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Int. J. Mol. Sci. 2012, 13(10), 13680-13690; doi:10.3390/ijms131013680
Published: 22 October 2012
Abstract: Type 2 diabetes is characterized by pancreatic β-cell dysfunction and insulin resistance, and the number of patients has markedly increased worldwide. In the diabetic state, hyperglycemia per se and subsequent induction of oxidative stress decrease insulin biosynthesis and secretion, leading to the aggravation of Type 2 diabetes. In addition, there is substantial reduction in expression and/or activities of several insulin gene transcription factors. This process is known as β-cell glucose toxicity, which is often observed under diabetic conditions. Taken together, it is likely that oxidative stress explains, at least in part, the molecular mechanism for β-cell glucose toxicity, which is often observed in Type 2 diabetes.
1. Natural History of Pancreatic β-Cell Failure Which Is Often Observed in Type 2 Diabetes
Type 2 diabetes is characterized by pancreatic β-cell dysfunction and insulin resistance. First, overeating and/or obesity lead to the development of insulin resistance, and normal β-cells secrete a larger amount of insulin to compensate for the increased insulin resistance. Next, large adipocytes secrete more free fatty acids (FFAs) and/or various inflammatory cytokines, which gradually deteriorate β-cell function and finally lead to the onset of diabetes. This process is known as “β-cell lipotoxicity”. Indeed, it has been reported that when islets or β-cell-derived cell lines are exposed to FFAs, oxidative stress is induced, which leads to the reduction of insulin secretion [1–5]. It has been also reported that FFA-mediated induction of inducible nitric oxide synthase (iNOS) and excess nitric oxide (NO) generation are involved in the progression of β-cell dysfunction . It is noted here that since most of these experiments were performed in a cell culture system, further in vivo studies would be necessary to demonstrate the importance of “β-cell lipotoxicity” in the deterioration of β-cell function. In addition, the primary cause of Type 2 diabetes is not necessarily due to the aggravation of insulin resistance induced by overeating and/or obesity. It has been thought recently that Type 2 diabetes is fundamentally a polygenic disease involving primary β-cell insufficiency. Indeed, obesity and insulin resistance are not necessarily observed in Type 2 diabetes.
Once hyperglycemia becomes apparent, β-cell function such as insulin biosynthesis and secretion progressively deteriorates. This process is known as “β-cell glucose toxicity” which is often observed under diabetic conditions. In the diabetic state, hyperglycemia per se and subsequent induction of oxidative stress decrease insulin gene expression and secretion and finally bring about apoptotic cell death [7–32]. It is noted that although a variety of factors including ER stress, inflammatory cytokines and amyloid fibrils are likely involved in the mechanism for glucose toxicity which includes β-cell dysfunction and β-cell death, in this review we focus on the role of oxidative stress in the progression of β-cell dysfunction, especially suppression of insulin biosynthesis, found in Type 2 diabetes.
Furthermore, very recently a new concept was proposed about the natural history of β-cell failure; it was reported that loss of β-cell mass was due to β-cell dedifferentiation, but not due to β-cell death. Indeed, the lineage-tracing experiments showed that dedifferentiated β-cells converted into progenitor-like cells and adopted the α-cell fate. These findings show that the process of dedifferentiation of β-cells plays a crucial role in the natural history of β-cell failure .
2. Oxidative Stress Is involved in Pancreatic β-Cell Glucose Toxicity, Which Is Often Observed in Type 2 Diabetes
It has been shown that oxidative stress is provoked in various tissues under diabetic conditions. There are several sources of reactive oxygen species (ROS) in cells such as the non-enzymatic glycosylation reaction , the electron transport chain in mitochondria . The glycation reaction produces Schiff base, Amadori product, and finally advanced glycosylation end products (AGE). During the process, oxidative stress is provoked. The electron transport chain in mitochondria is also an important pathway to induce oxidative stress. Under diabetic conditions, the electron transport chain is activated, which leads to production of larger amounts of ROS (Figure 1).
Under diabetic conditions, oxidative stress is induced and involved in the β-cell glucose toxicity. β-Cells express GLUT2, a high-Km glucose transporter, and thereby display highly efficient glucose uptake when exposed to a high glucose concentration. Indeed, it was shown that expression levels of oxidative stress markers such as 8-hydroxy-2′-deoxyguanosine (8-OHdG) and 4-hydroxy-2,3-nonenal (4-HNE) were increased in islets under diabetic conditions. In addition, β-cells are rather vulnerable to oxidative stress due to the relatively low expression of antioxidant enzymes such as catalase and glutathione peroxidase [36,37]. Therefore, it is likely that oxidative stress is involved in the deterioration of β-cell function found in diabetes. It was shown that when β-cell-derived cell lines or rat-isolated islets were exposed to oxidative stress, insulin gene promoter activity and mRNA expression were suppressed. In addition, when they were exposed to oxidative stress, bindings of PDX-1 and/or MafA to the insulin gene promoter were reduced. It is noted here that PDX-1 plays a crucial role in pancreas development, β-cell differentiation, induction of surrogate β-cells, and maintenance of mature β-cell function [38–50] and that MafA is a recently isolated β-cell-specific transcription factor and functions as a potent activator of insulin gene transcription [51–56].
Furthermore, it was shown that the decrease of insulin gene expression after chronic exposure to a high glucose concentration was prevented by treatment with antioxidants [19,26,29–32]. Reduction of expression and/or DNA binding activities of PDX-1 and MafA by chronic exposure to high glucose was also prevented by an antioxidant treatment. These results suggest that chronic hyperglycemia suppresses insulin biosynthesis and secretion by increasing oxidative stress, accompanied by reduction of expression and/or DNA binding activities of two important pancreatic transcription factors PDX-1 and MafA. Therefore, it is likely that the alteration of such transcription factors explains, at least in part, the suppression of insulin biosynthesis and secretion, and thereby is involved in β-cell glucose toxicity (Figure 2). Indeed, it was shown that the antioxidant treatment retained glucose-stimulated insulin secretion and moderately ameliorated glucose tolerance in obese diabetic C57BL/KsJ-db/db mice . Beta-Cell mass was significantly larger in the mice treated with the antioxidants, and insulin content was preserved by the antioxidant treatment. Furthermore, PDX-1 expression was more clearly visible in the nuclei of β-cells after the antioxidant treatment . Similar effects were observed with Zucker diabetic fatty rats, another model animal for Type 2 diabetes . Therefore, it is likely that antioxidant treatment can protect β-cells against glucose toxicity. It is noted, however, that since it remains unclear at this point whether the antioxidant treatment can have positive effects on insulin gene expression even in the presence of continuing hyperglycemia, further studies would be necessary to clarify this point.
3. Activation of the JNK Pathway Is Involved in Pancreatic β-Cell Glucose Toxicity
It has been suggested that activation of the c-Jun N-terminal kinase (JNK) pathway is involved in pancreatic β-cell dysfunction found in Type 2 diabetes. It was reported that activation of the JNK pathway is involved in reduction of insulin gene expression by oxidative stress and that suppression of the JNK pathway can protect β-cells from oxidative stress . When isolated rat islets were exposed to oxidative stress, the JNK pathway was activated, preceding the decrease of insulin gene expression. Adenoviral overexpression of dominant-negative type JNK1 (DN-JNK) protected insulin gene expression and secretion from oxidative stress. These results were correlated with change in the binding of PDX-1 to insulin gene promoter. Adenoviral overexpression of DN-JNK preserved PDX-1 DNA binding activity in the face of oxidative stress, while WT-JNK overexpression decreased PDX-1 DNA binding activity . Taken together, it is likely that activation of the JNK pathway leads to decreased PDX-1 activity and consequent suppression of insulin gene transcription found in the diabetic state.
Also, it was shown that PDX-1 is translocated from the nuclei to the cytoplasm in response to oxidative stress. When β-cell-derived HIT cells were exposed to oxidative stress, PDX-1 moved from the nuclei to the cytoplasm . DN-JNK overexpression inhibited the oxidative stress-induced PDX-1 translocation, suggesting that activation of the JNK pathway is involved in PDX-1 translocation by oxidative stress. Furthermore, leptomycin B, an inhibitor, which specifically suppresses the classical, leucine-rich nuclear export signal (NES), inhibited nucleo-cytoplasmic translocation of PDX-1 induced by oxidative stress . Taken together, it is likely that oxidative stress induces nucleo-cytoplasmic translocation of PDX-1 through activation of the JNK pathway, which leads to reduction of its DNA binding activity and suppression of insulin biosynthesis.
The forkhead transcription factor Foxo1 is known as one of the important fundamental transcription factors playing a key role in apoptosis, cellular proliferation and differentiation, and glucose metabolism through regulating the transcription of various target genes [59,60]. It was shown that Foxo1 regulates hepatic gluconeogenesis and thus contributes to insulin resistance . Insulin inhibits the function of Foxo1 through Akt-mediated phosphorylation and nuclear exclusion , and thereby suppresses hepatic gluconeogenesis. It was also shown that PDX-1 exhibits a counter localization to Foxo1 in β-cells; when Foxo1 is expressed in the cytoplasm, PDX-1 is expressed in the nuclei, and when Foxo1 is expressed in the nuclei, PDX-1 is expressed in the cytoplasm . Moreover, it was shown that Foxo1 plays a role as a mediator between the JNK pathway and PDX-1 . In β-cell-derived cell line HIT cells, Foxo1 changed its intracellular localization from the cytoplasm to the nucleus after exposure to oxidative stress. In contrast to Foxo1, the nuclear expression of PDX-1 was decreased and its cytoplasmic distribution was increased by oxidative stress. Activation of the JNK pathway also induced the nuclear localization of Foxo1. In addition, oxidative stress or activation of the JNK pathway decreased Akt phosphorylation in HIT cells, leading to the decreased phosphorylation of Foxo1 following nuclear localization . Taken together, oxidative stress and subsequent activation of the JNK pathway induce nuclear translocation of Foxo1 through the modification of the insulin signaling in β-cells, which leads to the nucleo-cytoplasmic translocation of PDX-1 and reduction of its DNA binding activity (Figure 3).
4. Induction of c-Jun Expression Is Involved in Pancreatic β-Cell Glucose Toxicity
It is known that c-Jun protein level and activity are increased in response to oxidative stress in various cells. We recently reported that c-Jun expression was not clearly detected in islets of control m/m mice and young diabetic db/db mice, but that the number of c-Jun-positive cells gradually increased with age in the islets of diabetic db/db mice . This expression pattern of c-Jun paralleled the loss of MafA expression. Quantitative real-time PCR analysis using freshly isolated islets from db/db mice clearly showed that the c-Jun mRNA level was significantly increased but that both MafA and insulin mRNA levels were markedly decreased with age . Furthermore, it was recently reported that expression levels of MafA in diabetic patients were lower compared to those in healthy subjects . These results imply that the increased level of c-Jun caused a decrease in MafA and insulin gene expression in old diabetic mice. Furthermore, in db/db mice nuclear MafA expression in pancreatic islets was markedly decreased with age and was not clearly detected in old mice, whereas in control m/m mice MafA expression was retained up to old age . In db/db mice insulin expression was also decreased in some cells in which MafA was undetectable or weakly expressed. MafA and insulin expression was suppressed in most c-Jun-positive cells. Similarly, in obese diabetic KK-Ay islets, the number of c-Jun-positive cells was increased with marked hyperglycemia, and both MafA and insulin protein levels were decreased in those cells . These findings suggest that c-Jun is involved in the suppression of MafA and insulin expression under diabetic conditions. In addition, c-Jun overexpression markedly decreased insulin promoter activity, which was consistent with previous reports [67,68].
Although c-Jun protein expression was almost undetectable in MIN6 cells, adenoviral c-Jun overexpression markedly suppressed MafA protein levels and its DNA-binding activity in MIN6 cells . Adenoviral overexpression of c-Jun in isolated mouse islets also markedly suppressed MafA mRNA and protein levels. Consistent with these results, mRNA levels of insulin 1 and 2 and insulin content were suppressed by c-Jun overexpression in both MIN6 cells and islets . These findings directly demonstrate that c-Jun suppresses the expression of both MafA and insulin. In addition, since MafA appears to not only regulate insulin expression but also to be involved in insulin secretion [69,70], it is likely that the suppression of MafA protein levels by c-Jun leads to insulin secretory defects that are often observed under diabetic conditions. In conclusion, the augmented expression of c-Jun in diabetic islets decreases MafA activity followed by reduced insulin biosynthesis and secretion, and thereby explains, at least in part, the molecular mechanism for β-cell glucose toxicity that is often observed in Type 2 diabetes (Figure 3).
Pancreatic β-cell dysfunction and insulin resistance are the hallmarks of Type 2 diabetes. Under diabetic conditions, hyperglycemia per se and subsequent induction of oxidative stress decrease insulin biosynthesis and secretion, accompanied by reduction in expression and/or activities of insulin gene transcription factors PDX-1 and MafA. This process is known as β-cell glucose toxicity, which is often observed under diabetic conditions.
- Carlsson, C.; Borg, L.A.; Welsh, N. Sodium palmitate induces partial mitochondrial uncoupling and reactive oxygen species in rat pancreatic islets in vitro. Endocrinology 1999, 140, 3422–3428.
- Joseph, J.W.; Koshkin, V.; Saleh, M.C.; Sivitz, W.I.; Zhang, C.Y.; Lowell, B.B.; Chan, C.B.; Wheeler, M.B. Free fatty acid-induced β-cell defects are dependent on uncoupling protein 2 expression. J. Biol. Chem 2004, 279, 51049–51056.
- Wang, X.; Li, H.; de Leo, D.; Guo, W.; Koshkin, V.; Fantus, I.G.; Giacca, A.; Chan, C.B.; Der, S.; Wheeler, M.B. Gene and protein kinase expression profiling of reactive oxygen species-associated lipotoxicity in the pancreatic β-cell line MIN6. Diabetes 2004, 53, 129–140.
- Oprescu, A.I.; Bikopoulos, G.; Naassan, A.; Allister, E.M.; Tang, C.; Park, E.; Uchino, H.; Lewis, G.F.; Fantus, I.G.; Rozakis-Adcock, M.; et al. Free fatty acid-induced reduction in glucose-stimulated insulin secretion: evidence for a role of oxidative stress in vitro and in vivo. Diabetes 2007, 56, 2927–2937.
- Bikopoulos, G.; da Silva Pimenta, A.; Lee, S.C.; Lakey, J.R.; Der, S.D.; Chan, C.B.; Ceddia, R.B.; Wheeler, M.B.; Rozakis-Adcock, M. Ex vivo transcriptional profiling of human pancreatic islets following chronic exposure to monounsaturated fatty acids. J. Endocrinol 2008, 196, 455–464.
- Shimabukuro, M.; Ohneda, M.; Lee, Y.; Unger, R.H. Role of nitric oxide in obesity-induced beta cell disease. J. Clin. Invest 1997, 46, 1276–1280.
- Weir, G.C.; Laybutt, D.R.; Kaneto, H.; Bonner-Weir, S.; Sharma, A. β-Cell adaptation and decompensation during the progression of diabetes. Diabetes 2001, 50, S154–S159.
- Poitout, V.; Robertson, R.P. Minireview: Secondary beta-cell failure in type 2 diabetes—A convergence of glucotoxicity and lipotoxicity. Endocrinology 2002, 143, 339–342.
- Robertson, R.P.; Harmon, J.; Tran, P.O.; Tanaka, Y.; Takahashi, H. Glucose toxicity in β-cells: Type 2 diabetes, good radicals gone bad and the glutathione connection. Diabetes 2003, 52, 581–587.
- Evans, J.L.; Goldfine, I.D.; Maddux, B.A.; Grodsky, G.M. Are oxidative stress-activated signaling pathways mediators of insulin resistance and β-cell dysfunction? Diabetes 2003, 52, 1–8.
- Prentki, M.; Nolan, C.J. Islet β cell failure in type 2 diabetes. J. Clin. Invest 2006, 116, 1802–1812.
- Kaneto, H.; Matsuoka, T.; Nakatani, Y.; Kawamori, D.; Miyatsuka, T.; Matsuhisa, M.; Yamasaki, Y. Oxidative stress, ER stress, and the JNK pathway in type 2 diabetes. J. Mol. Med 2005, 83, 429–439.
- Robertson, R.P.; Zhang, H.J.; Pyzdrowski, K.L.; Walseth, T.F. Preservation of insulin mRNA levels and insulin secretion in HIT cells by avoidance of chronic exposure to high glucose concentrations. J. Clin. Invest 1992, 90, 320–325.
- Olson, L.K.; Redmon, J.B.; Towle, H.C.; Robertson, R.P. Chronic exposure of HIT cells to high glucose concentrations paradoxically decreases insulin gene transcription and alters binding of insulin gene regulatory protein. J. Clin. Invest 1993, 92, 514–519.
- Olson, L.K.; Sharma, A.; Peshavaria, M.; Wright, C.V.; Towle, H.C.; Robertson, R.P.; Stein, R. Reduction of insulin gene transcription in HIT-T15 β-cells chronically exposed to a supraphysiologic glucose concentration is associated with loss of STF-1 transcription factor expression. Proc. Natl. Acad. Sci. USA 1995, 92, 514–519.
- Poitout, V.; Olson, L.K.; Robertson, R.P. Chronic exposure of βTC-6 cells to supraphysiologic concentrations of glucose decreases binding of the RIPE3b1 insulin gene transcription activator. J. Clin. Invest 1996, 97, 1041–1046.
- Sharma, A.; Fusco-DeMane, D.; Henderson, E.; Efrat, S.; Stein, R. The role of the insulin control element and RIPE3b1 activators in glucose-stimulated transcription of the insulin gene. Mol. Endocrinol 1995, 9, 1468–1488.
- Moran, A.; Zhang, H.-J.; Olson, L.K.; Harmon, J.S.; Poitout, V.; Robertson, R.P. Differentiation of glucose toxicity from beta cell exhaustion during the evolution of defective insulin gene expression in the pancreatic islet cell line, HIT-T15. J. Clin. Invest 1997, 99, 534–539.
- Tanaka, Y.; Gleason, C.E.; Tran, P.O.T.; Harmon, J.S.; Robertson, R.P. Prevention of glucose toxicity in HIT-T15 cells and Zucker diabetic fatty rats by antioxidants. Proc. Natl. Acad. Sci. USA 1999, 96, 10857–10862.
- Tanaka, Y.; Tran, P.O.T.; Harmon, J.; Robertson, R.P. A role of glutathione peroxidase in protecting pancreatic β cells against oxidative stress in a model of glucose toxicity. Proc. Natl. Acad. Sci. USA 2002, 99, 12363–12368.
- Kaneto, H.; Fujii, J.; Myint, T.; Islam, K.N.; Miyazawa, N.; Suzuki, K.; Kawasaki, Y.; Nakamura, M.; Tatsumi, H.; Yamasaki, Y.; et al. Reducing sugar triggers oxidative modification and apoptosis in pancreatic β-cells by provoking oxidative stress through the glycation reaction. Biochem. J 1996, 320, 855–863.
- Matsuoka, T.; Kajimoto, Y.; Watada, H.; Kaneto, H.; Kishimoto, M.; Umayahara, Y.; Fujitani, Y.; Kamada, T.; Kawamori, R.; Yamasaki, Y. Glycation-dependent, reactive oxygen species-mediated suppression of the insulin gene promoter activity in HIT cells. J. Clin. Invest 1997, 99, 144–150.
- Ihara, Y.; Toyokuni, S.; Uchida, K.; Odaka, H.; Tanaka, T.; Ikeda, H.; Hiai, H.; Seino, Y.; Yamada, Y. Hyperglycemia causes oxidative stress in pancreatic β-cells of GK rats, a model of type 2 diabetes. Diabetes 1999, 48, 927–932.
- Kajimoto, Y.; Matsuoka, T.; Kaneto, H.; Watada, H.; Fujitani, Y.; Kishimoto, M.; Sakamoto, K.; Matsuhisa, M.; Kawamori, R.; Yamasaki, Y.; et al. Induction of glycation suppresses glucokinase gene expression in HIT-T15 cells. Diabetologia 1999, 42, 1417–1424.
- Maechler, P.; Jornot, L.; Wollheim, C.B. Hydrogen peroxide alters mitochondrial activation and insulin secretion in pancreatic beta cells. J. Biol. Chem 1999, 274, 27905–27913.
- Kaneto, H.; Kajimoto, Y.; Miyagawa, J.; Matsuoka, T.; Fujitani, Y.; Umayahara, Y.; Hanafusa, T.; Matsuzawa, Y.; Yamasaki, Y.; Hori, M. Beneficial effects of antioxidants for diabetes: Possible protection of pancreatic β-cells against glucose toxicity. Diabetes 1999, 48, 2398–2406.
- Kaneto, H.; Xu, G.; Song, K.H.; Suzuma, K.; Bonner-Weir, S.; Sharma, A.; Weir, G.C. Activation of the hexosamine pathway leads to deterioration of pancreatic β-cell function by provoking oxidative stress. J. Biol. Chem 2001, 276, 31099–31104.
- Sakai, K.; Matsumoto, K.; Nishikawa, T.; Suefuji, M.; Nakamaru, K.; Hirashima, Y.; Kawashima, J.; Shirotani, T.; Ichinose, K.; Brownlee, M.; et al. Mitochondrial reactive oxygen species reduce insulin secretion by pancreatic β-cells. Biochem. Biophys. Res. Commun 2003, 300, 216–222.
- Gorogawa, S.; Kajimoto, Y.; Umayahara, U.; Kaneto, H.; Watada, H.; Kuroda, A.; Kawamori, D.; Yasuda, T.; Matsuhisa, M.; Yamasaki, Y.; et al. Probucol preserves pancreatic β-cell function through reduction of oxidative stress in type 2 diabetes. Diabetes Res. Clin. Prac 2002, 57, 1–10.
- Harmon, J.S.; Stein, R.; Robertson, R.P. Oxidative stress-mediated, post-translational loss of MafA protein as a contributing mechanism to loss of insulin gene expression in glucotoxic beta cells. J. Biol. Chem 2005, 280, 11107–11113.
- Harmon, J.S.; Bogdani, M.; Parazolli, S.D.; Mak, S.S.; Oseid, E.A.; Berghmans, M.; LeBoeuf, R.C.; Robertson, R.P. β-cell specific overexpression of glutathione peroxidase preserves intranuclear MafA and reverses diabetes in db/db mice. Endocrinology 2009, 150, 4855–4862.
- Yamamoto, M.; Yamato, E.; Toyoda, S.; Tashiro, F.; Ikegami, H.; Yodoi, J.; Miyazaki, J. Transgenic expression of antioxidant protein thioredoxin in pancreatic β cells prevents progression of type 2 diabetes mellitus. Antioxid. Redox. Signal 2008, 10, 43–49.
- Talchai, C.; Xuan, S.; Lin, H.V.; Sussel, L.; Accili, D. Pancreatic β cell dedifferentiation as a mechanism of diabetic β cell failure. Cell 2012, 150, 1223–1234.
- Sakurai, T.; Tsuchiya, S. Superoxide production from nonenzymatically glycated protein. FEBS Lett 1988, 236, 406–410.
- Brownlee, M. Biochemistry and molecular cell biology of diabetic complications. Nature 2001, 414, 813–820.
- Grankvist, K; Marklund, S.L.; Taljedal, I.B. CuZn-superoxide dismutase, Mn-superoxide dismutase, catalase and glutathione peroxidase in pancreatic islets and other tissues in the mouse. Biochem. J 1981, 199, 393–398.
- Tiedge, M.; Lortz, S.; Drinkgern, J.; Lenzen, S. Relation between antioxidant enzyme gene expression and antioxidative defense status of insulin-producing cells. Diabetes 1997, 46, 1733–1742.
- Ohlsson, H.; Karlsson, K.; Edlund, T. IPF1, a homeodomain-containing-transactivator of the insulin gene. EMBO J 1993, 12, 4251–4259.
- Leonard, J.; Peers, B.; Johnson, T.; Ferreri, K.; Lee, S.; Montminy, M.R. Characterization of somatostatin transactivating factor-1, a novel homeobox factor that stimulates somatostatin expression in pancreatic islet cells. Mol. Endocrinol 1993, 7, 1275–1283.
- Miller, C.P.; McGehee, R.E.; Habener, J.F. IDX-1: A new homeodomain transcription factor expressed in rat pancreatic islets and duodenum that transactivates the somatostatin gene. EMBO J 1994, 13, 1145–1156.
- Jonsson, J.; Carlsson, L.; Edlund, T.; Edlund, H. Insulin-promoter-factor 1 is required for pancreas development in mice. Nature 1994, 37, 606–609.
- Stoffers, D.A.; Zinkin, N.T.; Stanojevic, V.; Clarke, W.L.; Habener, J.F. Pancreatic agenesis attributable to a single nucleotide deletion in the human IPF1 gene coding sequence. Nat. Genet 1997, 15, 106–110.
- Ahlgren, U.; Jonsson, J.; Jonsson, L.; Simu, K.; Edlund, H. β-cell-specific inactivation of the mouse Ipf1/Pdx1 gene results in loss of the β-cell phenotype and maturity onset diabetes. Genes Dev 1998, 12, 1763–1768.
- Ferber, S.; Halkin, A.; Cohen, H.; Ber, I.; Einav, Y.; Goldberg, I.; Barshack, I.; Seijffers, R.; Kopolovic, J.; Kaiser, N.; et al. Pancreatic and duodenal homeobox gene 1 induces expression of insulin genes in liver and ameliorates streptozotocin-induced hyperglycemia. Nat. Med 2000, 6, 568–572.
- Holland, A.M.; Hale, M.A.; Kagami, H.; Hammer, R.E.; MacDonald, R.J. Experimental control of pancreatic development and maintenance. Proc. Natl. Acad. Sci. USA 2002, 99, 12236–12241.
- Noguchi, H.; Kaneto, H.; Weir, G.C.; Bonner-Weir, S. PDX-1 protein containing its own Antennapedia-like protein transduction domain can transduce pancreatic duct and islet cells. Diabetes 2003, 52, 1732–1737.
- Miyazaki, S.; Yamato, E.; Miyazaki, J. Regulated expression of pdx-1 promotes in vitro differentiation of insulin-producing cells from embryonic stem cells. Diabetes 2004, 53, 1030–1037.
- Kaneto, H.; Nakatani, Y.; Miyatsuka, T.; Matsuoka, T.; Matsuhisa, M.; Hori, M.; Yamasaki, Y. PDX-1/VP16 fusion protein, together with NeuroD or Ngn3, markedly induces insulin gene transcription and ameliorates glucose tolerance. Diabetes 2005, 54, 1009–1022.
- Kaneto, H.; Miyatsuka, T.; Shiraiwa, T.; Yamamoto, K.; Kato, K.; Fujitani, Y.; Matsuoka, T. Crucial role of PDX-1 in pancreas development, β-cell differentiation, and induction of surrogate β-cells. Curr. Med. Chem 2007, 14, 103–112.
- Kaneto, H.; Miyatsuka, T.; Kawamori, D.; Yamamoto, K.; Kato, K.; Shiraiwa, T.; Katakami, N.; Yamasaki, Y.; Matsuhisa, M.; Matsuoka, T. PDX-1 and MafA play a crucial role in pancreatic β-cell differentiation and maintenance of mature β-cell function. Endocr. J 2008, 55, 235–252.
- Olbrot, M.; Rud, J.; Moss, L.G.; Sharma, A. Identification of β-cell-specific insulin gene transcription factor RIPE3b1 as mammalian MafA. Proc. Natl. Acad. Sci. USA 2002, 99, 6737–6742.
- Kataoka, K.; Han, S.I.; Shioda, S.; Hirai, M.; Nishizawa, M.; Handa, H. MafA is a glucose-regulated and pancreatic β-cell-specific transcriptional activator for the insulin gene. J. Biol. Chem 2002, 277, 49903–49910.
- Matsuoka, T.; Zhao, L.; Artner, I.; Jarrett, H.W.; Friedman, D.; Means, A.; Stein, R. Members of the large Maf transcription family regulate insulin gene transcription in islet β cells. Mol. Cell. Biol 2003, 23, 6049–6062.
- Matsuoka, T.; Artner, I.; Henderson, E.; Means, A.; Sander, M.; Stein, R. The MafA transcription factor appears to be responsible for tissue-specific expression of insulin. Proc. Natl. Acad. Sci. USA 2004, 101, 2930–2933.
- Kaneto, H.; Matsuoka, T.; Nakatani, Y.; Miyatsuka, T.; Matsuhisa, M.; Hori, M.; Yamasaki, Y. A crucial role of MafA as a novel therapeutic target for diabetes. J. Biol. Chem 2005, 280, 15047–15052.
- Matsuoka, T.; Kaneto, H.; Stein, R.; Miyatsuka, T.; Kawamori, D.; Henderson, E.; Kojima, I.; Matsuhisa, M.; Hori, M.; Yamasaki, Y. MafA regulates expression of genes important to islet β cell function. Mol. Endocrinol 2007, 21, 2764–2774.
- Kaneto, H.; Xu, G.; Fujii, N.; Kim, S.; Bonner-Weir, S.; Weir, G.C. Involvement of c-Jun N-terminal kinase in oxidative stress-mediated suppression of insulin gene expression. J. Biol. Chem 2002, 277, 30010–30018.
- Kawamori, D.; Kajimoto, Y.; Kaneto, H.; Umayahara, Y.; Fujitani, Y.; Miyatsuka, T.; Watada, H.; Leibiger, I.B.; Yamasaki, Y.; Hori, M. Oxidative stress induces nucleo-cytoplasmic translocation of pancreatic transcription factor PDX-1 through activation of c-Jun N-terminal kinase. Diabetes 2003, 52, 2896–2904.
- Ogg, S.; Paradis, S.; Gottlieb, S.; Patterson, G.I.; Lee, L.; Tissenbaum, H.A.; Ruvkun, G. The Fork head transcription factor DAF-16 transduces insulin-like metabolic and longevity signals in C. elegans. Nature 1997, 389, 994–999.
- Accili, D.; Arden, K.C. FoxOs at the crossroads of cellular metabolism, differentiation, and transformation. Cell 2004, 117, 421–426.
- Nakae, J.; Biggs, W.H., III; Kitamura, T.; Cavenee, W.K.; Wright, C.V.; Arden, K.C.; Accili, D. Regulation of insulin action and pancreatic b-cell function by mutated alleles of the gene encoding forkhead transcription factor Foxo1. Nat. Genet 2002, 32, 245–253.
- Biggs, W.H., III; Meisenhelder, J.; Hunter, T.; Cavenee, W.K.; Arden, K.C. Protein kinase B/Akt-mediated phosphorylation promotes nuclear exclusion of the winged helix transcription factor FKHR1. Proc. Natl. Acad. Sci. USA 1999, 96, 7421–7426.
- Kitamura, T.; Nakae, J.; Kitamura, Y.; Kido, Y.; Biggs, W.H., III; Wright, C.V.; White, M.F.; Arden, K.C.; Accili, D. The forkhead transcription factor Foxo1 links insulin signaling to Pdx1 regulation of pancreatic β cell growth. J. Clin. Invest 2002, 110, 1839–1847.
- Kawamori, D.; Kaneto, H.; Nakatani, Y.; Matsuoka, T.; Matsuhisa, M.; Hori, M.; Yamasaki, Y. The forkhead transcription factor Foxo1 bridges the JNK pathway and the transcription factor PDX-1 through its intracellular translocation. J. Biol. Chem 2006, 281, 1091–1098.
- Matsuoka, T.; Kaneto, H.; Miyatsuka, T.; Yamamoto, T.; Yamamoto, K.; Kato, K.; Shimomura, I.; Stein, R.; Matsuhisa, M. Regulation of MafA expression in pancreatic β-cells in db/db mice with diabetes. Diabetes 2010, 59, 1709–1720.
- Butler, A.E.; Robertson, R.P.; Hernandez, R.; Matveyenko, A.V.; Gurlo, T.; Butler, P.C. Beta cell nuclear musculoaponeurotic fibrosarcoma oncogene family A (MafA) is deficient in type 2 diabetes. Diabetologia 2012, doi:10.1007/s00125-012-2666-2.
- Inagaki, N.; Maekawa, T; Sudo, T.; Ishii, S.; Seino, Y.; Imura, H. c-Jun represses the human insulin promoter activity that depends on multiple cAMP response elements. Proc. Natl. Acad. Sci. USA 1992, 89, 1045–1049.
- Henderson, E.; Stein, R. c-jun inhibits transcriptional activation by the insulin enhancer; the insulin control element is the target of control. Mol. Cell. Biol 1994, 14, 655–662.
- Zhang, C.; Moriguchi, T.; Kajihara, M.; Esaki, R.; Harada, A.; Shimohata, H.; Oishi, H.; Hamada, M.; Morito, N.; Hasegawa, K.; et al. MafA is a key regulator of glucose-stimulated insulin secretion. Mol. Cell. Biol 2005, 25, 4969–4976.
- Wang, H.; Brun, T.; Kataoka, K.; Sharma, A.J.; Wollheim, C.B. MAFA controls genes implicated in insulin biosynthesis and secretion. Diabetologia 2007, 50, 348–358.
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