In vitro modulation of TCF7L2 gene expression in human pancreatic cells

Khalooghi, Keynoosh; Hashemi, Saeid; Mehraban, Nahid; Amiri, Parvin; Bazzaz, Javad Tavakkoly; Larijani, Bagher; Amoli, Mahsa M.

doi:10.1007/s11033-009-9452-3

Cited by 9 publications

(10 citation statements)

References 22 publications

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“…Curcumin also decreased β -cell volume in rat pancreas [142]. Fifth, in a human pancreatic cell line, curcumin increased expression of the transcription factor 7-like 2 ( TCF7L2 ) gene [143] in the Wnt signaling pathway, which is associated with type 2 diabetes [144]. Sixth, type 2 diabetes involved aberrant misfolding of human islet amyloid polypeptide (h-IAPP) and formation of pancreatic amyloid deposits [145].…”

Section: Effect Of Curcumin On Pancreatic β-Cell Dysfunctionmentioning

confidence: 99%

Curcumin and Diabetes: A Systematic Review

Zhang

et al. 2013

Evidence-Based Complementary and Alternative Medicine

257

175

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Turmeric (Curcuma longa), a rhizomatous herbaceous perennial plant of the ginger family, has been used for the treatment of diabetes in Ayurvedic and traditional Chinese medicine. The active component of turmeric, curcumin, has caught attention as a potential treatment for diabetes and its complications primarily because it is a relatively safe and inexpensive drug that reduces glycemia and hyperlipidemia in rodent models of diabetes. Here, we review the recent literature on the applications of curcumin for glycemia and diabetes-related liver disorders, adipocyte dysfunction, neuropathy, nephropathy, vascular diseases, pancreatic disorders, and other complications, and we also discuss its antioxidant and anti-inflammatory properties. The applications of additional curcuminoid compounds for diabetes prevention and treatment are also included in this paper. Finally, we mention the approaches that are currently being sought to generate a “super curcumin” through improvement of the bioavailability to bring this promising natural product to the forefront of diabetes therapeutics.

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Section: Effect Of Curcumin On Pancreatic β-Cell Dysfunctionmentioning

confidence: 99%

Curcumin and Diabetes: A Systematic Review

Zhang

et al. 2013

Evidence-Based Complementary and Alternative Medicine

257

175

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“…Further, while studies on the role of TCF7L2 in T2D susceptibility have largely focused on pancreatic islets (Loos et al 2007;Liu and Habener 2008;Loder et al 2008;Shu et al 2008Shu et al , 2009da Silva Xavier et al 2009;Khalooghi et al 2009), our unbiased approach localized cis-regulatory activity for a wide array of tissues involved in glucose homeostasis to the associated interval, suggesting that the role of TCF7L2 in the pathogenesis of T2D may not be solely limited to the pancreas. To that end, we did not identify pancreatic islet expression in adult mice, and the same SNP rs7903146 associated with T2D has also been associated with an increased risk of colorectal cancer (Folsom et al 2008), independent of diabetes.…”

Section: Tcf7l2 Is a Key Regulator Of Glucose Metabolismmentioning

confidence: 99%

Alterations in TCF7L2 expression define its role as a key regulator of glucose metabolism

Savic¹,

Ye²,

Aneas³

et al. 2011

Genome Res.

132

145

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Genome-wide association studies (GWAS) have consistently implicated noncoding variation within the TCF7L2 locus with type 2 diabetes (T2D) risk. While this locus represents the strongest genetic determinant for T2D risk in humans, it remains unclear how these noncoding variants affect disease etiology. To test the hypothesis that the T2D-associated interval harbors cis-regulatory elements controlling TCF7L2 expression, we conducted in vivo transgenic reporter assays to characterize the TCF7L2 regulatory landscape. We found that the 92-kb genomic interval associated with T2D harbors longrange enhancers regulating various aspects of the spatial-temporal expression patterns of TCF7L2, including expression in tissues involved in the control of glucose homeostasis. By selectively deleting this interval, we establish a critical role for these enhancers in robust TCF7L2 expression. To further determine whether variation in Tcf7l2 expression may lead to diabetes, we developed a Tcf7l2 copy-number allelic series in mice. We show that a null Tcf7l2 allele leads, in a dosedependent manner, to lower glycemic profiles. Tcf7l2 null mice also display enhanced glucose tolerance coupled to significantly lowered insulin levels, suggesting that these mice are protected against T2D. Confirming these observations, transgenic mice harboring multiple Tcf7l2 copies and overexpressing this gene display reciprocal phenotypes, including glucose intolerance. These results directly demonstrate that Tcf7l2 plays a role in regulating glucose tolerance, suggesting that overexpression of this gene is associated with increased risk of T2D. These data highlight the role of enhancer elements as mediators of T2D risk in humans, strengthening the evidence that variation in cis-regulatory elements may be a paradigm for genetic predispositions to common disease.[Supplemental material is available for this article.]Recent GWAS have uncovered a number of loci affecting risk of T2D (Voight et al. 2010). While some of these loci include genes known to play a role in glucose metabolism and diabetes pathogenesis (PPARG, KCNJ11) (Willson et al. 2001;Gloyn et al. 2006), others represent genomic regions with unknown functional roles in disease etiology. Among these, a set of single nucleotide polymorphisms (SNPs) on chromosome 10q25.2 shows strong and consistent association with T2D in virtually every population tested, constituting the greatest effect on risk identified to date, with a cumulative allelic odds ratio of 1.46 (Grant et al. 2006;Cauchi et al. 2007;Lyssenko 2008). These SNPs map to a 92-kb interval within TCF7L2, a gene encoding a transcription factor of the canonical Wnt signaling pathway known to have developmental roles in determining cell fate, survival, proliferation, and movement (Moon et al. 2004;Clevers 2006;MacDonald et al. 2009). Given the complexity of this pathway, establishing a definitive role for TCF7L2 in the etiology of T2D has been challenging (Pearson 2009).While the TCF7L2 T2D-associated interval spans coding sequence, exonic v...

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“…Curcumin induced heme oxygenase (HO)-1 synthesis, which enhanced cAMP synthesis to stimulate insulin release [18,19], and inhibited JNK, which was a signaling molecule linking inflammation to insulin resistance [20]. Curcumin significantly increased transcription factor 7-like 2 (TCF7L2) gene expression, which played a role in insulin release in pancreatic islets [21]. …”

Section: Introductionmentioning

confidence: 99%

Effects of a novel curcumin derivative on insulin synthesis and secretion in streptozotocin-treated rat pancreatic islets in vitro

et al. 2014

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BackgroundHyperglycemia induces activation of the c-Jun N-terminal kinase (JNK) pathway, which suppresses insulin gene expression and reduces DNA binding of pancreatic and duodenal homeobox factor (PDX)-1. This study aims to investigate the effects of a novel curcumin derivative (NCD) on JNK signaling pathway on insulin synthesis and secretion in streptozotocin (STZ)-treated rat pancreatic islets in vitro.MethodsIsolated rat pancreatic islets were divided into five groups: untreated control group; group treated with NCD (10 μM); group exposed to STZ (5 mM); group treated with NCD (10 μM) and then exposed to STZ (5 mM); and group exposed to STZ (5 mM) and then treated with NCD (10 μM). The pancreatic islets from all groups were used for DNA fragmentation assays and quantitative assessments of the JNK, Pdx1, glucose transporter-2 (GLUT2), heme oxygenase (HO)-1, transcription factor 7-like 2 (TCF7L2), and glucagon-like peptide (GLP)-1 gene expression levels. The intracellular calcium, zinc, and the phosphorylated and total JNK protein levels were assessed. The insulin (secreted/total) and C-peptide levels were examined in islet culture medium.ResultsNCD protected pancreatic islets against STZ-induced DNA damage, improved total insulin (P = 0.001), secreted insulin (P = 0.001), and C-peptide levels (P = 0.001), normalized mRNA expressions of insulin, Pdx1, and GLUT2 (P = 0.0001), and significantly elevated calcium and zinc levels (P = 0.0001). All effects were significant when islets were treated with NCD before STZ (P = 0.05). JNK gene overexpression and JNK protein levels induced by STZ were significantly inhibited after NCD treatment of islets ( P = 0.0001). NCD-treated islets showed significantly elevated gene expressions of HO-1, TCF7L2, and GLP-1 (P = 0.0001), and these upregulated gene expressions were more significantly elevated with NCD treatment before STZ than after STZ (P = 0.05).ConclusionsNCD improved insulin synthesis and secretion in vitro in isolated pancreatic islets treated with STZ through inhibition of the JNK pathway, up-regulation of the gene expressions of HO-1, TCF7L2, and GLP-1 and enhancing effects on calcium and zinc levels.

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In vitro modulation of TCF7L2 gene expression in human pancreatic cells

Cited by 9 publications

References 22 publications

Curcumin and Diabetes: A Systematic Review

Curcumin and Diabetes: A Systematic Review

Alterations in TCF7L2 expression define its role as a key regulator of glucose metabolism

Effects of a novel curcumin derivative on insulin synthesis and secretion in streptozotocin-treated rat pancreatic islets in vitro

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