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Transcription factors involved in glucose-stimulated insulin secretion of pancreatic beta cells
Biochemical and Biophysical Research Communications 384 (2009) 401–404
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Mini Review
Transcription factors involved in glucose-stimulated insulin secretion of pancreatic beta cells Shiying Shao a,*, Zhong Fang b, Xuefeng Yu a, Muxun Zhang a a b
Division of Endocrinology, Tongji Hospital, Tongji Medical College of Huazhong University of Science & Technology, Wuhan, PR China Division of Orthopedics, Tongji Hospital, Tongji Medical College of Huazhong University of Science & Technology, Wuhan, PR China
a r t i c l e
i n f o
Article history: Received 9 April 2009 Available online 3 May 2009
Keywords: Glucose-stimulated insulin secretion Transcription factor
a b s t r a c t GSIS, the most important function of pancreatic beta cell, is essential for maintaining the glucose homeostasis. Transcription factors are known to control different biological processes such as differentiation, proliferation and apoptosis. In pancreas, some transcription factors are involved in regulating the function of beta cells. In this review, the role of these transcription factors including Pdx-1, FoxO1, SREBP1c, and MafA in GSIS is highlighted. The related molecular mechanisms are analyzed as well. Furthermore, the association between the role of transcription factors in GSIS and the development of T2DM is discussed. Ó 2009 Published by Elsevier Inc.
Introduction Type 2 diabetes (T2DM) is a common metabolic disorder and its pathogenesis involves two core defects: insulin resistance and beta cell dysfunction. It is known that pancreatic beta cells maintain blood glucose homeostasis by their capacity to secrete insulin upon glucose stimulation and this is the most important beta cell function. Impaired glucose-stimulated insulin secretion (GSIS) is an early feature of T2DM characterized by the elevated basal secretion and reduced responsiveness to glucose stimulation [1]. Due to the importance of GSIS in the development of T2DM, substantial work has been done to understand the whole event of GSIS in beta cell: glucose enters cytoplasm through the facilitative glucose transporters, especially glucose transporter 2 (Glut2), followed by the phosphorylation of glucose-6-phosphate (G6P) with several enzymes including glucokinase (GK); ATP/ADP ratio is increased resulting in the membrane depolarization, KATP channels closure, Ca2+ influx, and exocytosis of insulin granules [2]. This process is related to a complicated molecular network in which some transcription factors may take participation. However, majority of these factors and their role in GSIS have not been entirely identified. Transcription factors control different biological processes such as differentiation, proliferation and apoptosis. It has been reported that islets in T2DM show abnormal expression of genes which are involved in a multiplicity of beta cell functions [3]. Support for this
* Corresponding author. Address: Division of Endocrinology, Tongji Hospital, Tongji Medical College of Huazhong University of Science & Technology, Jiefang Road 1095, Wuhan, Hubei Provience 430030, PR China. Fax: +86 27 8362883. E-mail address: [email protected] (S. Shao). 0006-291X/$ - see front matter Ó 2009 Published by Elsevier Inc. doi:10.1016/j.bbrc.2009.04.135
idea comes from studies of maturity-onset diabetes of the young (MODY) which is a monogenic form of T2DM and characterized by early age of onset and autosomal dominant transmission [4]. With the exception of MODY-2 (mutation in GK), MODY-1 -3 -4 5 and -6 has been related to mutations in genes coding for the transcription factors, respectively, hepatocyte nuclear factor (HNF) -4a, HNF-1a, insulin promoter factor (IPF)-1/pancreatic and duodenal homeobox (Pdx)-1, HNF-1band NeuroD/BETA-2. These transcription factors regulate the expression of genes key to various aspects of beta cell function [5]. Moreover, there are other transcription factors which may also account for impaired GSIS in T2DM. Among these, forkhead box-containing protein O (FoxO)-1, sterol regulatory element-binding protein (SREBP)-1c, and V-maf musculoaponeurotic fibrosarcoma oncogene homolog (Maf) A are studied by most researchers recently (Table 1) [6–8]. However, the detailed plot still remains to be further explored. Pdx-1 Pdx-1 is one of the well-studied transcription factors that are critical to both beta cell development and function. It is the first pancreas-enriched gene product expressed in early pancreatic endocrine, exocrine, and ductal progenitors. In mature pancreas, Pdx-1 is principally localized to beta cells [9]. Pdx-1 plays an essential role in the regulation of beta cell neogenesis, differentiation and perhaps apoptosis [9]. In addition, it has been reported that chronic hyperglycemia deteriorates beta cell function by provoking oxidative stress, accompanied by reduction of Pdx-1 DNA binding activities [10]. Prolonged exposure of islets to palmitate inhibits insulin gene transcription by impairing nuclear localization of Pdx-1 [11]. Moreover, Pdx-1 is associated
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Table 1 Examples of transcription factors involved in GSIS and their established functions besides GSIS. Transcription factors involved in GSIS
Abbreviation
Function besides GSIS
Pancreatic duodenal homeobox-1 Forkhead box-containing protein O-1
Pdx-1 FoxO1
Sterol regulatory element-binding protein-1c V-maf musculoaponeurotic fibrosarcoma oncogene homolog, subtype A
SREBP-1c MafA
Beta cell neogenesis, differentiation and apoptosis Glucose and lipid production in liver, food intake in hypothalamus, and cell differentiation in preadipocytes, myoblasts and vascular endothelium Nutritional regulator of lipogenic enzymes in liver Beta-cell-specific insulin gene expression
with diabetes-MODY-4 in human [4]. These studies indicated that expression and/or activation of Pdx-1 in beta cells are reduced under diabetic conditions. Additionally, specific removal of Pdx-1 in mice led to a severe diabetic phenotype due to beta cell dysfunction [12]. Based on these findings, Pdx-1, besides the function in beta cell differentiation, is also important as a regulator of beta cell function. Consequently, much effort is being directed to define the underlying mechanisms of Pdx-1 in beta cell function, especially the GSIS. It is anticipated that such new perspective will make contribution to the development of new treatment strategies aimed to improve beta cell function in diabetic patients. Wang et al. [13] suppressed the expression of Pdx-1 in INS-1 cells. It was found that down-regulation of Pdx-1 suppressed the expression of glucagon-like peptide-1receptor (GLP-1R), which resulted in marked reduction of both basal and GLP-1 agonist Exenatide (EX-4)-stimulated cellular cAMP level. It has been reported that GLP-1 is a powerful incretion which has actions on enhancing GSIS through GLP-1R activation. The result of this GLP-1/GLP-1R signaling is the synergistic enhancement of KATP channel closure, subsequent cell membrane depolarization and influx of calcium channels [14]. Therefore, the down-regulation of GLP-1R induced by Pdx-1 deficiency may contribute to the beta cell dysfunction. These findings do provide some valuable insight in the role of Pdx-1 in GSIS, which demonstrated that GLP/GLP-1R pathway may contribute in this event. However, few reports, to date, indicate whether GLP/GLP-1R is the unique pathway involved in Pdx1 medicated GSIS regulation. Other downstream effectors remained to be identified.
negative regulation of FoxO1 transcriptional activity by Insulin and IGF-1 was through phosphorylation by PI3-kinase/Akt pathway. This resulted in the export of FoxO1 from the nucleus to the cytoplasm [19]. Furthermore, down-regulation of pancreatic islet GK activity through suppressing IGF-1R expression was reported by Kazuya et al [6] and PI3K/Akt/FoxO1 pathway was involved in it. Additionally, Pdx-1 was reported to be regulated by another forkhead transcription factor FoxA2 (HNF3b) [20]. FoxO1 and FoxA2 share common DNA-binding sites in the Pdx-1 promoter. Thus, FoxO1 could inhibit the transcription of Pdx-1 through competing the binding sites with FoxA2. Moreover, it was reported that FoxO1 localized to cytoplasm in Pdx-1-positive beta cells. On the contrary, in Pdx-1-negative beta cells, FoxO1 localizes to the nucleus [15]. This mutual exclusion of FoxO1 and Pdx-1 was consistent with the hypothesis that FoxO1 is a negative regulator of Pdx-1. However, it is uncertain whether insulin/IGF-1/IRS2 pathway could up-regulate the transcription and/or activity of Pdx-1 by negative regulating FoxO1. This may be followed by a speculation that the downstream GLP/GLP-1R pathway in Pdx-1 regulated GSIS may be affected. Further study is needed to identify whether there are other biomolecules and/or transcription factors, besides GK and Pdx-1, involved in insulin/IGF-1/IRS2/FoxO1 pathway. Furthermore, recent studies have revealed that there are other kinases involved in phosphorylation and regulation of FoxO1 besides PI3K/Akt pathway. Huang et al. [21] showed that FoxO1 was phosphorylated by the cycline-dependent kinase 2 (CDK2), which caused nuclear exclusion of FoxO1 as well. Whether this kinase contributes to regulate beta cell function through FoxO1 is remained to be explored.
FoxO1 SREBP-1c FoxO proteins (FoxO1, FoxO3a and FoxO4) are transcription factors of the forkhead family which play critical role in cellular differentiation, proliferation, apoptosis and stress resistance. FoxO1 is the most abundant isoform in liver, adipose tissue, and beta cells and is conventionally viewed as a regulator in glucose and lipid production in liver; food intake in hypothalamus and cell differentiation in preadipocytes, myoblasts and vascular endothelium [15]. Recent studies revealed that FoxO1 may be involved in the insulin/insulin like growth factor-1 (IGF-1)/insulin receptor substrate (IRS)-2 pathway to regulate beta cell function, especially the GSIS. Insulin and IGF-1 belong to a family of growth factors that regulate metabolism, growth, and cell differentiation and survival. IRS2 is the primary and predominant protein delivering insulin/IGF-1 signaling in beta cells [16]. Much effort has been done to prove that down-regulation insulin receptor (IR) and/or IGF-1 receptor (IGF1R) in beta cells impaired GSIS, finally resulting in beta cell failure [16,17]. Moreover, overexpression of IRS2 in beta cells is found to improve glucose homeostasis by enhancing GSIS [18]. These findings evoked the studies directed on identification of downstream pathways of Insulin/IGF-1/IRS-2 and the activity of FoxO1 was found to be negatively regulated by this cascade. Conventionally, it has been considered that FoxO1 is phosphorylated by protein kinase B (PKB)/Akt, resulting in nuclear exclusion. The
SREBP-1c is a member of the membrane-bound transcription factor basic helix-loop-helix (bHLH) leucine zipper family. Conventionally, SREBP-1 is viewed as a nutritional regulator of lipogenic enzymes in liver. It is up-regulated by dietary intake of carbohydrates, sugars, and saturated fatty acids and down-regulated by polyunsaturated fatty acids such as eicosapentaenoate (EPA). This type of nutritional SREBP-1c regulation is recently observed in cultured beta cells and isolated islets of mice as well [22]. Based on the epidemiological evidences, it was found that changes in nutritional states could trigger metabolic disturbance in beta cells (glucolipotoxicity). Together with experimental observations that SREBP-1c is highly regulated by nutrition, studies on the role of SREBP-1c in diabetes are revealed of essential significance. In pancreatic beta cells, activation of SREBP-1c has been shown to be involved in impaired insulin secretion. Takahashi and colleague [23] used transgenic mice overexpressing the active form of SREBP-1c and found that these mice exhibited impaired glucose tolerance in vivo and had impaired GSIS of islets. Investigation of the effects of palmitate, a typical saturated fatty acid, on GSIS in isolated islets demonstrated that palmitate impaired GSIS. This effect was abolished in SREBP-1-null islets. Meanwhile, islets iso-
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lated from SREBP-1c-knock-out mice exhibited reduction of basal insulin secretion and an immunity to impaired insulin secretion caused by saturated fatty acids [22]. These findings establish an association between SREBP-1c and beta cell dysfunction, provoking the following studies targeting on identifying the underlying mechanisms. Since SREBP-1c is a transcription factor, the SREBP-1c targeting genes is being studied and the list is continually expanding. In addition to predictable genes involved in lipid synthesis such as enzyme genes on the pathways of lipogenesis, some other unexpected genes are also found to have sterol regulatory elements in their promoters. These reported genes are summarized below: (1) IRS-2: recent studies have highlighted the role of insulin/IGF1/IRS2 signaling pathway in regulating beta cell function. This signaling pathway has been discussed in FoxO1 section [6,19]. Additionally, it was reported that SREBP-1c could suppress IRS2 activity through the direct binding to IRS2 promoter [24]. This may make some contribution in accounting for the role of SREEBP-1c in GSIS of beta cell. (2) Pdx-1: overexpression of SREBP-1c was found to suppress Pdx-1 expression both in vivo and in vitro. On the contrary, SREBP-1c knock-out islets exhibited up-regulation of Pdx-1 expression [25]. Its precise molecular mechanism is under investigation. Since Pdx-1 is a crucial transcription factor for beta cell function which has been discussed in Pdx-1 section, the suppression of Pdx-1 by SREBP-1c may also stimulate secondary negative effects on insulin secretion. (3) Granuphilin: the Rab27a (a monomeric GTPase) effector granuphilin is specifically localized in insulin granules and regulates the vesicle transport for exocytosis. It was reported that granuphilin was up-regulated in some diabetic animal models, leading to suppression of insulin secretion [26]. Furthermore, granuphilin was found to be a direct target of SREBP-1c and its knockdown restored insulin secretion [27]. Therefore, granuphilin should be on the list of mediators involved in the role of SREBP-1c in regulating beta cell function. (4) Uncoupling protein 2 (UCP2): UCP2 is a member of uncoupling protein family which mediates uncouple of energy usage and ATP production from mitochondrial and it was found to have function in regulating insulin secretion in pancreatic beta cells [28]. This may be attributed to its negative regulation of cytoplasmic ATP/ADP - the key signal in GSIS. Nuclear SREBP-1c was found to accumulate UCP2 in beta cells in a state of high nutrition [29]. Moreover, Kato et al. reported the crucial role of UCP2 in the palmitate stimulated insulin secretion inhibition [22]. Together, the effect of SREBP-1 on UCP2 regulation may partially explain the SREBP-1c induced GSIS impairment. (5) Other factors: Kir6.2, Kv1.2, Syntaxin-1a and Munc18-1 which are related to electrophysiological functions of cellular membranes seem to be regulated by SREBP-1c [30]. Although precise molecular dissection has not been fully understood, regulation of these molecules provides a new perspective of SREBP-1c action on ion channel.
This basic leucine zipper transcription factor MafA was found to specifically localize in nuclei of insulin-positive cells and could activate the insulin gene promoter through interacting with Pdx1 and Beta2 in a synergistic faction. Additionally, up-regulation of MafA alone was sufficient to improve endogenous insulin mRNA levels [32]. Besides, it is recently identified that MafA transcription factor is not only critical to regulate the transcription of insulin but also important to the beta cell function. It is noteworthy that reduced MafA activity was implicated in the development of beta cell dysfunction. Zhang et al. [33] reported that mice deficient in MafA developed diabetes due to impaired insulin secretion. This study also revealed that MafA knock-out mice displayed reduced expression levels of Insulin1, Insulin2, Pdx-1, NeuroD1, and Glut-2. Furthermore, a more recent study highlighted the role of MafA in GSIS regulation [34]. In this study, overexpression of MafA caused increased GSIS. In addition, the expression of important beta cell genes including Glut2, Pdx-1, Nkx6.1, GLP-1R, and pyruvate carboxylase (PC) was also mentioned to be regulated positively by MafA. These results indicate that MafA may qualify as a crucial master regulator of genes implicated in maintaining beta cell function, in particular the GSIS. Future work GSIS is the most important function of beta cells to maintain the glucose homeostasis. To date, many effectors have been found to be involved in GSIS (Fig. 1). Pdx-1 is reported to regulate GLP-1R expression, thus influencing the GLP-1/GLP-1R signaling pathway which could potentially enhance GSIS through elevating cytoplasmic cAMP level. Additionally, Pdx-1 is regulated by FoxO1, SREBP1c and MafA. However, it is unclear whether the effect of these three transcription factors on regulating Pdx-1 is equal. Additionally, it is required to identify whether there are other transcription factors which may affect the expression and/or activity of Pdx-1 as well. The activity of FoxO1 is regulated by Akt phosphorylation. Other kinases have been found to exert similar effect as Akt does on FoxO1 regulation. Identification of the whole signaling pathway may open a new perspective in FoxO1 related GSIS. Furthermore, GK and Pdx-1 are found to be the downstream signal mediators
Ion channels Insulin/IGF-1 IR/IGF-1R granuphilin IRS2 UCP2 Akt
MafA RIPE3b (in rat)/C1 (in human) is one of the most important cisregulatory elements to control beta cell selective insulin transcription. The gene which encodes the RIPE3b/C1 activator has been cloned and identified as MafA [31].
SREBP-1c GLP-1
FoxO1
Together, these findings reveal that SREBP-1c is related to multiple pathways required for regulation of beta cell function. Therefore, the expression and/or activity of SREBP-1c may contribute to the development of T2DM.
exocytosis
Enzymes in glycolytic pathway
Pdx-1
GLP-1R Elevation of cAMP MafA
NKX6.1 PC Glut2
NeuroD MODY
Fig. 1. Schematic diagram of transcription factor intercrossing network. FoxO1 is in Insulin/IGF-1 pathway. Pdx-1 is regulated by FoxO1, SREBP-1c and MafA. SREBP-1c is involved in multiple gene regulation including IRS2, Pdx-1, granuphilin, UCP2 and ion channels. Expression of Pdx-1, GLP-1R, Nkx6.1, PC, Glut2 and NeuroD are regulated by MafA.
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in Insulin/IGF-1/IRS2/FoxO1 pathway. It is unclear whether GLP-1R could be regulated in this pathway as well. Other possible downstream signal mediators are remained to be identified. SREBP-1c exerts influence on IRS2, Pdx-1, UCP2, granuphilin and ion channels. Thus, further study is needed to identify whether SREBP-1c could regulate FoxO1 through IRS/Akt pathway and/or regulate GLP-1R through Pdx-1/GLP-1R pathway. Furthermore, Pdx-1, GLP-1R, Nkx6.1, PC, Glut2, NeuroD, and enzymes in glycolytic pathway are all involved in MafA mediated GSIS regulation. Due to the powerful controlling capability of MafA, many reporters consider MafA as a master transcription factors in regulating GSIS. Future work is required to extend the list of genes that MafA has effect on. Although substantial work has been done, the entire blueprint related to GSIS regulation is still not obtained. Furthermore, application of these involved transcription factors into the clinical therapy for T2DM is still in the infant stage. Together, to entirely understand the molecular network related to GSIS could contribute not only to identify the mechanism of beta cell dysfunction in T2DM but also to develop the treatment strategies with new perspectives. References [1] R.H. Unger, Lipotoxicity in the pathogenesis of obesity-dependent NIDDM, genetic and clinical implications, Diabetes 44 (1995) 863–970. [2] J.C. Bruning, J. Winnay, S. Bonner-Weir, S.I. Taylor, D. Accili, C.R. Kahn, Development of a novel polygenic model of NIDDM in mice heterozygous for IR and IRS-1 null alleles, Cell 88 (1997) 561–572. [3] D.A. Stoffers, N.T. Zinkin, Pancreatic agenesis attributable to a single nucleotide deletion in the human IPF1 gene coding sequence, Nat. Genet. 15 (1997) 106– 110. [4] J.F. Habener, D.A. Stoffers, V. Stanojevic, W.L. Clarke, J.F. Habener, A newly discovered role of transcription factors involved in pancreas development and the pathogenesis of diabetes mellitus, Proc. Assoc. Am. Physicians 110 (1998) 12–21. [5] S.S. Fajans, G.I. Bell, K.S. Polonsky, Molecular mechanisms and clinical pathophysiology of maturity-onset diabetes of the young, N. Engl. J. Med. 345 (2001) 971–980. [6] Y. Kazuya, K. Yoshida, K. Murao, H. Imachi, W.M. Cao, X. Yu, J. Li, R.A. Ahmed, N. Kitanaka, N.C. Wong, T.G. Unterman, M.A. Magnuson, T. Ishida, Pancreatic glucokinase is activated by insulin-like growth factor-1, Endocrinology 148 (2007) 2904–2913. [7] F. Diraison, L. Parton, P. Ferré, F. Foufelle, C.P. Briscoe, I. Leclerc, G.A. Rutter, Over-expression of sterol-regulatory-element-binding protein-1c (SREBP1c) in rat pancreatic islets induces lipogenesis and decreases glucose-stimulated insulin release: modulation by 5-aminoimidazole-4-carboxamide ribonucleoside (AICAR), Biochem. J. 378 (2004) 769–778. [8] Y.I. Kitamura, T. Kitamura, J.P. Kruse, J.C. Raum, R. Stein, W. Gu, D. Accili, FoxO1 protects against pancreatic beta cell failure through NeuroD and MafA induction, Cell Metab. 2 (2005) 153–163. [9] J. Jonsson, L. Carlsson, T. Edlund, H. Edlund, Insulin-promoter-factor 1 is required for pancreas development in mice, Nature 371 (1994) 606–609. [10] U. Ahlgren, J. Jonsson, L. Jonsson, K. Simu, H. Edlund, Beta-cell-specific inactivation of the mouse Ipf1/Pdx1 gene results in loss of the beta-cell phenotype and maturity onset diabetes, Genes Dev. 12 (1998) 1763–1768. [11] D.K. Hagman, L.B. Hays, S.D. Parazzoli, V. Poitout, Palmitate inhibits insulin gene expression by altering PDX-1 nuclear localization and reducing mafA expression in isolated rat islets of Langerhans, J. Biol. Chem. 280 (2005) 32413–32418. [12] M. Ganno, E.T. Ables, L. Crawford, D. Lowe, M.F. Offield, M.A. Magnuson, C.V. Wright, pdx-1 function is specifically required in embryonic beta cells to generate appropriate numbers of endocrine cell types and maintain glucose homeostasis, Dev. Biol. 314 (2008) 406–417. [13] H.Wang.M. Iezzi, S. Theander, P.A. Antinozzi, B.R. Gauthier, P.A. Halban, C.B. Wollheim, Suppression of pdx-1 perturbs proinsulin processing, insulin secretion and GLP-1 signalling in INS-1 cells, Diabetologia 48 (2005) 720–731.
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Mini Review
Transcription factors involved in glucose-stimulated insulin secretion of pancreatic beta cells Shiying Shao a,*, Zhong Fang b, Xuefeng Yu a, Muxun Zhang a a b
Division of Endocrinology, Tongji Hospital, Tongji Medical College of Huazhong University of Science & Technology, Wuhan, PR China Division of Orthopedics, Tongji Hospital, Tongji Medical College of Huazhong University of Science & Technology, Wuhan, PR China
a r t i c l e
i n f o
Article history: Received 9 April 2009 Available online 3 May 2009
Keywords: Glucose-stimulated insulin secretion Transcription factor
a b s t r a c t GSIS, the most important function of pancreatic beta cell, is essential for maintaining the glucose homeostasis. Transcription factors are known to control different biological processes such as differentiation, proliferation and apoptosis. In pancreas, some transcription factors are involved in regulating the function of beta cells. In this review, the role of these transcription factors including Pdx-1, FoxO1, SREBP1c, and MafA in GSIS is highlighted. The related molecular mechanisms are analyzed as well. Furthermore, the association between the role of transcription factors in GSIS and the development of T2DM is discussed. Ó 2009 Published by Elsevier Inc.
Introduction Type 2 diabetes (T2DM) is a common metabolic disorder and its pathogenesis involves two core defects: insulin resistance and beta cell dysfunction. It is known that pancreatic beta cells maintain blood glucose homeostasis by their capacity to secrete insulin upon glucose stimulation and this is the most important beta cell function. Impaired glucose-stimulated insulin secretion (GSIS) is an early feature of T2DM characterized by the elevated basal secretion and reduced responsiveness to glucose stimulation [1]. Due to the importance of GSIS in the development of T2DM, substantial work has been done to understand the whole event of GSIS in beta cell: glucose enters cytoplasm through the facilitative glucose transporters, especially glucose transporter 2 (Glut2), followed by the phosphorylation of glucose-6-phosphate (G6P) with several enzymes including glucokinase (GK); ATP/ADP ratio is increased resulting in the membrane depolarization, KATP channels closure, Ca2+ influx, and exocytosis of insulin granules [2]. This process is related to a complicated molecular network in which some transcription factors may take participation. However, majority of these factors and their role in GSIS have not been entirely identified. Transcription factors control different biological processes such as differentiation, proliferation and apoptosis. It has been reported that islets in T2DM show abnormal expression of genes which are involved in a multiplicity of beta cell functions [3]. Support for this
* Corresponding author. Address: Division of Endocrinology, Tongji Hospital, Tongji Medical College of Huazhong University of Science & Technology, Jiefang Road 1095, Wuhan, Hubei Provience 430030, PR China. Fax: +86 27 8362883. E-mail address: [email protected] (S. Shao). 0006-291X/$ - see front matter Ó 2009 Published by Elsevier Inc. doi:10.1016/j.bbrc.2009.04.135
idea comes from studies of maturity-onset diabetes of the young (MODY) which is a monogenic form of T2DM and characterized by early age of onset and autosomal dominant transmission [4]. With the exception of MODY-2 (mutation in GK), MODY-1 -3 -4 5 and -6 has been related to mutations in genes coding for the transcription factors, respectively, hepatocyte nuclear factor (HNF) -4a, HNF-1a, insulin promoter factor (IPF)-1/pancreatic and duodenal homeobox (Pdx)-1, HNF-1band NeuroD/BETA-2. These transcription factors regulate the expression of genes key to various aspects of beta cell function [5]. Moreover, there are other transcription factors which may also account for impaired GSIS in T2DM. Among these, forkhead box-containing protein O (FoxO)-1, sterol regulatory element-binding protein (SREBP)-1c, and V-maf musculoaponeurotic fibrosarcoma oncogene homolog (Maf) A are studied by most researchers recently (Table 1) [6–8]. However, the detailed plot still remains to be further explored. Pdx-1 Pdx-1 is one of the well-studied transcription factors that are critical to both beta cell development and function. It is the first pancreas-enriched gene product expressed in early pancreatic endocrine, exocrine, and ductal progenitors. In mature pancreas, Pdx-1 is principally localized to beta cells [9]. Pdx-1 plays an essential role in the regulation of beta cell neogenesis, differentiation and perhaps apoptosis [9]. In addition, it has been reported that chronic hyperglycemia deteriorates beta cell function by provoking oxidative stress, accompanied by reduction of Pdx-1 DNA binding activities [10]. Prolonged exposure of islets to palmitate inhibits insulin gene transcription by impairing nuclear localization of Pdx-1 [11]. Moreover, Pdx-1 is associated
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Table 1 Examples of transcription factors involved in GSIS and their established functions besides GSIS. Transcription factors involved in GSIS
Abbreviation
Function besides GSIS
Pancreatic duodenal homeobox-1 Forkhead box-containing protein O-1
Pdx-1 FoxO1
Sterol regulatory element-binding protein-1c V-maf musculoaponeurotic fibrosarcoma oncogene homolog, subtype A
SREBP-1c MafA
Beta cell neogenesis, differentiation and apoptosis Glucose and lipid production in liver, food intake in hypothalamus, and cell differentiation in preadipocytes, myoblasts and vascular endothelium Nutritional regulator of lipogenic enzymes in liver Beta-cell-specific insulin gene expression
with diabetes-MODY-4 in human [4]. These studies indicated that expression and/or activation of Pdx-1 in beta cells are reduced under diabetic conditions. Additionally, specific removal of Pdx-1 in mice led to a severe diabetic phenotype due to beta cell dysfunction [12]. Based on these findings, Pdx-1, besides the function in beta cell differentiation, is also important as a regulator of beta cell function. Consequently, much effort is being directed to define the underlying mechanisms of Pdx-1 in beta cell function, especially the GSIS. It is anticipated that such new perspective will make contribution to the development of new treatment strategies aimed to improve beta cell function in diabetic patients. Wang et al. [13] suppressed the expression of Pdx-1 in INS-1 cells. It was found that down-regulation of Pdx-1 suppressed the expression of glucagon-like peptide-1receptor (GLP-1R), which resulted in marked reduction of both basal and GLP-1 agonist Exenatide (EX-4)-stimulated cellular cAMP level. It has been reported that GLP-1 is a powerful incretion which has actions on enhancing GSIS through GLP-1R activation. The result of this GLP-1/GLP-1R signaling is the synergistic enhancement of KATP channel closure, subsequent cell membrane depolarization and influx of calcium channels [14]. Therefore, the down-regulation of GLP-1R induced by Pdx-1 deficiency may contribute to the beta cell dysfunction. These findings do provide some valuable insight in the role of Pdx-1 in GSIS, which demonstrated that GLP/GLP-1R pathway may contribute in this event. However, few reports, to date, indicate whether GLP/GLP-1R is the unique pathway involved in Pdx1 medicated GSIS regulation. Other downstream effectors remained to be identified.
negative regulation of FoxO1 transcriptional activity by Insulin and IGF-1 was through phosphorylation by PI3-kinase/Akt pathway. This resulted in the export of FoxO1 from the nucleus to the cytoplasm [19]. Furthermore, down-regulation of pancreatic islet GK activity through suppressing IGF-1R expression was reported by Kazuya et al [6] and PI3K/Akt/FoxO1 pathway was involved in it. Additionally, Pdx-1 was reported to be regulated by another forkhead transcription factor FoxA2 (HNF3b) [20]. FoxO1 and FoxA2 share common DNA-binding sites in the Pdx-1 promoter. Thus, FoxO1 could inhibit the transcription of Pdx-1 through competing the binding sites with FoxA2. Moreover, it was reported that FoxO1 localized to cytoplasm in Pdx-1-positive beta cells. On the contrary, in Pdx-1-negative beta cells, FoxO1 localizes to the nucleus [15]. This mutual exclusion of FoxO1 and Pdx-1 was consistent with the hypothesis that FoxO1 is a negative regulator of Pdx-1. However, it is uncertain whether insulin/IGF-1/IRS2 pathway could up-regulate the transcription and/or activity of Pdx-1 by negative regulating FoxO1. This may be followed by a speculation that the downstream GLP/GLP-1R pathway in Pdx-1 regulated GSIS may be affected. Further study is needed to identify whether there are other biomolecules and/or transcription factors, besides GK and Pdx-1, involved in insulin/IGF-1/IRS2/FoxO1 pathway. Furthermore, recent studies have revealed that there are other kinases involved in phosphorylation and regulation of FoxO1 besides PI3K/Akt pathway. Huang et al. [21] showed that FoxO1 was phosphorylated by the cycline-dependent kinase 2 (CDK2), which caused nuclear exclusion of FoxO1 as well. Whether this kinase contributes to regulate beta cell function through FoxO1 is remained to be explored.
FoxO1 SREBP-1c FoxO proteins (FoxO1, FoxO3a and FoxO4) are transcription factors of the forkhead family which play critical role in cellular differentiation, proliferation, apoptosis and stress resistance. FoxO1 is the most abundant isoform in liver, adipose tissue, and beta cells and is conventionally viewed as a regulator in glucose and lipid production in liver; food intake in hypothalamus and cell differentiation in preadipocytes, myoblasts and vascular endothelium [15]. Recent studies revealed that FoxO1 may be involved in the insulin/insulin like growth factor-1 (IGF-1)/insulin receptor substrate (IRS)-2 pathway to regulate beta cell function, especially the GSIS. Insulin and IGF-1 belong to a family of growth factors that regulate metabolism, growth, and cell differentiation and survival. IRS2 is the primary and predominant protein delivering insulin/IGF-1 signaling in beta cells [16]. Much effort has been done to prove that down-regulation insulin receptor (IR) and/or IGF-1 receptor (IGF1R) in beta cells impaired GSIS, finally resulting in beta cell failure [16,17]. Moreover, overexpression of IRS2 in beta cells is found to improve glucose homeostasis by enhancing GSIS [18]. These findings evoked the studies directed on identification of downstream pathways of Insulin/IGF-1/IRS-2 and the activity of FoxO1 was found to be negatively regulated by this cascade. Conventionally, it has been considered that FoxO1 is phosphorylated by protein kinase B (PKB)/Akt, resulting in nuclear exclusion. The
SREBP-1c is a member of the membrane-bound transcription factor basic helix-loop-helix (bHLH) leucine zipper family. Conventionally, SREBP-1 is viewed as a nutritional regulator of lipogenic enzymes in liver. It is up-regulated by dietary intake of carbohydrates, sugars, and saturated fatty acids and down-regulated by polyunsaturated fatty acids such as eicosapentaenoate (EPA). This type of nutritional SREBP-1c regulation is recently observed in cultured beta cells and isolated islets of mice as well [22]. Based on the epidemiological evidences, it was found that changes in nutritional states could trigger metabolic disturbance in beta cells (glucolipotoxicity). Together with experimental observations that SREBP-1c is highly regulated by nutrition, studies on the role of SREBP-1c in diabetes are revealed of essential significance. In pancreatic beta cells, activation of SREBP-1c has been shown to be involved in impaired insulin secretion. Takahashi and colleague [23] used transgenic mice overexpressing the active form of SREBP-1c and found that these mice exhibited impaired glucose tolerance in vivo and had impaired GSIS of islets. Investigation of the effects of palmitate, a typical saturated fatty acid, on GSIS in isolated islets demonstrated that palmitate impaired GSIS. This effect was abolished in SREBP-1-null islets. Meanwhile, islets iso-
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lated from SREBP-1c-knock-out mice exhibited reduction of basal insulin secretion and an immunity to impaired insulin secretion caused by saturated fatty acids [22]. These findings establish an association between SREBP-1c and beta cell dysfunction, provoking the following studies targeting on identifying the underlying mechanisms. Since SREBP-1c is a transcription factor, the SREBP-1c targeting genes is being studied and the list is continually expanding. In addition to predictable genes involved in lipid synthesis such as enzyme genes on the pathways of lipogenesis, some other unexpected genes are also found to have sterol regulatory elements in their promoters. These reported genes are summarized below: (1) IRS-2: recent studies have highlighted the role of insulin/IGF1/IRS2 signaling pathway in regulating beta cell function. This signaling pathway has been discussed in FoxO1 section [6,19]. Additionally, it was reported that SREBP-1c could suppress IRS2 activity through the direct binding to IRS2 promoter [24]. This may make some contribution in accounting for the role of SREEBP-1c in GSIS of beta cell. (2) Pdx-1: overexpression of SREBP-1c was found to suppress Pdx-1 expression both in vivo and in vitro. On the contrary, SREBP-1c knock-out islets exhibited up-regulation of Pdx-1 expression [25]. Its precise molecular mechanism is under investigation. Since Pdx-1 is a crucial transcription factor for beta cell function which has been discussed in Pdx-1 section, the suppression of Pdx-1 by SREBP-1c may also stimulate secondary negative effects on insulin secretion. (3) Granuphilin: the Rab27a (a monomeric GTPase) effector granuphilin is specifically localized in insulin granules and regulates the vesicle transport for exocytosis. It was reported that granuphilin was up-regulated in some diabetic animal models, leading to suppression of insulin secretion [26]. Furthermore, granuphilin was found to be a direct target of SREBP-1c and its knockdown restored insulin secretion [27]. Therefore, granuphilin should be on the list of mediators involved in the role of SREBP-1c in regulating beta cell function. (4) Uncoupling protein 2 (UCP2): UCP2 is a member of uncoupling protein family which mediates uncouple of energy usage and ATP production from mitochondrial and it was found to have function in regulating insulin secretion in pancreatic beta cells [28]. This may be attributed to its negative regulation of cytoplasmic ATP/ADP - the key signal in GSIS. Nuclear SREBP-1c was found to accumulate UCP2 in beta cells in a state of high nutrition [29]. Moreover, Kato et al. reported the crucial role of UCP2 in the palmitate stimulated insulin secretion inhibition [22]. Together, the effect of SREBP-1 on UCP2 regulation may partially explain the SREBP-1c induced GSIS impairment. (5) Other factors: Kir6.2, Kv1.2, Syntaxin-1a and Munc18-1 which are related to electrophysiological functions of cellular membranes seem to be regulated by SREBP-1c [30]. Although precise molecular dissection has not been fully understood, regulation of these molecules provides a new perspective of SREBP-1c action on ion channel.
This basic leucine zipper transcription factor MafA was found to specifically localize in nuclei of insulin-positive cells and could activate the insulin gene promoter through interacting with Pdx1 and Beta2 in a synergistic faction. Additionally, up-regulation of MafA alone was sufficient to improve endogenous insulin mRNA levels [32]. Besides, it is recently identified that MafA transcription factor is not only critical to regulate the transcription of insulin but also important to the beta cell function. It is noteworthy that reduced MafA activity was implicated in the development of beta cell dysfunction. Zhang et al. [33] reported that mice deficient in MafA developed diabetes due to impaired insulin secretion. This study also revealed that MafA knock-out mice displayed reduced expression levels of Insulin1, Insulin2, Pdx-1, NeuroD1, and Glut-2. Furthermore, a more recent study highlighted the role of MafA in GSIS regulation [34]. In this study, overexpression of MafA caused increased GSIS. In addition, the expression of important beta cell genes including Glut2, Pdx-1, Nkx6.1, GLP-1R, and pyruvate carboxylase (PC) was also mentioned to be regulated positively by MafA. These results indicate that MafA may qualify as a crucial master regulator of genes implicated in maintaining beta cell function, in particular the GSIS. Future work GSIS is the most important function of beta cells to maintain the glucose homeostasis. To date, many effectors have been found to be involved in GSIS (Fig. 1). Pdx-1 is reported to regulate GLP-1R expression, thus influencing the GLP-1/GLP-1R signaling pathway which could potentially enhance GSIS through elevating cytoplasmic cAMP level. Additionally, Pdx-1 is regulated by FoxO1, SREBP1c and MafA. However, it is unclear whether the effect of these three transcription factors on regulating Pdx-1 is equal. Additionally, it is required to identify whether there are other transcription factors which may affect the expression and/or activity of Pdx-1 as well. The activity of FoxO1 is regulated by Akt phosphorylation. Other kinases have been found to exert similar effect as Akt does on FoxO1 regulation. Identification of the whole signaling pathway may open a new perspective in FoxO1 related GSIS. Furthermore, GK and Pdx-1 are found to be the downstream signal mediators
Ion channels Insulin/IGF-1 IR/IGF-1R granuphilin IRS2 UCP2 Akt
MafA RIPE3b (in rat)/C1 (in human) is one of the most important cisregulatory elements to control beta cell selective insulin transcription. The gene which encodes the RIPE3b/C1 activator has been cloned and identified as MafA [31].
SREBP-1c GLP-1
FoxO1
Together, these findings reveal that SREBP-1c is related to multiple pathways required for regulation of beta cell function. Therefore, the expression and/or activity of SREBP-1c may contribute to the development of T2DM.
exocytosis
Enzymes in glycolytic pathway
Pdx-1
GLP-1R Elevation of cAMP MafA
NKX6.1 PC Glut2
NeuroD MODY
Fig. 1. Schematic diagram of transcription factor intercrossing network. FoxO1 is in Insulin/IGF-1 pathway. Pdx-1 is regulated by FoxO1, SREBP-1c and MafA. SREBP-1c is involved in multiple gene regulation including IRS2, Pdx-1, granuphilin, UCP2 and ion channels. Expression of Pdx-1, GLP-1R, Nkx6.1, PC, Glut2 and NeuroD are regulated by MafA.
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in Insulin/IGF-1/IRS2/FoxO1 pathway. It is unclear whether GLP-1R could be regulated in this pathway as well. Other possible downstream signal mediators are remained to be identified. SREBP-1c exerts influence on IRS2, Pdx-1, UCP2, granuphilin and ion channels. Thus, further study is needed to identify whether SREBP-1c could regulate FoxO1 through IRS/Akt pathway and/or regulate GLP-1R through Pdx-1/GLP-1R pathway. Furthermore, Pdx-1, GLP-1R, Nkx6.1, PC, Glut2, NeuroD, and enzymes in glycolytic pathway are all involved in MafA mediated GSIS regulation. Due to the powerful controlling capability of MafA, many reporters consider MafA as a master transcription factors in regulating GSIS. Future work is required to extend the list of genes that MafA has effect on. Although substantial work has been done, the entire blueprint related to GSIS regulation is still not obtained. Furthermore, application of these involved transcription factors into the clinical therapy for T2DM is still in the infant stage. Together, to entirely understand the molecular network related to GSIS could contribute not only to identify the mechanism of beta cell dysfunction in T2DM but also to develop the treatment strategies with new perspectives. References [1] R.H. Unger, Lipotoxicity in the pathogenesis of obesity-dependent NIDDM, genetic and clinical implications, Diabetes 44 (1995) 863–970. [2] J.C. Bruning, J. Winnay, S. Bonner-Weir, S.I. Taylor, D. Accili, C.R. Kahn, Development of a novel polygenic model of NIDDM in mice heterozygous for IR and IRS-1 null alleles, Cell 88 (1997) 561–572. [3] D.A. Stoffers, N.T. Zinkin, Pancreatic agenesis attributable to a single nucleotide deletion in the human IPF1 gene coding sequence, Nat. Genet. 15 (1997) 106– 110. [4] J.F. Habener, D.A. Stoffers, V. Stanojevic, W.L. Clarke, J.F. Habener, A newly discovered role of transcription factors involved in pancreas development and the pathogenesis of diabetes mellitus, Proc. Assoc. Am. Physicians 110 (1998) 12–21. [5] S.S. Fajans, G.I. Bell, K.S. Polonsky, Molecular mechanisms and clinical pathophysiology of maturity-onset diabetes of the young, N. Engl. J. Med. 345 (2001) 971–980. [6] Y. Kazuya, K. Yoshida, K. Murao, H. Imachi, W.M. Cao, X. Yu, J. Li, R.A. Ahmed, N. Kitanaka, N.C. Wong, T.G. Unterman, M.A. Magnuson, T. Ishida, Pancreatic glucokinase is activated by insulin-like growth factor-1, Endocrinology 148 (2007) 2904–2913. [7] F. Diraison, L. Parton, P. Ferré, F. Foufelle, C.P. Briscoe, I. Leclerc, G.A. Rutter, Over-expression of sterol-regulatory-element-binding protein-1c (SREBP1c) in rat pancreatic islets induces lipogenesis and decreases glucose-stimulated insulin release: modulation by 5-aminoimidazole-4-carboxamide ribonucleoside (AICAR), Biochem. J. 378 (2004) 769–778. [8] Y.I. Kitamura, T. Kitamura, J.P. Kruse, J.C. Raum, R. Stein, W. Gu, D. Accili, FoxO1 protects against pancreatic beta cell failure through NeuroD and MafA induction, Cell Metab. 2 (2005) 153–163. [9] J. Jonsson, L. Carlsson, T. Edlund, H. Edlund, Insulin-promoter-factor 1 is required for pancreas development in mice, Nature 371 (1994) 606–609. [10] U. Ahlgren, J. Jonsson, L. Jonsson, K. Simu, H. Edlund, Beta-cell-specific inactivation of the mouse Ipf1/Pdx1 gene results in loss of the beta-cell phenotype and maturity onset diabetes, Genes Dev. 12 (1998) 1763–1768. [11] D.K. Hagman, L.B. Hays, S.D. Parazzoli, V. Poitout, Palmitate inhibits insulin gene expression by altering PDX-1 nuclear localization and reducing mafA expression in isolated rat islets of Langerhans, J. Biol. Chem. 280 (2005) 32413–32418. [12] M. Ganno, E.T. Ables, L. Crawford, D. Lowe, M.F. Offield, M.A. Magnuson, C.V. Wright, pdx-1 function is specifically required in embryonic beta cells to generate appropriate numbers of endocrine cell types and maintain glucose homeostasis, Dev. Biol. 314 (2008) 406–417. [13] H.Wang.M. Iezzi, S. Theander, P.A. Antinozzi, B.R. Gauthier, P.A. Halban, C.B. Wollheim, Suppression of pdx-1 perturbs proinsulin processing, insulin secretion and GLP-1 signalling in INS-1 cells, Diabetologia 48 (2005) 720–731.
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