequential loss of transcriptional factors: A hallmark of β‐cell failure in type 2 diabetes?

The compensatory increase in the mass of b-cells in response to peripheral insulin resistance contributes to the prevention of diabetes. Glucokinase-mediated glucose signaling and insulin receptor substrate (IRS)-2-mediated insulin signaling in the b-cells play crucial roles in the proliferation of the b-cells in this process. When the b-cell mass fails to increase to compensate for the increased insulin demand, type 2 diabetes becomes manifest. Loss of b-cell functional activity results in the development of the absolute or relative insulin insufficiency observed in patients with type 1 and type 2 diabetes, respectively. On the basis of the pathophysiological mechanism, rescue from b-cell failure is an essential target for appropriate diabetes therapy. In the presence of diabetes, b-cells are exposed to hyperglycemia, increased free fatty acids, advanced glycation end-products, glycated serum substances, inflammatory cytokines, hypoxia and abnormal neural regulation. These factors coordinately lead to oxidative stress, endoplasmic reticulum (ER) stress, uncontrolled autophagy, decreased proliferative capacity and cell death of b-cells. Oxidative stress is thought to be the primary mechanism underlying the b-cell dysfunction induced by chronic exposure to hyperglycemia, namely, glucose toxicity. Oxidative stress is also linked to ER stress and inflammation in b-cells. b-Cells show extraordinary vulnerability to superoxide damage as a result of the low levels of expression of anti-oxidant enzyme genes. Musculoaponeurotic fibrosarcoma oncogene family A (MAFA) is one of the large Maf transcription factors, a subgroup of the basic leucine-zipper family including MAFA, MAFB, c-MAF and neural retina leucine zipper (NRL). These proteins are characterized by N-terminal transactivation and C-terminal basic leucine-zipper deoxyribonucleic acid (DNA)-binding domains. MAFA is heavily phosphorylated in vivo, which affects its stability, DNA-binding capacity, transactivation and oncogenic potential. Dephosphorylation by phosphatases has been shown to inhibit the DNA-binding properties of MAFA in vitro. Pancreatic duodenal homeobox 1 (PDX1), a member of the large family of homeodomain (HD)-containing transcription factors, is associated with both type 2 diabetes and maturityonset diabetes of the young (MODY)-4. PDX1 is expressed in the precursors in the endocrine and exocrine compartments of the pancreas, and plays essential roles in pancreas development, b-cell differentiation and maintenance of mature b-cell function by regulating several b-cellrelated genes. MAFA binding to the C1 element in the insulin gene enhancer region is crucial for insulin gene transcription, together with PDX1 binding to the A3 element and neurogenic differentiation-1 binding to the E1 element. The expression levels and DNA-binding capacity of MAFA and PDX1 are reportedly decreased in the presence of oxidative stress induced by chronic high glucose exposure of b-cells. Reduction of these transcription factors has been shown to be correlated with the loss of insulin gene expression. Anti-oxidant treatment was shown to recover the failure, induced by chronic exposure to high glucose concentrations, of MAFA and PDX1 expressions, and of their DNA binding. In the presence of chronically high glucose levels, downregulation of MAFA occurred earlier than that of PDX1. These stress conditions affect PDX1 by altering its subcellular localization from the nucleus to the cytoplasm, but inhibit MAFA activity through messenger ribonucleic acid processing, stabilization and changing the cellular localization. Although the nuclear PDX1 level is unaffected under oxidative stress in db/db mice, MAFA is translocated to the cytoplasm, and p38 mitogen-activated protein kinase (MAPK)-mediated degradation is increased. Transgenic b-cell-specific overexpression of glutathione peroxidase-1 (Gpx1) rescues the b-cell functions, islet b-cell ratio, insulin granulation and nuclear MAFA content in db/db mice. Prolonged exposure of the islets to fatty acids also inhibits insulin gene transcription by impairing MAFA expression and PDX1 nuclear localization. However, the temporal, ordinal, and selective control of these transcription factors and other molecules in the b-cells during the onset and progression of diabetes remains unclear. Recently, Guo et al. found that selective loss of MAFA, MAFB, NK transcription factor-related, gene family 6, locus 1 (NKX6.1) and PDX1 contribute to b-cell failure in the course of development of diabetes (Figure 1). They showed that MAFA and/or MAFB are early and very sensitive targets of oxidative stress in b-cells. Furthermore, they showed that NKX6.1 and PDX1 are the subsequent targets in the b-cells under conditions of oxidative stress. Under oxidative stress conditions induced by hydrogen peroxide (H2O2), MAFA were translocated from the nucleus to the cytoplasm and dephosphorylated, which was mediated by covalent dimer formation by the C-terminal cysteines in the b-cells. Treatment with H2O2 also evoked dephosphorylation and *Corresponding author. Yasuo Terauchi Tel.: +81-45-787-2639 Fax: +81-45-781-5379 E-mail address: [email protected] Received 23 January 2014; accepted 27 January 2014