Production and secretion of insulin from the β-cells of the pancreas is very crucial in maintaining normoglycaemia. This is achieved by tight regulation of insulin synthesis and exocytosis from the β-cells in response to changes in blood glucose levels. The synthesis of insulin is regulated by blood glucose levels at the transcriptional and post-transcriptional levels. Although many transcription factors have been implicated in the regulation of insulin gene transcription, three β-cell-specific transcriptional regulators, Pdx-1 (pancreatic and duodenal homeobox-1), NeuroD1 (neurogenic differentiation 1) and MafA (V-maf musculoaponeurotic fibrosarcoma oncogene homologue A), have been demonstrated to play a crucial role in glucose induction of insulin gene transcription and pancreatic β-cell function. These three transcription factors activate insulin gene expression in a co-ordinated and synergistic manner in response to increasing glucose levels. It has been shown that changes in glucose concentrations modulate the function of these β-cell transcription factors at multiple levels. These include changes in expression levels, subcellular localization, DNA-binding activity, transactivation capability and interaction with other proteins. Furthermore, all three transcription factors are able to induce insulin gene expression when expressed in non-β-cells, including liver and intestinal cells. The present review summarizes the recent findings on how glucose modulates the function of the β-cell transcription factors Pdx-1, NeuroD1 and MafA, and thereby tightly regulates insulin synthesis in accordance with blood glucose levels.

INTRODUCTION

Increases in blood glucose levels stimulate insulin gene transcription and insulin secretion [1,2]. Insulin gene transcription is mainly controlled by a 340 bp promoter region upstream of the transcription start site of the insulin gene. The insulin promoter is organized in a complex arrangement of discrete cis-acting sequence motifs, which serve as binding sites for both ubiquitous and β-cell-specific transcription factors [3,4]. The co-ordinated interaction between cis-elements and trans-acting factors at the promoter contributes to both the β-cell-specific expression of the insulin gene and the regulation of expression in response to glucose, calcium levels, nutrient availability and hormone signalling [5,6]. Much of the glucose responsiveness inherent to the insulin promoter is conferred by the A3, E1 and C1 sites, which are bound by the transcription factors Pdx-1 (pancreatic and duodenal homeobox-1) [714], NeuroD1 (neurogenic differentiation 1)/Beta2 [1517] and MafA (V-maf musculoaponeurotic fibrosarcoma oncogene homologue A) [12,18,19] respectively. These three transcription factors act in a co-ordinated and synergistic manner to stimulate insulin gene expression in response to increased glucose levels [2022] (Figure 1).

Co-ordinated and synergistic activation of insulin gene expression by Pdx-1, NeuroD1 and MafA

Figure 1
Co-ordinated and synergistic activation of insulin gene expression by Pdx-1, NeuroD1 and MafA

Pdx-1 binds to the A-boxes, NeuroD1 to the E-boxes and MafA to the C1 element within the 400 bp region of the insulin promoter and activate insulin gene expression in a co-ordinated and synergistic manner in the presence of elevated blood glucose levels. All three elements are conserved within the insulin promoters of various species, including human and rodent insulin promoters. NeuroD1 binds to the E1 element as a heterodimer with the ubiquitous transcription factor E47.

Figure 1
Co-ordinated and synergistic activation of insulin gene expression by Pdx-1, NeuroD1 and MafA

Pdx-1 binds to the A-boxes, NeuroD1 to the E-boxes and MafA to the C1 element within the 400 bp region of the insulin promoter and activate insulin gene expression in a co-ordinated and synergistic manner in the presence of elevated blood glucose levels. All three elements are conserved within the insulin promoters of various species, including human and rodent insulin promoters. NeuroD1 binds to the E1 element as a heterodimer with the ubiquitous transcription factor E47.

Compared with humans, rodents (rat and mouse) have two insulin genes, of which the insulin II gene and its promoter is mostly similar to that of humans [23]. On the basis of the analysis of transcription factor-binding sites and spacing of the cis-regulatory elements, there are significant differences between rodent and human insulin gene promoters [24]. However, a detailed comparative analysis of the insulin promoters from various species suggest that all three regulatory elements (A3, E1 and C1), important for glucose regulation of insulin gene expression, are conserved between species with the A-box (A3) to which Pdx-1 binds being the most highly conserved one [24].

Although Pdx-1, NeuroD1 and MafA have been shown to be crucial for glucose regulation of insulin gene transcription, the exact mechanisms by which glucose modulates the function of these transcription factors remains to be established. Studies from several laboratories, including ours, suggest that glucose regulates the function of these transcription factors by different mechanisms. In the case of Pdx-1, it has been proposed that glucose modulates the function of Pdx-1 by regulating the localization, DNA-binding activity and interaction of Pdx-1 with multiple proteins [2531]. Several lines of evidence suggest that NeuroD1 changes its localization in response to changing glucose levels. Under normal glucose conditions, NeuroD1 is mainly cytosolic, and exposure to high glucose causes its translocation into the nucleus [32,33]. MafA expression itself requires high glucose. Although expression of MafA is very low under normal glucose conditions, MafA transcription increases drastically in response to high glucose [3437]. The major focus of the present review is on the recent findings on glucose regulation of Pdx-1, NeuroD1 and MafA in pancreatic β-cells and the implication of these findings on insulin synthesis and pancreatic β-cell function. Furthermore, the mechanisms by which these β-cell-specific transcription factors activate insulin gene transcription will also be discussed.

ROLE OF PDX-1 IN GLUCOSE REGULATION OF INSULIN GENE EXPRESSION

Role of Pdx-1 in pancreatic β-cell function

Pdx-1 {also known as STF-1 (somatostatin transactivating factor 1) [38], IPF-1 (insulin promoter factor 1) [39], IUF-1 (insulin upstream factor 1) [40], IDX-1 (islet and duodenal homeobox 1) [41] and GSF (glucose-sensitive factor) [42]} is the major regulator of glucose-stimulated insulin gene transcription and is essential for embryonic development of the pancreas [812,14,43,44]. The homeodomain transcription factor Pdx-1 is first expressed in the primitive gut tube during embryonic development of the pancreas around E (embryonic day) 8.5. Pdx-1 homozygous knockout mice fail to develop a pancreas and die shortly after birth, because of a lack of insulin [4547]. Heterozygous Pdx-1 mice have a normal pancreas, but are hyperglycaemic, which is caused by decreased insulin production. Pancreatic agenesis is also observed in a patient carrying a homozygous single nucleotide deletion in the PDX1 gene [48]. β-Cell-specific disruption of the PDX1 gene results in diabetes with aging and suggests that Pdx-1 is essential for maintenance of β-cell identity [49]. These findings indicate that Pdx-1 is required for early development of the pancreas as well as for pancreatic β-cell maturation and function.

In the fully developed pancreas, Pdx-1 expression is mainly restricted to the insulin-producing β-cells and somatostatin-producing δ-cells within the pancreatic islets. However, Pdx-1 expression also has been observed in the epithelial cells of the duodenum [38,41]. Pdx-1 primarily acts in the β-cell to up-regulate the transcription of several β-cell-specific genes, including insulin, GLUT2 (glucose transporter-2) [50], glucokinase [51], somatostatin [38,52], islet amyloid polypeptide [52] and MafA [53], as well as auto-regulating its own expression. It also has been reported that Pdx-1 functions as a transcriptional repressor for glucagon [49,54], cytokeratin K19 [55] and c-Myc [56]. The repressor activity of Pdx-1 appears to be important in maintenance of β-cell identity by inhibiting the expression of genes specific for α-cells (glucagon) and pancreatic ductal cells (cytokeratin K19).

The transactivation domain of Pdx-1 is at the N-terminus, and this domain also mediates unique protein–protein interactions with other transcription factors such as NeuroD1 and transcriptional co-regulators, including p300 [22,29,5761]. Pdx-1 also contains a central DNA-binding homeodomain with a novel nuclear localization signal [62,63]. Activation of insulin gene transcription by Pdx-1 occurs via binding to the A-elements of the insulin promoter. Various point mutations in the PDX1 gene have been shown to result in pancreatic agenesis, impaired glucose tolerance and/or diabetes in humans. Specific point mutations in PDX1 also are associated with MODY (maturity-onset diabetes of the young) 4 and late-onset Type 2 diabetes, characterized by a decline in β-cell function [48,64,65].

Molecular mechanisms of Pdx-1-mediated activation of insulin gene transcription

Recent findings suggest that one of the mechanisms by which Pdx-1 promotes insulin gene transcription is by mediating histone modifications at the insulin promoter. Pdx-1 has been demonstrated to recruit the HAT (histone acetyltransferase) p300 to the insulin promoter only at high levels of glucose (10–30 mM), which leads to increased acetylation of histones [57,58,66]. The histone methyltransferase Set9 has also been shown to be recruited to the insulin promoter via Pdx-1, leading to dimethylation of histone H3 Lys4 [67]. These histone acetylation and methylation events lead to changes in the chromatin structure that promote insulin gene transcription [6770]. Binding of Pdx-1 to the insulin promoter is required for pol II (RNA polymerase II) to adopt the elongation isoform for active transcription. In the absence of Pdx-1, pol II appears to be unable to switch from the initiation (pSer5) to the elongation (pSer2) isoform, which is required for active transcriptional elongation [67,71]. These observations suggest that Pdx-1 regulates insulin gene transcription by promoting a transcriptionally active chromatin structure, which enhances elongation by pol II.

There is also evidence that Pdx-1 participates in repression of gene expression and mediates transcriptional repression of glucagon [54], cytokeratin K19 and c-Myc [55,56]. However, it is not known whether the ability of Pdx-1 to repress transcription is related to changes in chromatin structure. Interestingly, Pdx-1 has been shown to recruit HDAC (histone deacetylase)-1 and -2 to the insulin promoter in response to low glucose levels (1–3 mM) to down-regulate insulin gene transcription [29]. It is therefore likely that Pdx-1 mediates repression of gene expression by recruiting co-repressors. Pdx-1 is also reported to interact with PCIF-1 (Pdx-1 C-terminus-interacting factor-1), a TRAF (tumour-necrosis-factor-receptor-associated factor) and POZ domain-containing nuclear factor that inhibits Pdx-1-transactivation potential independent of histone co-repressor/HDAC recruitment [72,73]. However, the exact mechanism by which PCIF-1 inhibits transactivation by Pdx-1 remains to be established. Bridge-1 (PSMD9) is another protein that has been shown to interact with Pdx-1 and stimulate Pdx-1 transcriptional activity. The co-regulator Bridge-1 is a PDZ-like domain protein, and its ability to activate transcription appears to be dependent on its interaction with the HAT p300 [60,74]. In summary, Pdx-1 appears to regulate gene transcription by promoting the assembly of multiprotein complexes at the insulin promoter.

Regulation of Pdx-1 function by glucose and other signalling pathways

Glucose, the physiological regulator of insulin gene transcription, modulates Pdx-1 function in pancreatic β-cells by multiple mechanisms. We have discovered that glucose regulates the interaction of Pdx-1 with various co-regulators in a phosphorylationdependent manner in the mouse insulinoma cell line MIN6. Under low or normal glucose conditions (1–3 mM), Pdx-1 is mainly associated with HDAC-1 and HDAC-2 to down-regulate insulin gene expression [29]. Increases in glucose levels (10–30 mM) disrupt the interaction of Pdx-1 with HDACs and promote its association with the HAT p300, which leads to hyperacetylation of histone H4 and induction of insulin gene transcription [58,66]. This switch in Pdx-1 interaction in response to high glucose requires a phosphorylation event that causes changes in Pdx-1 localization [58]. On low glucose, Pdx-1 is localized mainly to the nuclear periphery and interacts with HDAC-1 and HDAC-2, whereas on high glucose, Pdx-1 interacts with p300 and is localized throughout the nucleus. Blocking of Pdx-1 localization to the nuclear periphery on low glucose by treatment with the phosphatase inhibitor okadaic acid disrupts the ability of Pdx-1 to interact with HDAC-1 and HDAC-2 and promotes its interaction with the HAT p300 [29,58].

Changes in glucose levels regulate the subcellular localization of Pdx-1. On low glucose (1–3 mM), Pdx-1 is mainly localized to the nuclear periphery and, in response to glucose stimulation, Pdx-1 becomes phosphorylated and shuttles to the nucleoplasm and is associated with target gene promoters [27,75]. Several signalling pathways including the p38/SAPK (stress-activated protein kinase) [75,76], PI3K (phosphoinositide 3-kinase) [77], atypical PKC (protein kinase C) [78] and MAPK (mitogen-activated protein kinase) pathways [79,80], as well as PAS (Per-Arnt-Sim) kinase [81] have been implicated in Pdx-1 phosphorylation, nucleocytoplasmic shuttling, DNA binding and transactivation potential. Ser61 and Ser66 of Pdx-1 have been demonstrated to be phosphorylated in response to p38, MAPK and PI3K signalling. Thr152 has been shown to be phosphorylated by PAS kinase and to regulate the nucleocytoplasmic shuttling and transactivation potential of Pdx-1 [81]. However, the exact residues that become phosphorylated by the various kinases and their physiological significance still remain to be determined.

Various studies indicate that modification by phosphorylation also regulates the stability of the Pdx-1 protein. The DNA-dependent protein kinase has been shown to phosphorylate Thr11 in Pdx-1 in response to radiation-induced DNA damage to promote Pdx-1 protein degradation [30]. Another study has demonstrated that GSK3 (glycogen synthase kinase 3) phosphorylates Pdx-1 on Ser61 and/or Ser66 in response to oxidative stress, which also results in degradation of the Pdx-1 protein [82,83]. These studies provide a possible mechanism for previous observations where Pdx-1 protein levels have been shown to be reduced under glucotoxic and oxidative stress conditions [26,8486]. However, other studies have shown that oxidative stress inhibits Pdx-1 nuclear localization and DNA binding through activation of the JNK (c-Jun N-terminal kinase) pathway [87]. The nuclear exclusion of Pdx-1 would also explain the decreases in insulin gene transcription observed under oxidative stress conditions. The interplay of Pdx-1 protein stability and intracellular localization requires further investigation to elucidate fully the role of Pdx-1 in β-cell dysfunction under oxidative stress conditions.

Several studies suggest that Pdx-1 may be subject to a number of other post-translational modifications, including SUMOylation [88] and O-linked glycosylation [28]. Although SUMOylation of Pdx-1 appears to modulate Pdx-1 localization and stability [88], glycosylation of Pdx-1 has been reported to regulate Pdx-1 DNA-binding activity [28]. Exposure of pancreatic islets to elevated levels of fatty acids such as palmitate has been shown to reduce the nuclear localization and expression levels of Pdx-1 [8991]. Other factors that regulate Pdx-1 levels include the GLP1 (glucagon-like peptide 1), which is produced in the intestine and promotes glucose-regulated transcription of insulin [92,93]. GLP1 has been shown to increase Pdx-1 levels, as well as enhance the transactivation domain and DNA-binding activity of Pdx-1 and its nuclear localization [92,94,95]. Expression of Pdx-1 in pancreatic β-cells appears to be independent of the glucose concentration; however, glucotoxic conditions lead to reduction in Pdx-1 levels.

In summary, changes in glucose levels have been shown to regulate the nuclear localization, DNA binding and transactivation capacity of Pdx-1 and its interaction with co-regulators. Nuclear localization and Pdx-1 interaction with co-activators appears to be dependent on phosphorylation of Pdx-1 (Figure 2). On the basis of the published results, Pdx-1 is mainly in the nuclear periphery under low or normal glucose conditions and interacts with HDACs. In response to high glucose, Pdx-1 becomes phosphorylated and translocates into the nucleoplasm and interacts with the HAT p300 to stimulate insulin gene expression (Figure 2).

Glucose regulates the subcellular localization and interaction of Pdx-1 with co-regulators

Figure 2
Glucose regulates the subcellular localization and interaction of Pdx-1 with co-regulators

Under low-glucose conditions, Pdx-1 is mainly localized to the nuclear periphery. Results from our laboratory suggest that Pdx-1 interacts with co-repressors (HDACs) under low-glucose conditions (1–3 mM) to down-regulate insulin gene expression. Elevated levels of glucose (10–30 mM) mediate the phosphorylation of Pdx-1, which disrupts the localization of Pdx-1 to the nuclear periphery and enables its interaction with co-activators such as the HAT p300 and the histone methyltransferase Set7/9 in order to activate insulin gene transcription. Symbols: A, A-box; P, phospho group; ∼ insulin mRNA.

Figure 2
Glucose regulates the subcellular localization and interaction of Pdx-1 with co-regulators

Under low-glucose conditions, Pdx-1 is mainly localized to the nuclear periphery. Results from our laboratory suggest that Pdx-1 interacts with co-repressors (HDACs) under low-glucose conditions (1–3 mM) to down-regulate insulin gene expression. Elevated levels of glucose (10–30 mM) mediate the phosphorylation of Pdx-1, which disrupts the localization of Pdx-1 to the nuclear periphery and enables its interaction with co-activators such as the HAT p300 and the histone methyltransferase Set7/9 in order to activate insulin gene transcription. Symbols: A, A-box; P, phospho group; ∼ insulin mRNA.

FUNCTION OF NeuroD1 IN GLUCOSE-INDUCTION OF INSULIN GENE EXPRESSION

Role of NeuroD1 in pancreatic β-cell function

NeuroD1, also known as Beta2, belongs to the bHLH (basic helix–loop–helix) family of transcription factors and functions in a complex with the ubiquitously expressed E47 protein [16,96]. The NeuroD1 protein consists of 355 amino acids with the bHLH DNA-binding domain located at residues 100–155. Defects in NeuroD1 function have been associated with many diseases, including ataxia, deafness, and Type 1 and Type 2 diabetes [15]. NeuroD1 is required for terminal neuronal differentiation and ectopic expression of NeuroD1 in Xenopus embryos mediates the conversion of epidermal cells into neurons [9698]. NeuroD1 is expressed widely throughout the developing CNS (central nervous system) and the auditory and vestibular systems [99].

In addition to neuronal cells, NeuroD1 is also expressed in both the developing and adult pancreas [16,17]. In the developing pancreas, NeuroD1 is detected as early as E9.5 in the pancreatic primordia, indicating that NeuroD1 is present in early precursor cells. At E17.5, NeuroD1 is mainly expressed in small clusters of endocrine cells. NeuroD1 is present in all mature β-cells and in approx. 2% of α-cells. NeuroD1 has been implicated in regulation of insulin and glucagon gene expression [16,100]. Homozygous NeuroD1−/− newborn mice are hyperglycaemic and have ketonuria, and die within 5 days of birth [101]. Further analysis suggests that the severe diabetes observed in these mice is due to a significant reduction in the number of islet cells, which is due to a failure of endocrine cells to aggregate into mature islets. However, the viability of the homozygous NeuroD1 mice appears to be dependent on genetic background [102]. Specific mutations in NeuroD1 have been linked to the MODY6 locus [103,104]. A polymorphism in Ala45 to threonine has been associated with Type 1 diabetes in some populations [105,106].

NeuroD1 is also implicated in regulation of insulin secretion by glucose via modulation of the expression of genes such as neuronatin (Nna), which is an ion channel transporter [107], and Sur1, which forms potassium channels with Kir6.2 [108]. In a recent study, introduction of NeuroD1 into a human fetal epithelial cell line induced the expression of several genes required for vesicular trafficking and exocytosis, including Sec24D, SNAP25 (25 kDa synaptosome-associated protein), syntaxin1 and Munc18 [109]. This finding suggests that NeuroD1 may regulate insulin exocytosis in pancreatic β-cells by directly inducing the expression of genes involved in exocytosis. Other targets of NeuroD1 include IGRP (islet-specific glucose-6-phophatase catalytic-subunit-related protein) [110] and glucokinase [111].

Regulation of insulin gene transcription by NeuroD1

NeuroD1-directed transcription of insulin has been shown to occur via a DNA consensus sequence known as E-box (CANNTG) within the insulin promoter [57]. NeuroD1 itself is unable to bind DNA and associates with DNA as a heterodimer with another ubiquitously expressed bHLH protein E47 [112,113]. The ability of NeuroD1 to activate transcription is enhanced by its interaction with the co-activator p300 or CBP [CREB (cAMP-response-element-binding protein)-binding protein] [57,114,115]. NeuroD1 also has been shown to interact with SHP (small heterodimer partner), an orphan nuclear receptor that functions as a repressor of transcription [116]. SHP has been demonstrated to compete for p300 binding to NeuroD1 and therefore functions as a co-repressor. NeuroD1 interaction with Pdx-1 is essential to synergistically activate insulin gene transcription in β-cells [57,113].

Modulation of NeuroD1 function by glucose

Glucose has been shown to regulate the nuclear localization as well as transactivation capacity of NeuroD1 via post-transcriptional modification. NeuroD1 is modified by phosphorylation by ERK1/2 (extracellular-signal-regulated kinase 1/2) [80] and GSK3β [117], by acetylation by p300 [118] and by O-linked glycosylation by OGT (O-linked GlcNAc transferase) [32]. The MAPKs ERK1/2 have been implicated in regulation of insulin gene transcription in pancreatic β-cells, and the activity of ERK1/2 is increased in response to glucose [79,80,119]. In the presence of high glucose, NeuroD1 becomes phosphorylated by ERK2 at multiple sites within its transactivation domain, which enhances the transactivation capacity of NeuroD1 [80]. Regulation of insulin gene transcription by ERK1/2 is mediated by phosphorylation of Pdx-1, NeuroD1 and E47.

Glucose-mediated phosphorylation has also been proposed to regulate NeuroD1 nuclear localization. In low-glucose-incubated MIN6 cells, NeuroD1 has been shown to be mainly localized in the cytosol, whereas exposure to high glucose caused NeuroD1 translocation into the nucleus [33]. Treatment of pancreatic β-cells with the MEK (MAPK/ERK kinase) inhibitor PD98059 blocked the nuclear translocation of NeuroD1 in pancreatic β-cells. Furthermore, a serine-to-alanine mutation of NeuroD1 at Ser274 interfered with NeuroD1 nuclear translocation, dimerization with E47 and DNA-binding activity [33]. Another kinase that has been implicated in regulation of NeuroD1 function is GSK3β. Phosphorylation of NeuroD1 by GSK3β has been shown to inhibit NeuroD1-induced ectopic neurogenesis [117]. Phosphorylation of NeuroD1 by CaMKII (Ca2+/calmodulin-dependent protein kinase II) at Ser336 in primary neurons has been demonstrated to be important for induction of dendritic morphogenesis [120]. However, the role of GSK3β and CaMKII in regulation of NeuroD1 function in pancreatic β-cells remains unknown. Acetylation of NeuroD1 by P/CAF (p300/CBP-associated factor) appears to regulate the DNA-binding and transactivation capacity of NeuroD1 in insulinoma cell lines [118].

Recent findings from our laboratory suggest that increased flux via the HBP (hexosamine biosynthetic pathway) (caused by high levels of glucose) mediates the O-GlcNAc modification of NeuroD1 [32] (Figure 3). Under high-glucose conditions (10–30 mM), NeuroD1 interacts with OGT and becomes O-GlcNAc-modified. This modification causes NeuroD1 to translocate from the cytosol into the nucleus (Figure 4). On the other hand, under low-glucose conditions (1–3 mM), NeuroD1 becomes deglycosylated by interacting with the O-GlcNAcase (O-linked N-acetylglucosaminidase), which causes its exit from the nucleus (Figure 4). Since phosphorylation has also been implicated in NeuroD1 nuclear translocation, it is possible that there is a Yin–Yang relationship between phosphorylation and O-GlcNAc modification of NeuroD1. Indeed, Ser274, which has been shown to be phosphorylated by MAPKs, is predicted to be also O-GlcNAc-modified [32,33].

UDP-GlcNAc synthesis via the HBP and O-linked glycosylation of proteins by OGT

Figure 3
UDP-GlcNAc synthesis via the HBP and O-linked glycosylation of proteins by OGT

Flux through the HBP leads to the synthesis of UDP-GlcNAc, which is used as the substrate for OGT. O-GlcNAcase is responsible for removing O-GlcNAc from modified proteins. AGM1, N-acetylglucosamine phosphomutase 1; DON, 6-diazo-5-oxo-L-norleucine; GFAT, glutamine:fructose-6-phosphate amidotransferase; GNA, glucosamine-6-phosphate acetyltransferase; PUGNAc, O-(2-acetamido-2-deoxy-D-glucopyranosylidene) amino-N-phenylcarbamate; UAP, UDP-N-acetylglucosamine pyrophosphorylase.

Figure 3
UDP-GlcNAc synthesis via the HBP and O-linked glycosylation of proteins by OGT

Flux through the HBP leads to the synthesis of UDP-GlcNAc, which is used as the substrate for OGT. O-GlcNAcase is responsible for removing O-GlcNAc from modified proteins. AGM1, N-acetylglucosamine phosphomutase 1; DON, 6-diazo-5-oxo-L-norleucine; GFAT, glutamine:fructose-6-phosphate amidotransferase; GNA, glucosamine-6-phosphate acetyltransferase; PUGNAc, O-(2-acetamido-2-deoxy-D-glucopyranosylidene) amino-N-phenylcarbamate; UAP, UDP-N-acetylglucosamine pyrophosphorylase.

High levels of glucose mediate the O-GlcNAc modification of NeuroD1 and its translocation into the nucleus

Figure 4
High levels of glucose mediate the O-GlcNAc modification of NeuroD1 and its translocation into the nucleus

In the presence of low glucose (1–3 mM), NeuroD1 is mainly localized to the cytosol. In response to high glucose (10–30 mM), it becomes O-GlcNAc-modified by OGT in the cytosol, which causes its translocation into the nucleus. Once in the nucleus, NeuroD1 heterodimerizes with E47 and activates insulin gene expression by recruiting co-activators such as p300. Phosphorylation of NeuroD1 by ERK has also been shown to mediate its translocation into the nucleus. E47, which heterodimerizes with NeuroD1 and binds to the E1 element within the insulin promoter, is also phosphorylated by ERK, and phosphorylated E47 translocates into the nucleus. Symbols: Ac, acetyl group; G, GlcNAc; NPC, nuclear pore complex; P, phospho group.

Figure 4
High levels of glucose mediate the O-GlcNAc modification of NeuroD1 and its translocation into the nucleus

In the presence of low glucose (1–3 mM), NeuroD1 is mainly localized to the cytosol. In response to high glucose (10–30 mM), it becomes O-GlcNAc-modified by OGT in the cytosol, which causes its translocation into the nucleus. Once in the nucleus, NeuroD1 heterodimerizes with E47 and activates insulin gene expression by recruiting co-activators such as p300. Phosphorylation of NeuroD1 by ERK has also been shown to mediate its translocation into the nucleus. E47, which heterodimerizes with NeuroD1 and binds to the E1 element within the insulin promoter, is also phosphorylated by ERK, and phosphorylated E47 translocates into the nucleus. Symbols: Ac, acetyl group; G, GlcNAc; NPC, nuclear pore complex; P, phospho group.

REGULATION OF INSULIN GENE TRANSCRIPTION BY MafA

Role of MafA in β-cell function

MafA is a basic leucine zipper transcription factor belonging to the large Maf family of transcription factors. Large Maf transcription factors have an N-terminal transactivation domain, a leucine zipper domain (responsible for homodimerization) and a DNA-recognition region (responsible for binding DNA elements termed Maf recognition elements or MAREs) [121,122]. MafA is expressed in pancreatic β-cells, as well as in the eye, and has been implicated in lens development [123,124]. In pancreatic β-cells, MafA plays an important role in glucose regulation of insulin gene expression [34,35,37,125]. Beyond insulin expression, MafA also appears to play a role in mediating the expression of a number of other genes, including granuphilin [126], adiponectin [127], GLUT2 [20,128,129], Nkx6.1 (NK6 homeobox 1) [128], Pdx-1 [128,130], pyruvate carboxylase [128], prohormone convertase 1/3 [128,131] and CHOP [C/EBP (CCAAT/enhancer-binding protein)-homologous protein] [132]. However, it is unclear whether many of these genes are bona fide MafA target genes or whether their regulation by MafA is indirect.

Expression of MafA is observed at later stages of β-cell development around E13.5, suggesting a role for MafA in β-cell maintenance [125]. MafA-knockout mice are viable, but develop diabetes with age as the result of decreased expression of β-cell-specific genes, including insulin, reduced insulin secretion, decreased β-cell number and altered islet architecture [129]. The MafA-knockout animals do not have as severe a phenotype as the Pdx-1 [46] or NeuroD1 [101] -knockout animals. The reason for this could be that MafA expression is restricted to the β-cells of the pancreas [37,125], unlike Pdx-1 and NeuroD1, or because the other large Maf family members, MafB or c-Maf, may compensate for the loss of MafA. MafB and c-Maf have been shown to be expressed in insulin-positive cells and can activate the insulin promoter in in vitro experiments [37,133,134]. Furthermore, recent findings suggest that, during β-cell development, MafB is expressed before MafA expression and is replaced by MafA after insulin expression is initiated [133,135]. These data suggest that, although MafB is important for differentiation of α- and β-cells, MafA plays a role in β-cell function after birth, which is consistent with the finding that MafA-knockout mice have normal islet structure at birth. Gene-transfer experiments indicate that MafA is capable of inducing insulin gene expression in liver cells [21,136,137] and in intestinal cells [20,131]. As in β-cells, MafA synergizes with Pdx-1 and NeuroD1 to enhance the synthesis of insulin in non-β-cells [20,21,136,137].

Regulation of insulin gene expression by MafA

MafA binds to the C1 element within the insulin promoter, which was originally designated as the RIPE3b1 element and demonstrated to be important for expression of the rat insulin II gene [138,139]. Earlier studies demonstrated that the C1 element is important for the β-cell-specific expression of insulin [138,140142] and for the glucose-dependent regulation of insulin expression [139,143,144]. Later studies indicated that a β-cell-specific transcription factor(s) is bound to the C1 element in a glucose- and phosphorylation-dependent manner [141,143146].

Like other Maf-binding elements, the C1 element contains a MARE, which is required for MafA binding [34,125]. The binding of MafA to the C1 element is a crucial event leading to transcriptional up-regulation of insulin both in vitro [34,35,37,125,143,147,148] and in vivo [127,129]. The mechanism by which MafA participates in insulin transcription includes binding to and synergizing with Pdx-1, NeuroD1 and NFAT (nuclear factor of activated T-cells) [148150].

Regulation of MafA levels by glucose and other signals

MafA binds to the C1 element of the insulin promoter in a glucose-dependent manner [143,144], and this is due to accumulation of MafA in response to high glucose (10–25 mM) conditions. Both MafA mRNA and protein levels increase in response to high glucose [34,36,147,148]. We have determined recently that the high glucose-dependent up-regulation of MafA is dependent on the HBP and O-linked glycosylation of an unknown protein(s) [36] (Figures 3 and 5). Our findings suggest that a transcription factor regulating MafA expression may be O-GlcNAc-modified and thereby induces MafA expression [36] (Figure 5). Recently, biochemical studies revealed that Fox (Forkhead box) O1, FoxA2, Nkx2.2 (NK2 homeobox 2) and Pdx-1 bind directly to the MafA promoter and mediate MafA transcription [53,151,152]. Bioinformatics analysis indicates that NeuroD1 may also bind to the promoter of MafA [53]. Of these factors, Pdx-1 and NeuroD1 are known to be O-GlcNAc-modified, which promotes their binding to the insulin promoter [28,32]. Previous findings suggest that FoxO1, which has been shown to regulate MafA expression [152], is also O-GlcNAc-modified [153,154]. Therefore Pdx-1, NeuroD1 and FoxO1 may be crucial factors in regulating the high-glucose-dependent expression of MafA via O-linked glycosylation.

Glucose regulation of MafA transcription requires O-GlcNAc modification of proteins

Figure 5
Glucose regulation of MafA transcription requires O-GlcNAc modification of proteins

Our recent findings suggest that low-glucose conditions (1–3 mM) down-regulate MafA levels by decreasing MafA transcription. High concentrations of glucose (10–25 mM) stimulate MafA transcription via O-GlcNAc of unknown transcription factor(s) (X) and/or other signalling proteins. Once MafA levels increase, a portion of it is ubiquitinated and degraded in a proteasome-dependent manner. The remaining MafA translocates to the nucleus and participates in the glucose-dependent transcription of the insulin gene. Symbols: G, GlcNAc; ∼, insulin mRNA.

Figure 5
Glucose regulation of MafA transcription requires O-GlcNAc modification of proteins

Our recent findings suggest that low-glucose conditions (1–3 mM) down-regulate MafA levels by decreasing MafA transcription. High concentrations of glucose (10–25 mM) stimulate MafA transcription via O-GlcNAc of unknown transcription factor(s) (X) and/or other signalling proteins. Once MafA levels increase, a portion of it is ubiquitinated and degraded in a proteasome-dependent manner. The remaining MafA translocates to the nucleus and participates in the glucose-dependent transcription of the insulin gene. Symbols: G, GlcNAc; ∼, insulin mRNA.

MafA levels in β-cells also appear to be regulated by post-transcriptional mechanisms. Recently, GSK3 was demonstrated to be responsible for constitutively phosphorylating MafA at multiple residues, leading to its destabilization and degradation by the proteasome [155,156]. Phosphorylation of Ser61, Thr57, Thr53 and Ser49 by GSK3 causes MafA ubiquitination and degradation [156].

In addition to regulating MafA protein levels, phosphorylation has been implicated in modulating the binding of MafA to the insulin promoter [145,146] and to the CHOP promoter in pancreatic β-cells [132]. Furthermore, phosphorylation may regulate the transactivation potential of MafA via recruitment of the co-activator P/CAF [156]. In the neuroretina, phosphorylation of Ser14 and Ser65 within the transactivation domain of MafA has been shown to be critical for activation of crystallin genes by MafA [157,158]. The importance of Ser14 and Ser65 within MafA for induction of transcription from a MARE-containing reporter gene was confirmed in another independent study [159]. The MAPK p38 also has been shown to phosphorylate MafA at Thr57 and Thr113 within the transactivation domain. Furthermore, using MS, Ser272 located in the C-terminus of MafA was demonstrated to be a substrate for p38 [160]. A mutant MafA protein lacking all three p38 phosphorylation sites was unable to induce the lens differentiation programme [160]. However, the exact role of phosphorylation in regulating the transactivation capacity of MafA in pancreatic β-cell remains to be determined.

The current findings suggest that enhanced production of MafA under high-glucose conditions may regulate the glucose-dependent insulin gene transcription, whereas decreased production and proteasomal degradation of MafA probably allows for rapid inhibition of insulin transcription under low-glucose conditions (Figure 5). This model assumes that β-cells must up-regulate MafA expression before the induction of insulin transcription. However, it is currently unknown whether MafA expression and MafA binding to the insulin promoter occurs before the induction of glucose-dependent insulin transcription.

Chronic hyperglycaemia or glucotoxicity is a hallmark of diabetes, which leads to β-cell failure, including a loss of insulin expression [84,86,161163]. Several in vitro studies indicate that one of the major factors contributing to decreased insulin expression during glucotoxicity is decreased expression of MafA followed by its reduced binding to the insulin promoter [8486,89,162166]. These findings indicate that the loss of MafA may cause or enhance the glucotoxic effects in β-cells during hyperglycaemia. Consistent with this idea, MafA expression is lost or reduced in several diabetic animal models, including FoxO307 mice [152,167], insulin receptor L2 mutant mice [152,168], βDKO (β-cell double-knockout) mice lacking both the insulin and IGF-1 (insulin-like growth factor 1) receptors [169], Pdx-1PBHNF6 [transgenic mice in which HNF6 (hepatic nuclear factor 6) expression is maintained in postnatal islets] mice [170] and the NZO (New Zealand obese) mice [171]. Moreover, the MafA-knockout animals themselves also develop diabetes [129]. Chronically increased levels of lipids (lipotoxicity) have also been shown to reduce MafA levels by inhibiting MafA gene expression [89,161]. Exposure to pro-inflammatory cytokines also causes down-regulation of MafA levels [172,173]. Down-regulation of MafA levels is observed under various disease conditions and may contribute to the development of diabetes.

CONCLUSIONS AND PERSPECTIVES

The transcription factors Pdx-1, NeuroD1 and MafA are major regulators of insulin gene transcription and β-cell function in general. These β-cell-specific transcription factors interact with each other to tightly control insulin gene expression in a co-ordinated and synergistic manner (Figure 1). Although glucose modulates the function of all three of these transcription factors, the mechanisms by which glucose regulates their function is distinctive. In the case of Pdx-1, glucose appears to mainly regulate the interaction of Pdx-1 with various proteins such as co-activators and co-repressors in a phosphorylation-dependent manner in order to control β-cell-specific gene transcription (Figure 2). Nuclear localization as well as the transactivation capability of Pdx-1 has been shown to be regulated by glucose (Figure 2). Glucose regulation of NeuroD1 involves changes in NeuroD1 subcellular localization. Although NeuroD1 is mainly cytosolic on low glucose, exposure to high glucose causes O-linked glycosylation and phosphorylation of NeuroD1 and its translocation into the nucleus, where it can activate transcription in a co-ordinated manner (Figure 4). Interestingly, the expression of MafA itself is responsive to changes in glucose levels. Transcription of MafA is only induced when high glucose is present, whereas MafA transcription is down-regulated in response to low glucose (Figure 5). All three of these transcription factors have been demonstrated to induce the expression of the normally silent insulin gene in liver and other non-β-cells and are therefore of therapeutic interest. Because of the major importance of Pdx-1, NeuroD1 and MafA in pancreatic β-cell function, it is not surprising that the mechanisms by which glucose regulates their function is complex and involves several pathways and signals in addition to glucose. Detailed understanding of the mechanisms by which changes in glucose levels modulate the function of these β-cell-specific transcription factors may contribute to the development of novel strategies to treat and prevent diabetes and its associated complications.

M. L. S. and N. L. V. are supported by an American Heart Association Predoctoral Fellowship from Great Rivers Affiliate. S. Ö. is supported by Grant Number R01DK067581 from NIDDK (National Institute of Diabetes and Digestive and Kidney Disease) and 1-05-CD-15 from the American Diabetes Association. We apologize to all authors whose original work we were unable to cite owing to space constraints.

Abbreviations

     
  • bHLH

    basic helix–loop–helix

  •  
  • CAMKII

    Ca2+/calmodulin-dependent protein kinase II

  •  
  • CBP

    CREB (cAMP-response-element-binding protein)-binding protein

  •  
  • CHOP

    C/EBP (CCAAT/enhancer-binding protein)-homologous protein

  •  
  • E

    embryonic day

  •  
  • ERK

    extracellular-signal-regulated kinase

  •  
  • Fox

    Forkhead box

  •  
  • GLP1

    glucagon-like peptide 1

  •  
  • GLUT2

    glucose transporter 2

  •  
  • GSK3

    glycogen synthase kinase 3

  •  
  • HAT

    histone acetyltransferase

  •  
  • HBP

    hexosamine biosynthetic pathway

  •  
  • HDAC

    histone deacetylase

  •  
  • MafA

    V-maf musculoaponeurotic fibrosarcoma oncogene homologue A

  •  
  • MAPK

    mitogen-activated protein kinase

  •  
  • MARE

    Maf recognition element

  •  
  • MODY

    maturity-onset diabetes of the young

  •  
  • NeuroD1

    neurogenic differentiation 1

  •  
  • O-GlcNAcase
  •  
  • O-linked N-acetylglucosaminidase
  •  
  • OGT

    O-linked GlcNAc transferase

  •  
  • PAS

    Per-Arnt-Sim

  •  
  • P/CAF

    p300/CBP-associated factor

  •  
  • PCIF-1

    Pdx-1 C-terminus-interacting factor-1

  •  
  • Pdx-1

    pancreatic and duodenal homeobox-1

  •  
  • PI3K

    phosphoinositide 3-kinase

  •  
  • pol II

    RNA polymerase II

  •  
  • SHP

    small heterodimer partner

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Author notes

1

These authors made an equal contribution to this review.