ABSTRACT
Background: Type 2 diabetes etiology has a strong genetic component. More than 20 genetic variants have been associated with diabetes and other metabolic markers. However, the polymorphism rs7903146 of the TCF7L2 gene has shown the strongest association. Aim: To investigate the association of TCF7L2 (rs7903146) genotype with adiposity and metabolic markers in the Chilean adult population. Material and Methods: The association of TCF7L2 (rs7093146) with adiposity and metabolic markers was studied in 301 participants. The outcomes of the study were adiposity markers (body weight, body mass index (BMI), fat mass and waist circumference) and metabolic markers (blood glucose, insulin, HOMA-IR, lipid profile, high sensitivity C-reactive protein (CRP), alanine aminotransferase (ALT), gamma glutamyl transpeptidase (GGT) and leptin). Results: There was an association between the polymorphism TCF7L2 genotype and fasting blood glucose. The latter increased by 4.86 mg/dl per each copy of the risk allele [(95% confidence intervals (CI): 0.48; 9.24), p = 0.03] in the unadjusted adjusted model. However, this association was slightly attenuated in the fully adjusted model [4.38 mg/dl (95% IC: 0.16; 8.60), p = 0.04)]. There were no associations between the TCF7L2 genotype and any other metabolic or adiposity outcome. Conclusions: These findings confirm the association between the TCF7L2 (rs7903146) and fasting glucose in the Chilean population. However, further studies are needed to confirm the association between the TCF7L2 and diabetes risk in the Chilean population.
Subject(s)
Humans , Male , Female , Adult , Middle Aged , Young Adult , Polymorphism, Single Nucleotide , Diabetes Mellitus, Type 2/genetics , Adiposity/genetics , Transcription Factor 7-Like 2 Protein/genetics , Reference Values , Blood Glucose/genetics , Genetic Markers , Linear Models , Chile , Anthropometry , Nutritional Status , Cross-Sectional Studies , Risk Factors , Diabetes Mellitus, Type 2/metabolism , Alleles , Adiposity/ethnology , Genetic Association Studies , Gene Frequency , GenotypeABSTRACT
Objective To evaluate the effects of transcription factor 7-like 2 (TCF7L2) silence on the expression of insulin degrading enzyme (IDE) in insulin resistance (IR) model HepG2 cells and its possible mechanism. Methods The HepG2 cells were divided into blank group, TCF7L2 interference group, empty vector group, IR group, IR+TCF7L2 interference group, IR+empty vector group. IR-HepG2 cell model was induced by in vitro cultivation o the cells in high concentration of insulin (5 X 10-6 mol/L) for 24 hours; GOD-POD and 2-NBDG method was used to verify successful reproduction of IR-cell model. TCF7L2 specific siRNA lentivirus vector (LV-TCF7L2-siRNA) was constructed with TCF7L2 mRNA coding sequence as the interference target, and it was used to transfect the cells in blank group and IR group. Empty vector virus was used to transfect the cells in empty vector group and IR+empty vector group. The expressions of TCF7L2 and IDE mRNA were detected by qRT-PCR, and the changes in the expression of TCF7L2, IDE, insulin stimulated protein kinase B(AKT) and phosphorylated protein kinase B(p-AKT) were detected by Western blotting. The uptake rate of 2-deoxy-D-glucose (2-NBDG) was analyzed by flow cytometry. Results Compared with that in control group, the glucose consumption and the uptake rate of 2-NBDG significantly decreased in IR group (P<0.01), proving that the IR cell model had been reproduced successfully. Western bloting and qRT-PCR revealed that the expression levels of TCF7L2 and IDE mRNA and protein were obviously decreased in IR group compared with that in blank group (P<0.05), in TCF7L2 interference group than in blank group and empty vector group, and in IR+TCF7L2 interference group than in blank group and IR+empty vector group (P<0.05). Afer physiological insulin stimulation, the expression levels of p-AKT protein decreased more signifcantly in IR group and IR+TCF7L2 interference group than in blank group (P<0.01), while no statistically signifcant difference in the total AKT protein level was found among all the groups. 2-NBDG uptake rate was significantly decreased in TCF7L2 interference group as compared with that in blank group and empty vector group, and also in IR+TCF7L2 interference group than in IR group and IR+empty vector group, respectively P<0.01. ConclusionTe mechanism of IR induced by the interaction of TCF7L2 and IDE might be related to the decreased expression of the insulin signaling pathway key enzyme p-AKT protein.
ABSTRACT
Objective To investigate the relationship between single nucleotide polymorphism (SNP) of transcription factor 7-like 2 (TCF7L2) at locus rs7903146,rs290487,rsl1196205,rs 12255372 and genetic susceptibility in women with gestational diabetes mellitus (GDM).Methods As a case-control study,100 pregnant women with GDM and 100 healthy pregnant women in the Maternal and Children Health Hospital of Jiangxi Province were recruited from January 2010 to July 2013.Clinical parameters,including body mass index (BMI),fasting insulin (FINS),fasting plasma glucose (FPG) and homeostatic model assessment-insulin resistance index (HOMA-IR) were measured after admission to hospital.Allelespecific PCR was used to analyze the SNP of TCF7L2 at locus rs7903146,rs290487,rs11196205,rs12255372.Results (1)The BMI,FPG,FINS and HOMA-IR in GDM group were(27.4±3.0) kg/m2,(5.6±1.0) mmol/L,(6.2±3.4) mU/L and 1.8± 1.0,and were (24.2±2.9) kg/m2,(5.3±0.8) mmol/L,(4.5±2.8) mU/L,1.2± 0.8 in the control group,respectively.The differences had statistically significance (P＜0.05).(2)The SNP of TCF7L2 gene,locus rs7903146 were CC,CT and TT genotype; the SNP of locus rs290487 were CC,CT and TT genotype; and the SNP of locus rs1 1196205 were GG and CC genotype; while the SNP of locus rs12255372 was GG genotype.(3)The distribution frequencies of genotype CC,CT and TT at locus rs7903146 in the GDM group were 40％ (40/100),36％ (36/100) and 24％ (24/100),respectively.While in the control group,they were 55％ (55/100),38％ (38/100) and 7％ (7/100),respectively.The frequencies of C and T allele of rs7903146 were 58％and 42％ in the GDM group,and in the control group they were 74％ (148/200) and 26％ (52/200).The differences of genotype distribution and C/T allele frequency of rs7903146 between the two groups were statistically significant (P＜0.05).(4)The distribution frequencies of genotype CC,CT and TT at locus rs290487 in the GDM group were 12 ％ (12/100),36 ％ (36/100) and 52％ (52/100),and were 16％ (16/100),34％ (34/100) and 50％ (50/100) in the control group.The frequencies of C and T allele of rs290487 were 30％ (60/200) and 70％ (140/200) in the GDM group,and were 33％ (66/200) and 67％ (134/200) in the control group.There was no difference of genotype distribution and C/T allele frequency of rs290487 between the two groups (P＞0.05).(5)The distribution frequencies of genotype GG and CC at locus rs1 1196205 in the GDM group were 99％ (99/100) and 1％ (1/ 100),while those in the control group were 100％(100/100) and 0％.The frequency of G and C allele of rs1 1196205 were 99％(198/200) and 1％(2/200) in the GDM group,while in the control group were 100％ (200/200) and 0.There was no difference of genotype distribution and G/C allele frequency of rs11196205 between the two groups (P＞0.05).(6)The distribution frequencies of genotype GG at locus rs12255372 were 100％(100/100) in both the GDM group and the control group.The frequencies of G allele of rs12255372 were 100％ (200/200) in both the GDM group and the control group.There was no difference of genotype distribution and G allele frequency of rs12255372 between the two groups (P＞0.05).(7)After adjusting for age,gestational age,BMI,FPG and FINS,pregnant women with TT genotype at locus rs7903146 were more likely to have hyperglycemia compared with the C allele carriers (OR=2.77,95％ CI:1.03-7.57,P＜0.05).Conclusions The polymorphism of locus rs7903146 in TCF7L2 gene may be associated with genetic susceptibility in women with GDM.TT genotype is likely to be risk factor in the pathogenesis of GDM.