Impact of<i>TCF7L2</i>rs7903146 on Insulin Secretion and Action in Young and Elderly Danish Twins

Wegner, Lise; Hussain, Meena S.; Pilgaard, Kasper; Hansen, Torben; Pedersen, Oluf; Vaag, Allan; Poulsen, Pernille

doi:10.1210/jc.2008-0855

Cited by 58 publications

(71 citation statements)

References 34 publications

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“…Two other recent studies reported a disproportionately increased basal rate of EGP and hepatic insulin resistance in carriers of the risk T allele of rs7903146 [11,35]. Expanding on those recent findings, we found the absolute rate of EGP to be elevated in the basal state as well as during a high physiological insulin infusion in carriers of the risk T allele.…”

Section: Discussionsupporting

confidence: 81%

The T allele of rs7903146 TCF7L2 is associated with impaired insulinotropic action of incretin hormones, reduced 24 h profiles of plasma insulin and glucagon, and increased hepatic glucose production in young healthy men

et al. 2009

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Aims/hypothesis We studied the physiological, metabolic and hormonal mechanisms underlying the elevated risk of type 2 diabetes in carriers of TCF7L2 gene. Methods We undertook genotyping of 81 healthy young Danish men for rs7903146 of TCF7L2 and carried out various beta cell tests including: 24 h glucose, insulin and glucagon profiles; OGTT; mixed meal test; IVGTT; hyperglycaemic clamp with co-infusion of glucagon-like peptide (GLP)-1 or glucose-dependent insulinotropic polypeptide (GIP); and a euglycaemic-hyperinsulinaemic clamp combined with glucose tracer infusion to study hepatic and peripheral insulin action. Results Carriers of the T allele were characterised by reduced 24 h insulin concentrations (p<0.05) and reduced insulin secretion relative to glucose during a mixed meal test (beta index: p<0.003), but not during an IVGTT. This was further supported by reduced late-phase insulinotropic action of GLP-1 (p=0.03) and GIP (p=0.07) during a 7 mmol/l hyperglycaemic clamp. Secretion of GLP-1 and GIP during the mixed meal test was normal. Despite elevated hepatic glucose production, carriers of the T allele Diabetologia (2009) 52:1298-1307 DOI 10.1007/s00125-009-1307-x Electronic supplementary

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Section: Discussionsupporting

confidence: 81%

The T allele of rs7903146 TCF7L2 is associated with impaired insulinotropic action of incretin hormones, reduced 24 h profiles of plasma insulin and glucagon, and increased hepatic glucose production in young healthy men

et al. 2009

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“…Human carriers of the TCF7L2 rs7903146 risk T allele have also been reported to have elevated hepatic glucose production [15][16][17][18]. An initial study of alternatively spliced Mature mRNA transcript Transcript number N-terminal C-terminal TCF4 nomination [13] Major pancreatic and liver TCF7L2 isoforms [12 [19].…”

Section: Introductionmentioning

confidence: 99%

Alternative human liver transcripts of TCF7L2 bind to the gluconeogenesis regulator HNF4α at the protein level

et al. 2014

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Aims/hypothesis Gene polymorphisms of TCF7L2 are associated with increased risk of type 2 diabetes and transcription factor 7-like 2 (TCF7L2) plays a role in hepatic glucose metabolism. We therefore addressed the impact of TCF7L2 isoforms on hepatocyte nuclear factor 4α (HNF4α) and the regulation of gluconeogenesis genes.Methods Liver TCF7L2 transcripts were analysed by quantitative PCR in 33 non-diabetic and 31 type 2 diabetic obese individuals genotyped for TCF7L2 rs7903146. To analyse transcriptional regulation by TCF7L2, small interfering R N A t r a n s f e c t i o n , l u c if e r a s e r e p o r t e r a n d c oimmunoprecipitation assays were performed in human hepatoma HepG2 cells. Results In livers of diabetic compared with normoglycaemic individuals, five C-terminal TCF7L2 transcripts showed increased expression. The type 2 diabetes risk allele of rs7903146 positively correlated with TCF7L2 expression in livers from normoglycaemic individuals only. In HepG2 cells, transcript and TCF7L2 protein levels were increased upon incubation in high glucose and insulin. Of the exon 13 transcripts, six were increased in a glucose doseresponsive manner. TCF7L2 transcriptionally regulated 29 genes related to glucose metabolism, including glucose-6-phosphatase. In cultured HepG2 cells, TCF7L2 did not regulate HNF4Α and FOXO1 transcription, but did affect HNF4α protein expression. The TCF7L2 isoforms T6 and T8 (without exon 13 and with exon 15/14, respectively) specifically interacted with HNF4α. Conclusions/interpretation The different levels of expression of alternative C-terminal TCF7L2 transcripts in HepG2 cells, in livers of normoglycaemic individuals carrying the rs7901346 type 2 diabetes risk allele and in livers of diabetic individuals suggest that these transcripts play a role in the pathophysiology of type 2 diabetes. We also report for the first time a protein interaction in HepG2 cells between HNF4α and the T6 and T8 isoforms of TCF7L2, which suggests a distinct role for these specific alternative transcripts.

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“…Previous studies on correlation of TCF7L2 expression levels and risk genotypes have not taken into account the splicing pattern. Furthermore, most of these studies have investigated adipose and/or skeletal muscle tissue [5][6][7][8][9]. While experiments in vitro have shown that a reduction of TCF7L2 expression leads to impaired beta cell function [10,11] we have previously observed increased expression of TCF7L2 in islets of Langerhans from diabetic patients [12].…”

Section: Introductionmentioning

confidence: 99%

Unique splicing pattern of the TCF7L2 gene in human pancreatic islets

et al. 2009

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Aims/hypothesis Intronic variation in the TCF7L2 gene exhibits the strongest association to type 2 diabetes observed to date, but the mechanism whereby this genetic variation translates into altered biological function is largely unknown. A possible explanation is a genotype-dependent difference in the complex splicing pattern; however, this has not previously been characterised in pancreatic or insulin target tissues. Here, the detailed TCF7L2 splicing pattern in five human tissues is described and dependence on risk genotype explored. Methods RT-PCR and quantitative real-time PCR were employed to characterise TCF7L2 splicing in pancreatic islets, blood lymphocytes, skeletal muscle and subcutaneous and visceral adipose tissue from non-diabetic individuals. Results The mapping of TCF7L2 splice variants shows a specific pattern in pancreatic islets, with four predominant transcripts and high usage of the variable exons 4 and 15. The overall concentration of TCF7L2 mRNA is highest in islets and fat and lower in blood and muscle. No significant difference in overall amount or splicing pattern was observed between carriers and non-carriers of the rs7903146 risk (T) allele. However, incorporation of exon 4 in islets correlates positively with plasma HbA 1c levels (r=0.758; p=0.018).Conclusions/interpretation There were pronounced tissuespecific differences in the splicing of TCF7L2 with forms containing exon 4 and 15 being most abundant in islets. The incorporation of exon 4 in islets correlated with HbA 1c levels. Further experiments will be needed to determine the direction of this correlation, and larger cohorts needed to unequivocally resolve whether there is a relationship between genotype and splicing in islets.

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Impact ofTCF7L2rs7903146 on Insulin Secretion and Action in Young and Elderly Danish Twins

Cited by 58 publications

References 34 publications

The T allele of rs7903146 TCF7L2 is associated with impaired insulinotropic action of incretin hormones, reduced 24 h profiles of plasma insulin and glucagon, and increased hepatic glucose production in young healthy men

The T allele of rs7903146 TCF7L2 is associated with impaired insulinotropic action of incretin hormones, reduced 24 h profiles of plasma insulin and glucagon, and increased hepatic glucose production in young healthy men

Alternative human liver transcripts of TCF7L2 bind to the gluconeogenesis regulator HNF4α at the protein level

Unique splicing pattern of the TCF7L2 gene in human pancreatic islets

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