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* Department of Medicine, University of Montréal, Montréal, QC, Canada; Centre de Recherche du Centre Hospitalier de l'Université de Montréal, QC, Canada; ** Department of Molecular Physiology and Biophysics, Vanderbilt University Medical Center, Nashville, TN; Pacific Northwest Research Institute, Seattle, WA; and Departments of Medicine and Pharmacology, University of Washington, Seattle, WA
2 To whom correspondence should be addressed. E-mail: vincent.poitout{at}umontreal.ca.
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ABSTRACT |
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 TOP ABSTRACT LITERATURE CITED |
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KEY WORDS: • B-cell • diabetes • insulin
Insulin is secreted uniquely from the islet ß-cells of the pancreas and plays a major role in the maintenance of energy homeostasis. Insulin secretion is tightly regulated to maintain blood glucose levels within a narrow physiological range. Insufficient secretion of insulin from ß-cells contributes to the chronic hyperglycemia characteristic of diabetes, a disease that affects >20 million Americans. Short-term regulation of insulin secretion, such as in response to a meal, occurs mainly at the level of exocytosis. However, the maintenance of adequate intracellular stores of insulin on a long-term basis relies on the transcriptional and translational regulation of insulin biosynthesis. The 2 most important nutrients in mammals, glucose and fatty acids, profoundly affect preproinsulin gene (hereafter referred to as "insulin gene") expression under physiological and pathological circumstances. This review briefly describes the key control elements and their cognate transactivating factors involved in the metabolic regulation of insulin gene transcription. We then describe the manner in which glucose normally regulates insulin gene expression, and how dysregulation occurs upon prolonged exposure to glucose (glucotoxicity) and fatty acids (lipotoxicity).
Structure of the insulin gene and key transcription factors involved in metabolic regulation.
In adult mammals, expression of the insulin gene is essentially restricted to the pancreatic ß-cell. A highly conserved region lying 
340 bp immediately upstream of the transcription initiation start, hereafter referred to as the insulin promoter, confers both tissue-specific expression and metabolic regulation of the insulin gene. Many transcription factors act upon this region, forming a highly sophisticated transcriptional network that ensures precise regulation. The most critical cis-acting DNA elements involved in transcriptional activation in vitro are referred to the A3, C1, and E1 sites [Fig. 1; reviewed in (1)].
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Glucose regulation of insulin gene expression. Glucose is the major nutrient regulator of pancreatic ß-cell function and coordinately regulates insulin gene expression, insulin biosynthesis, and insulin secretion. Glucose controls all steps of insulin gene expression, including transcription, preRNA splicing, and mRNA stability. A3, E1, and C1 are the major glucose-responsive transcription control elements of the insulin gene. In addition, a more distal glucose-responsive element appears to bind a glucose-sensitive complex that is specifically present in primary islets but remains to be identified (9). Glucose promotes the binding of PDX-1 to the A3 site (2) and PDX-1 transactivating potency (10). In addition, it is now recognized that PDX-1 stimulation of insulin gene transcription involves recruitment of co-activators, such as p300 (11), that affect chromatin structure through post-translational modifications of histones such as methylation (12) and/or acetylation (13).
The signal transduction mechanisms by which glucose increases PDX-1 binding to the insulin promoter have been studied extensively but remain controversial. Glucose appears to promote translocation and modification of a cytoplasmic, inactive 31-kDa form to the nuclear, active 46-kDa species (14). Although this transformation likely requires phosphorylation, the large increase in apparent molecular mass suggests that PDX-1 undergoes multiple post-translational modifications, possibly by O-linked N-acetylglucosamine (15) or small ubiquitin-related modifier 1 (16). A number of kinases were proposed to mediate PDX-1 phosphorylation, including p38 mitogen-activated protein kinase (17), phosphatidylinositol-3 kinase (18), and extracellular signal-regulated kinases (19).
MafA and B2/E47 are also stimulated by glucose (20). Although it is unclear how B2/E47 is regulated, MafA expression and binding are activated directly by glucose (21). Importantly, PDX-1, MafA, and B2 do not act in an isolated manner, but interact with each other to induce synergistic activation of insulin transcription (21). Therefore, glucose enhances insulin gene transcription by a number of complementary mechanisms that include recruitment of transcription factors to regulatory sites, histone modifications, and initiation of transcription. Importantly, our understanding of the control of the insulin gene has been gleaned principally from in vitro systems, and their relevance to the endogenous gene in vivo has yet to be established.
In addition to its major effects on the rate of transcription, glucose markedly stabilizes preproinsulin mRNA (22). Two elements located in the 3'-untranslated region of the mRNA molecule were proposed as mediators of this effect, i.e., the conserved UUGAA sequence (23) and a pyrimidine-rich sequence (24). Stabilization appears to involve glucose-regulated binding of a polypyrimidine tract-binding protein to the pyrimidine-rich sequence (24).
Dysregulation of insulin gene expression. As discussed above, glucose is the major physiologic regulator of the insulin gene. In contrast, when ß-cells are exposed to elevated levels of glucose for prolonged periods of time, glucose becomes toxic to insulin secretion, gene expression, and ß-cell survival. This phenomenon is referred to as glucotoxicity (25). Similarly, chronically elevated levels of fatty acids adversely affect pancreatic ß-cell function through a process termed lipotoxicity (26). The relevance of nutrient-induced ß-cell dysfunction in humans comes from the fact that chronic hyperglycemia and associated disorders of lipid metabolism are thought to contribute to the deterioration of pancreatic ß-cell function observed in patients with type 2 diabetes (27).
Glucotoxicity Exposure of insulin-secreting cells to elevated glucose levels for several weeks impairs insulin gene expression; this is associated with diminished binding activity of PDX-1 and MafA [reviewed in (28)]. The decrease in PDX-1 binding activity appears to involve post-transcriptional control (29), although the precise mechanism(s) remains to be established. In vivo, PDX-1 expression is also reduced in partially pancreatectomized, hyperglycemic rats (30) and in the diabetic gerbil Psammomys obesus (31), and its binding activity is decreased in islets from Zucker Diabetic Fatty rats (32). The reduction in MafA binding activity in the glucotoxic insulin-secreting HIT-T15 cell was shown recently to be due to a loss of protein expression without changes in mRNA expression, suggesting that glucose reduces MafA activity through a post-translational mode of action (33). Importantly, MafA expression is also reduced in mouse diabetic models (34). In addition, the C/EBPß transcription factor may directly bind E47 and prevent formation of the B2/E47 activator complex under glucotoxic conditions (35). A recent study further proposed that CEBP/ß prevents MafA binding to its cognate sequence under chronic exposure to elevated glucose and, in turn, prevents the cooperative induction of transcription by MafA and B2 (36).
Much progress has been made in recent years in understanding the biochemical mechanisms of glucotoxicity. Ample evidence supports the involvement of oxidative stress in this process, as a result of long-term exposure to elevated glucose [reviewed in (37)]. For example, the decrease in insulin gene transcription (38) and MafA protein expression (33) is prevented by antioxidants in glucotoxic insulin-secreting cells. Moreover, treatment of Zucker Diabetic Fatty rats with antioxidants normalizes plasma glucose levels and restores insulin secretion, insulin content, and insulin mRNA levels (38). In addition, activation of the hexosamine pathway decreases insulin gene expression and insulin secretion in isolated islets via generation of oxidative stress but not via O-linked glycosylation (39).
The signaling pathways mediating inhibition of insulin gene expression by oxidative stress appear to involve, at least in part, stress-activated kinases. Overexpression of a dominant-negative form of c-jun N-terminal kinase (JNK) prevents the decrease in PDX-1 binding activity in response to oxidative stress in a c-jun-independent manner (40). On the other hand, c-jun can directly inhibit insulin gene transcription by interfering with bHLH-mediated transcriptional activity (41). It is therefore likely that several interrelated pathways negatively affect insulin gene transcription under conditions of oxidative stress (Fig. 2). Another possibility, not exclusive with the previous one, is that glucotoxicity induces dedifferentiation of the ß-cell, as suggested by the observed inhibition of genes associated with ß-cell function and derepression of genes not normally expressed in differentiated ß-cells (42). For example, the transcription factor c-myc is upregulated in islets from diabetic animals (43), and can inhibit insulin gene transcription by competing for B2 binding at the E-box (44) (Fig. 2).
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Palmitate impairment of insulin gene expression appears to be mediated by direct inhibition of insulin promoter activity (47). We showed recently in isolated rat islets that palmitate inhibits PDX-1 and MafA binding activities (46). Interestingly, PDX-1 and MafA appear to be affected by palmitate through different mechanisms. Culture of isolated islets in the presence of palmitate prevents the nuclear translocation of PDX-1 that normally occurs upon glucose stimulation, whereas it blocks glucose induction of MafA mRNA expression (46). Importantly, combined, adenovirus-mediated overexpression of PDX-1 and MafA prevents palmitate inhibition of insulin gene expression in isolated rat islets, consistent with an essential role for these 2 transcription factors in the mechanisms of lipotoxicity (46).
It is interesting that MafA and PDX-1 are common glucotoxicity and lipotoxicity targets, although affected by different mechanisms. Hence, glucotoxicity is associated with decreased protein expression of PDX-1 and MafA, whereas under lipotoxic conditions, PDX-1 is expressed but retained in the cytoplasm and MafA mRNA levels are decreased. It is therefore likely that these conditions, which occur concomitantly in most patients with type 2 diabetes, have deleterious effects on insulin gene expression.
Conclusions. Regulation of insulin gene expression under normal circumstances is controlled chiefly by changes in glucose concentrations. Glucose coordinately recruits a highly sophisticated network of transcription factors and co-activators to the insulin promoter, and also prolongs the half-life of insulin mRNA. In vitro and in vivo studies in rodents have provided evidence that under circumstances of chronically elevated levels of glucose and fatty acids, insulin gene expression is greatly reduced. The mechanisms of glucotoxicity and lipotoxicity involve the PDX-1 and MafA transcription factors, with such a convergence having severe adverse consequences on ß-cell function (e.g., insulin gene expression). The combined and deleterious effects of glucose and fatty acids on insulin gene expression are likely to contribute to ß-cell dysfunction in type 2 diabetes, although this hypothesis has yet to be tested in humans.
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FOOTNOTES |
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3 Abbreviations used: bHLH, basic helix-loop-helix ; B2, Beta2/NeuroD; C/EBPß, CCAAT/enhancer-binding protein ß; JNK, c-jun N-terminal kinase; MafA, mammalian homologue of avian MagfA/L-Maf; PDX-1, pancreatic/duodenal homeobox-1; TG, triglycerides.
Manuscript received 20 December 2005.
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LITERATURE CITED |
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TOPABSTRACTLITERATURE CITED |
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