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Huntington's disease and juvenile-onset schizophrenia have long been regarded as distinct disorders. However, both manifest cell-intrinsic abnormalities in glial differentiation, with resultant astrocytic dysfunction and hypomyelination. To assess whether a common mechanism might underlie the similar glial pathology of these otherwise disparate conditions, we used comparative correlation network approaches to analyse RNA-sequencing data from human glial progenitor cells (hGPCs) produced from disease-derived pluripotent stem cells. We identified gene sets preserved between Huntington's disease and schizophrenia hGPCs yet distinct from normal controls that included 174 highly connected genes in the shared disease-associated network, focusing on genes involved in synaptic signalling. These synaptic genes were largely suppressed in both schizophrenia and Huntington's disease hGPCs, and gene regulatory network analysis identified a core set of upstream regulators of this network, of which OLIG2 and TCF7L2 were prominent. Among their downstream targets, ADGRL3 , a modulator of glutamatergic synapses, was notably suppressed in both schizophrenia and Huntington's disease hGPCs. Chromatin immunoprecipitation sequencing confirmed that OLIG2 and TCF7L2 each bound to the regulatory region of ADGRL3 , whose expression was then rescued by lentiviral overexpression of these transcription factors. These data suggest that the disease-associated suppression of OLIG2 and TCF7L2-dependent transcription of glutamate signalling regulators may impair glial receptivity to neuronal glutamate. The consequent loss of activity-dependent mobilization of hGPCs may yield deficient oligodendrocyte production, and hence the hypomyelination noted in these disorders, as well as the disrupted astrocytic differentiation and attendant synaptic dysfunction associated with each. Together, these data highlight the importance of convergent glial molecular pathology in both the pathogenesis and phenotypic similarities of two otherwise unrelated disorders, Huntington's disease and schizophrenia. [ABSTRACT FROM AUTHOR]

Gestational diabetes mellitus (GDM) is one of the most frequent predictors of obstetric outcome among Romanian pregnant women. Thus, we aimed to investigate the role of rs7903146 (C/T) TCF7L2 gene polymorphism in the presence of GDM and to evaluate the influence on maternal-fetal outcomes in a cohort of pregnant women from Northern Transylvania. Our prospective case–control study was performed in a tertiary maternity center on 61 patients diagnosed with GDM and 55 normal pregnant patients. The patients were genotyped for rs7903146 (C/T) polymorphism of the TCF7L2 gene using the PCR-RFLP method between 24 and 28 weeks of gestation. The minor T allele was associated with a high risk of developing GDM (OR 1.71 [95% CI 0.82–3.59]) if both heterozygote and homozygote types were considered. Also, a higher risk of developing GDM was observed in homozygous carriers (OR 3.26 [95% CI 1.10–9.68]). Women with the TT genotype were more likely to require insulin therapy during pregnancy than other genotypes with a 5.67-fold increased risk ([1.61–19.97], p = 0.015). TT homozygote type was significantly associated with fetal macrosomia for birth weights greater than the 95th percentile (p = 0.034). The homozygous TT genotype is associated with an increased risk of developing GDM. Also, rs7903146 (C/T) TCF7L2 variant is accompanied by a high probability of developing insulin-dependent gestational diabetes mellitus (ID-GDM). The presence of at least one minor T allele was associated with a higher risk of fetal macrosomia. [ABSTRACT FROM AUTHOR]

We performed complex analysis of the association of polymorphic variants rs7903146 of the TCF7L2 gene and rs1801282 of the PPARG gene with metabolic parameters, insulin resistance, and β-cell function in a group of patients with early signs of carbohydrate metabolism disturbances in a sample of Tyumen citizens. The study group consisted of 64 people (39 women, 25 men) aged 40-70 years. The distribution of frequencies of alleles and genotypes of the polymorphic markers rs7903146 and rs1801282 was analyzed and associations of carriage of major homozygous polymorphisms with various phenotypic traits were identified. Genotyping for polymorphic variants of TCF7L2 and PPARG genes was performed using allele-specific PCR with primers provided by Synthol company. Carriers of homozygotes for allele C of the polymorphic marker rs7903146 significantly differed from other respondents by a higher level of C-peptide, as well as by the presence of associations with waist circumference, elevated level of glycated hemoglobin, and arterial hypertension. Carriers of homozygotes for the allele C of the rs1801282 polymorphism of the PPARG gene differed from the group of carriers of homozygotes for the allele G and the group of heterozygote carriers by higher levels of triglycerides, as well as the presence of associations with waist circumference and the level of glycated hemoglobin. [ABSTRACT FROM AUTHOR]

Malaria remains a disease of public health importance globally, especially in sub-Saharan Africa. Malaria deaths reduced globally steadily between 2000-2019, however there was a 10% increase in 2020 due to disruptions in medical service during the COVID-19 pandemic. Globally, about 96% of malaria deaths occurred in 29 countries; out of which, four countries (Nigeria, the Democratic Republic of the Congo, the Niger, and the United Republic of Tanzania) accounted for just over half of the malaria deaths. Nigeria leads the four countries with the highest malaria deaths (accounting for 31% globally). Parallelly, sub-Saharan Africa is faced with a rise in the incidence of Type 2 diabetes (T2D). Until recently, T2D was a disease of adulthood and old age. However, this is changing as T2D in children and adolescents is becoming an increasingly important public health problem. Nigeria has been reported to have the highest burden of diabetes in Africa with a prevalence of 5.77% in the country. Several studies conducted in the last decade investigating the interaction between malaria and T2D in developing countries have led to the emergence of the intra-uterine hypothesis. The hypothesis has arisen as a possible explanation for the rise of T2D in malaria endemic areas; malaria in pregnancy could lead to intra-uterine stress which could contribute to low birth weight and may be a potential cause of T2D later in life. Hence, previous, and continuous exposure to malaria infection leads to a higher risk of T2D. Current and emerging evidence suggests that an inflammation-mediated link exists between malaria and eventual T2D emergence. The inflammatory process thus, is an important link for the coexistence of malaria and T2D because these two diseases are inflammatoryrelated. A key feature of T2D is systemic inflammation, characterized by the upregulation of inflammatory cytokines such as tumor necrosis factor alpha (TNF-α) which leads to impaired insulin signaling. Malaria infection is an inflammatory disease in which TNF-α also plays a major role. TNF-α plays an important role in the pathogenesis and development of malaria and T2D. We therefore hypothesize that TNF-α is an important link in the increasing coexistence of T2D. [ABSTRACT FROM AUTHOR]

Introduction: Some studies have demonstrated the effect of the rs7903146 genetic variant on weight response after different dietary strategies. The objective of our study was to evaluate the role of this genetic variant of the TCF7L2 gene on weight loss and diabetes mellitus progression following a partial meal replacement (pMR) hypocaloric diet., Methods: We conducted an interventional study in 214 subjects with obesity and a body mass index (BMI) >35 kg/m2. The subjects received two servings per day of a normocaloric hyperproteic formula for 24 weeks as part of a pMR diet. Body weight, BMI, fat mass, waist circumference, lipid profile, fasting insulin levels, and HOMA-IR were determined. All patients were genotyped for rs7903146 and evaluated under a dominant model (CC vs. CT + TT)., Results: The decrease at 24 weeks was higher in non-T-allele carriers compared to T-allele carriers (BMI: -3.3 ± 0.3 kg/m2 vs. -2.2 ± 0.2 kg/m2; p = 0.02; weight: -9.5 ± 1.1 kg vs. -5.0 ± 1.0 kg; p = 0.01; fat mass: -8.7 ± 0.2 kg vs. -4.0 ± 0.2 kg; p = 0.04; waist circumference: -8.0 ± 0.2 cm vs. -3.0 ± 0.4 cm; p = 0.04; glucose levels: -7.1 ± 1.2 mg/dL vs. -1.2 ± 1.1 mg/dL; p = 0.01; insulin: -10.1 ± 1.1 µIU/L vs. -4.0 ± 1.0 µIU/L; p = 0.01; HOMA-IR: -2.1 ± 1.1 units vs. -0.5 ± 0.1 units; p = 0.01; C-reactive protein: -0.9 ± 0.1 mg/dL vs. -0.4 ± 0.2 mg/dL; p = 0.01; triglycerides: -17.1 ± 0.1 mg/dL vs. -9.1 ± 0.2 mg/dL; p = 0.01; and HbA1c: -1 ± 0.1% vs. -0.3 ± 0.2%; p = 0.01). Following the dietary intervention, only non-T-allele carriers showed a significant decrease in the frequency of hypertriglyceridemia, abdominal waist, hyperglycemia, and DM2., Conclusions: The TCF7L2 (rs7903146) polymorphism modulates pMR diet-induced changes in body weight, lipid metabolism, and insulin resistance. These changes lead to a significant decrease in the prevalence of hyperglycemia and other components of metabolic syndrome., (© 2025 S. Karger AG, Basel.)

Aim: TCF7L2 gene is believed to increase the risk of T2DM by its effects on insulin secretion. However, the exact mechanism of this enhanced risk is not clearly known. While TCF7L2 gene has been shown to affect lipid metabolism, these effects have remained largely unexplored in the context of diabetes risk. Methods: Postprandial lipid responses to a standardized fat challenge test were performed in 620 Asian Indian subjects (310 with NGT and 310 with T2DM/prediabetes) and compared between the risk and wild genotypes of the rs7903146 TCF7L2 gene. In 30 subjects scheduled to undergo abdominal surgery (10 each with NGT, Prediabetes and T2DM), adipocyte TCF7L2 gene expression was also performed by real time qPCR and confirmed by protein expression in western blot. Results: T allele of rs7903146 TCF7L2 gene was confirmed as the risk allele for T2DM (OR=1.8(1.2-2.74), p=0.005). TT+CT genotypes of rs7903146 TCF7L2 gene showed significantly higher 4hrTg (p<0.01), TgAUC (p<0.01), peakTg (p<0.01) as well as higher postprandial plasma glucose (p=.006) levels and HOMA-IR (p=0.03) and significantly lower adiponectin levels (p=0.02) as compared to CC genotype. The expression of TCF7L2 gene in VAT was 11-fold higher in prediabetes group as compared to NGT (P<0.01) and 5.7-fold higher in T2DM group as compared to NGT group(P=0.003) and was significantly associated with PPTg and glucose levels. Conclusion: There is significant PPTg dysmetabolism associated with the risk allele of rs7903146 polymorphism as well as adipocyte expression of TCF7L2 gene. Significant upregulation of TCF7L2 gene expression in VAT that correlates with PPTg and glycaemia is also seen in Asian Indians with glucose intolerance. Modulation of PPTg metabolism by TCF7L2 gene and the resultant PPHTg may be a novel mechanism that contributes to its diabetes risk in them. [ABSTRACT FROM AUTHOR]

In this paper, the study aimed to analyze the sequence and structure of Transcription Factor 7 Like 2 gene (TCF7L2) in Iraqi Diabetic Mellitus Type II (T2DM) Patients and was compared with standard sequence form National Center of Bioinformatics Tools (NCBI) using BLAST. Ten blood samples of (T2DM) Iraqi patients, was collected from Al-Mustansiriya University National Diabetes Centre in Baghdad Province/Iraq (17-65 year). DNA was extracted from whole blood of patients’ samples using the Quick-DNA™ Blood MiniPrep kit, then it was sent to Korea at Macrogen Corporartion Company, where they used automated DNA sequencing for sequence analysis. The results of the sequence analysis of (T2DM) patients’ samples, we found: six missense mutations, one deletion mutation, and three silent mutations detected using BLAST in (NCBI). All mutations appeared at the same sites of the gene which controls the rate of genetic information transcription that indicates to have a relationship with (T2DM). These mutations were recorded on the (NCBI). The physicochemical properties of (TCF7L2) determined in the present study included; alpha-helical structure and 3-Dimension structure appeared contrast when compared with the gene template. Briefly, mutations effected (TCF7L2) which influences the structure, physicochemical properties of the protein, and the secretion of insulin hormone which maintains glucose level in blood.

Background: Gestational diabetes mellitus (GDM) is a type of clinical diabetes characterized by insulin resistance and impaired insulin secretion because of environmental and genetic factors. The high risk of developing type 2 diabetes (T2D) in women with GDM and the high risk of developing GDM in women with a family history of T2D suggests that both diseases may have the same genetic basis. Therefore, genes and risk variants associated with the genetic architecture of T2D are being investigated for their effects on the development of GDM. In this study, we aim to investigate ABCC8, TCF7L2, Adiponectin, IRS1, and PPARG genes, which are known as T2D risk genes, to understand the genetic basis of GDM in a Turkish population. Materials and Methods: In our study, 74 pregnant women diagnosed with GDM according to the American Diabetes Association criteria and 49 healthy pregnant women were included. DNA isolations were made from peripheral blood cells collected from pregnant women and regions of targeted genes were scanned by the Polimerase Chain Reaction-Restriction fragment length polymorphism (PCR-RFLP) technique. The homeostatic model assessment for insulin resistance (HOMA-IR), which is an indicator of insulin resistance, was calculated for each individual in the biochemical examinations. The associations of genotypes detected in the target gene regions with the disease and their effects on the biochemical phenotypes were analyzed by establishing the dominant, recessive, and additive models along with calculating odd ratios. The P

Several previously published reports have suggested a relationship between type 2 diabetes mellitus (T2DM) and chromosome 10q. The results of genotyping of 228 microsatellite markers in Icelandic people with T2DMrevealed that a microsatellite, DG10S478, within intron 3 of the transcription factor 7-like 2 gene (TCF7L2; formerly TCF4) was associated with T2DM. The present study was aimed to analyze the sequence of TCF7L2 in Iraqi patients with T2DM. This study was performed on the blood samples of 10 patients within the age range of 18-70 years old with T2DM. The DNA was extracted from the whole blood samples and the TCF7L2 gene was purified and amplified using the polymerase chain reaction (PCR) technique. Afterward, the PCR products were run in gel electrophoresis to detect the gene. Moreover, the BLAST software was used to analyze the gene TCF7L2 sequence which was compared with the reference sequence of the template gene from NCBI. The results of TCF7L2 gene sequences obtained from the samples collected from the Iraqi patients with T2DMwere received from Macogen Company, Korea, and analyzed using the BLAST software. The findings showed mutations in the gene sequence of all patients, compared to the gene sequences in NCBI. Hence, the mutation in the TCF7L2 gene was present in Iraqi patients with T2DM, and it could be one of the factors causing and increasing the risk of T2DM disease.

AimTCF7L2 gene is believed to increase the risk of T2DM by its effects on insulin secretion. However, the exact mechanism of this enhanced risk is not clearly known. While TCF7L2 gene has been shown to affect lipid metabolism, these effects have remained largely unexplored in the context of diabetes risk.MethodsPostprandial lipid responses to a standardized fat challenge test were performed in 620 Asian Indian subjects (310 with NGT and 310 with T2DM/prediabetes) and compared between the risk and wild genotypes of the rs7903146 TCF7L2 gene. In 30 subjects scheduled to undergo abdominal surgery (10 each with NGT, Prediabetes and T2DM), adipocyte TCF7L2 gene expression was also performed by real time qPCR and confirmed by protein expression in western blot.ResultsT allele of rs7903146 TCF7L2 gene was confirmed as the risk allele for T2DM (OR=1.8(1.2-2.74), p=0.005). TT+CT genotypes of rs7903146 TCF7L2 gene showed significantly higher 4hrTg (p

Background: Transcription factor 7-like 2 (TCF7L2) gene polymorphisms are known risk factors for type 2 diabetes mellitus (T2DM). However, the relationship between TCF7L2 polymorphism and diabetic nephropathy (DN) is inconclusive. Objectives: to explore the association of TCF7L2 rs7903146 (C/T) gene polymorphism and DN in T2DM Egyptian patients. Methods: 80 patients with T2DM (40 patients without DN and 40 patients with DN) were enrolled in the study. Genotyping for the rs7903146 (C/T) polymorphism in TCF7L2 gene was performed by real time PCR. Results: The frequency of rs7903146 genotypes in diabetic patients without DN was ( CC: 57.5%; CT: 37.5%; TT: 5%), while in diabetic patients with DN was (CC: 2.5%; CT: 40%; TT: 57.5%). Patients with DN were exposed to the TT 25.7 times more than who didn’t develop DN (OR= 25.7, 95% CI= 0.43-94, P= 0.001**). Upon examining the allelic discrimination, C allele was present in 77.5% of patients without DN versus 23.8% of patients with DN, While T allele was found in 22.5% of patients without DN versus 76.3% of patients with DN. Patients with DN were exposed to the T allele 11 times more than who didn’t develop nephropathy (OR=11, 95% CI= 5.3-23.1 , P=

The TCF7L2 protein is a key transcriptional effector of the Wnt/β‐catenin signaling pathway, regulating gene expression. It was initially identified in cancer research and embryologic developmental studies. Later, the TCF7L2 gene was linked to type 2 diabetes (T2D), implicating TCF7L2 and Wnt‐signaling in metabolic disorders and homeostasis. In fact, TCF7L2‐T2D variants confer the greatest relative risk for T2D, unquestionably predicting conversion to T2D in individuals with impaired glucose tolerance. We aim to describe the relevance of TCF7L2 in other human disorders. The TCF7L2‐single nucleotide polymorphisms (SNPs) and T2D‐risk association have been replicated in numerous follow‐up studies, and research has now been performed in several other diseases. In this article, we discuss common TCF7L2‐T2D variants within the framework of their association with human diseases. The TCF7L2 functional regions need to be further investigated because the molecular and cellular mechanisms through which TCF7L2 contributes to risk associations with different diseases are still not fully elucidated. In this review, we show the association of common TCF7L2‐T2D variants with many types of diseases. However, the role of rare genetic variations in the TCF7L2 gene in distinct diseases and ethnic groups has not been explored, and understanding their impact on specific phenotypes will be of clinical relevance. This offers an excellent opportunity to gain a clearer picture of the role that the TCF7L2 gene plays in the pathophysiology of human diseases. The potential pleiotropic role of TCF7L2 may underlie a possible pathway for comorbidity in human disorders. [ABSTRACT FROM AUTHOR]

Background: The TCF7L2-gene (TCF7L2; Transcription factor 7-like 2) involves in regulation of cellular proliferation and differentiation. It also increased risk for type 2 diabetes (T2D), dose effect were reported for the rs7903146 variant. The risk alleles of TCF7L2 gene involves in progression of impaired glucose tolerance to diabetes prospectively and an increased severity of the disease Material and Methods: Prospective, randomised study. Combination of Metformin, Glimepride Voglibose has been prescribed in TCF7L2 gene associated type 2 diabetes mellitus patients s Results: TCF7L2 gene is associated with Type 2 diabetes mellitus. Genetic investigation was done in all 40 patients three genotypes have been identified 10 patients were on CC, 12 patients were on CT and 18 patients were on TT genotypes. Baseline values are higher in TT genotype when compared with CT & CC genotypes. There were significant improvement in blood glucose levels were as a controlled lipid profile was observed in CC genotype but no significant was observed in CT, TT and in group Conclusion: Patients HbA1c ranges from <9.0 - 9.5 % prescribed with triple drug combination therapy of metformin, Glimepride, voglibose shows significant improvement in blood glucose levels in all three genotypes but no significant was observed in CT, TT genotypes. As a result combination of triple drug combination therapy of metformin with glimepride, voglibose is the better drug of choice in CC genotype associated type 2 diabetes mellitus after 3 months of treatment. [ABSTRACT FROM AUTHOR]

Several previously published reports have suggested a relationship between type 2 diabetes mellitus (T2DM) and chromosome 10q. The results of genotyping of 228 microsatellite markers in Icelandic people with T2DMrevealed that a microsatellite, DG10S478, within intron 3 of the transcription factor 7-like 2 gene (TCF7L2; formerly TCF4) was associated with T2DM. The present study was aimed to analyze the sequence of TCF7L2 in Iraqi patients with T2DM. This study was performed on the blood samples of 10 patients within the age range of 18-70 years old with T2DM. The DNA was extracted from the whole blood samples and the TCF7L2 gene was purified and amplified using the polymerase chain reaction (PCR) technique. Afterward, the PCR products were run in gel electrophoresis to detect the gene. Moreover, the BLAST software was used to analyze the gene TCF7L2 sequence which was compared with the reference sequence of the template gene from NCBI. The results of TCF7L2 gene sequences obtained from the samples collected from the Iraqi patients with T2DMwere received from Macogen Company, Korea, and analyzed using the BLAST software. The findings showed mutations in the gene sequence of all patients, compared to the gene sequences in NCBI. Hence, the mutation in the TCF7L2 gene was present in Iraqi patients with T2DM, and it could be one of the factors causing and increasing the risk of T2DM disease. [ABSTRACT FROM AUTHOR]

Introduction Interaction between obesity and genetic factors involved in the regulatory pathways of glucose homeostasis may play a significant role in diabetes development in the obese. The aim of this study was to investigate the associations between the TCF7L2 rs7903146 polymorphism, adiponectin levels, age at onset of obesity and the occurrence of type 2 diabetes (T2D) in a sample of obese Polish adults. Material and methods A total of 474 unrelated obese subjects were included in this study. Real-time PCR was used to detect the TCF7L2 rs7903146 polymorphism. Serum level of adiponectin was determined by the ELISA method. Standard assays were used to measure total cholesterol, HDL cholesterol, triglycerides, glucose and HbA 1c concentrations. We used multiple logistic regression to identify factors associated with type 2 diabetes. Results We found that the T allele of rs7903146 was significantly associated with T2D risk (odds ratio of 1.59 for T allele, p = 0.005). This association persisted after adjusting for confounders in the recessive model (odds ratio of 3.54 for TT genotype, p = 0.011). Serum adiponectin levels were significantly lower in diabetic subjects than in nondiabetic individuals (3.6 vs. 5.6 µg/ml, p < 0.001). Participants who were obese at age ≥ 20 years had significantly higher odds of having T2D (OR = 4.94) than those with the onset of obesity before 20 years (p < 0.001). Conclusions Our study highlights the significance of the relationship between the TCF7L2 polymorphism, a person’s age at onset of obesity and the prevalence of T2D, and confirms lower adiponectin levels in obese diabetics in comparison to obese nondiabetics.

Introduction: Type 2 diabetes mellitus is a complex heterogeneous group of metabolic conditions characterized by increased levels of blood glucose due to impairment in insulin action and/or insulin secretion. The TCF7L2 gene is considered as one of the major genes susceptible to diabetes.The single nucleotide polymorphism rs7903146 is located in intron 3 of this gene, which is significantly effective in type 2 diabetes. Materials and methods: In this case-control study, 141 patients and 86 healthy subjects were present. 5cc peripheral blood of diabetics was collected in EDTA-containing tubes. Genomic DNA was extracted using salting-out method and polymorphism genotype was investigated using PCR-RFLP method. Findings: Genotype and allele frequencies of the rs7903146 polymorphism differed significantly between type 2 diabetic patients and non-diabetic subjects (P = 0.0468 and P = 0.0474 , respectively). The frequency of T allele was 54.5% in type 2 diabetes group and 39.5% in non-diabetic subjects, and this allele was significantly associated with type 2 diabetes risk (OR = 1.8333, 95% CI 1.0456 – 3.2144). Discussion & Conclusion: Our results confirmed the association between the rs7903146 polymorphism of the TCF7L2 gene and the increased risk of type 2 diabetes in the west-Mazandaran, Iran.

Obesity is a multifactorial disease that results from the complex interplay between genes and the environment. The aim of the research was to analyse polymorphisms (rs7903146, rs12255372 and rs1196205) of the TCF7L2 gene in the Roma and majority populations of eastern Slovakia. The group of the majority population consisted of 263 individuals and the group of the Roma population 132 individuals. Real-time PCR was used to genotyping the analysed samples. The results of the genetic analysis confirmed the association of the rs7903146 polymorphism of the TCF7L2 gene with obesity in the majority population. In the majority population, we found significant differences between different genotypes of the rs7903146 poly-morphism in body weight (p = 0.004) and in the BMI index (p = 0.035). The association of TCF7L2 gene polymorphisms with obesity in other polymorphisms was not statistically significant in the groups we studied. However, the results of the distribu-tion of genotypic and allele frequencies indicated a significant ethnic heterogeneity in the frequency of the risk allele (T) of the rs7903146 polymorphism as well as the rs12255372 polymorphism of the TCF7L2 gene. The frequencies of both risk alleles in the Roma population showed significant deviations from those reported for European populations. [ABSTRACT FROM AUTHOR]

The study was conducted to investigate the relationship between TCF7L2 gene polymorphism and the incidence of Type 2 diabetes mellitus (T2DM) in a sample of Iraqi male patients, and the association of the disease with some biochemical markers and hormones including fasting blood glucose (FBG), glycated hemoglobin (HbA1c), Follicle Stimulating Hormone (FSH), Luteinizing hormone (LH), Testosterone and Insulin. Fifty blood samples were collected from type 2 diabetic male patients at different age groups and duration of the disease, who attended the National Diabetes Center / Al-Mustansiiyiah University \ Baghdad Governorate. Forty blood samples were collected from normal healthy males served as control. The diabetic and control groups were divided into four age groups (31-40, 41-50, 51-60, and 61-70 years). Body mass index (BMI), the concentrations of biochemical markers and hormones were determined. The results showed that there was no significant (p>0.05) difference in BMI between patients and healthy control groups, while there was a significant (p>0.05) increase in serum concentration of FBG and HbA1c in comparison with their concentrations in serum samples of healthy control. Insulin concentration showed a significant (p<0.05) decrease in T2DM diabetic patients as compared to healthy control. Serum testosterone concentration in the first age group (31-40 years) showed a significant (p<0.05) increase in T2DM patients as compared to healthy control, while for other age groups (41-50, 51-60 and 61-70 years) there were non-significant (p>0.05) changes in T2DM patients when compared with the healthy control. The results of serum concentration of FSH showed significant (p<0.05) increase in only the third and fourth age groups (51-60 and 61-70 years) of T2DM patients as compared to healthy controls, while for other two groups (31-40 and 41-50 years) there were non-significant (p>0.05) changes. The serum concentration of LH showed a significant (p<0.05) increase in all age groups of T2DM patients as compared to healthy controls. Molecular study of the variants of the TCF7L2 gene as a risk factor for the incidence of T2DM was examined. The studied SNPs were carried out by PCR using specific primers. The sequencing of nucleotide for the amplified fragments showed that for rs 12255372. The frequency of the TT genotype was significantly higher in diabetic patients than healthy control. It is concluded that T2DM is a disease resulting from failure to produce sufficient insulin or insulin resistance, T2DM patients show a decrease in serum insulin concentration and Hypothalamic-pituitary-testicular axis was disturbed in T2DM patients as evidenced by a general increase in serum FSH and LH concentration. TCF7L2 gene rs 12255372 has a non-significant effect on the distribution of (GG) genotype frequency between T2DM patients and healthy control and a significant effect in GT and TT genotype frequency between T2DM patients and healthy control. [ABSTRACT FROM AUTHOR]

Background. The continuously increasing incidence of type 2 diabetes mellitus (DMt2) is an important problem in current medicine. In addition to well-known environmental factors that may contribute to this disease, genetic factors may also play a role. One of the genes that may be responsible for an increased risk of DMt2 development is the transcription factor TCF7L2 gene. This work was aimed to assess a correlation between the rs7903146 polymorphism in the TCF7L2 gene and age at DMt2 diagnosis, presence of obesity, arterial hypertension, and time elapsed from DMt2 diagnosis to the start of insulin therapy. Methods. An analysis of the studied polymorphism was performed in 282 patients diagnosed with DMt2. Patients were divided into groups depending on the age of the onset of DMt2: group A (n = 82) -- DMt2 diagnosis below the age of 40 years, group B (n = 100) -- DMt2 diagnosis between the ages of 40 and 60 years, group C (n = 100) -- DMt2 diagnosis above the age of 60 years. Results. In group C, there was a significantly lower number of patients with a TT genotype of the studied polymorphism compared to the combined group A + B (P < 0.05). Conclusions. There is a correlation between the rs7903146 polymorphism in the TCF7L2 gene and age at DMt2 diagnosis. No correlation has been demonstrated between the studied polymorphism and the presence of obesity, arterial hypertension, and time elapsed from DMt2 diagnosis to the start of insulin therapy. [ABSTRACT FROM AUTHOR]

Background: Although less is known about the molecular mechanisms responsible for its genetic compatibility, regular training is identified as a non-pharmacological treatment for obesity and type-II diabetes. This study aimed to determine the effect of a 3 months aerobic training on pancreatic TCF7L2 expression and glycemic profile in type II diabetic rats. Materials and Methods: In this experimental study, type II diabetes was induced in male Wistar rats (n=16, weight: 220±30 g) by intraperitoneal injection of streptozotocin- nicotinamide. Animals were randomly divided into Exercise (n=8) and Control (n=8) groups. Exercise group, but not Control group, was completed a 3 month aerobic training (3 sessions/week). Forty-eight hours after the last exercise session, the relative expression of pancreatic TCF7L2, fasting glucose and serum insulin were measured in two groups. Results: Compared to Control rats, exercise resulted in a significant decrease in fasting glucose in Exercise group (P=0.001). Serum insulin was increased significantly by aerobic training in Exercise group compared to Control one (P=0.014). However, pancreatic TCF7L2 expression did not change by aerobic training (P=0.876). Conclusion: Based on these data, while we concluded that a long-term aerobic training effectively improves the glycemic profile and insulin concentration of type II diabetic rats, such improvements cannot be attributed to TCF7L2 expression in pancreatic tissue.

Currently, interest in studying obesity as a chronic inflammatory disease continues to grow. Despite numerous recommendations for reducing excess weight, the majority of the population does not assess the importance of this pathology for the development of serious cardiovascular diseases. Eating disorders and physical inactivity continue to prevail among the majority of the population, and especially, it is common among young people. Climatic factors also play an important role in changing fat metabolism. This is peculiar, especially to residents of the northern regions, where, under the influence of cold, lipid and carbohydrate metabolism is often disturbed, which contributes to the accumulation of abdominal fat. However, a genetic predisposition to obesity is one of the common causes of this disorder. The TCF7L2 gene (localization - 10q25.3) controls the synthesis of a transcription factor that regulates the expression of the proglucagon gene involved in carbohydrate metabolism [1]. So, the CT and TT alleles of rs7903146 of the TCF7L2 gene lead to insulin deficiency in the body. In addition, the TCF7L2 gene regulates the differentiation of adipose tissue cells [2; 3]. To study the association of rs7903146 of the TCF7L2 gene with a risk of developing abdominal obesity among young residents of the north [ABSTRACT FROM AUTHOR]

Type 2 diabetes (T2D) is a complex metabolic disease with numerous risk factors, including a growing number of genetic susceptibility variants. The TCF7L2 gene is closely associated with an increased risk of type 2 diabetes, but the association of TCF7L2 with weight-related traits in humans is unclear. The purpose of this study was to determine if TCF7L2 variants and body mass index/waist circumference (BMI/WC) act synergistically to influence the incidence of type 2 diabetes in a Chinese population. This is a large sample, case–control study. We recruited 1842 Chinese type 2 diabetes patients and 7777 healthy controls and collected demographic and anthropometric characteristics and blood samples. We extracted DNA and genotyped the TCF7L2 single nucleotide polymorphisms rs7903146 and rs290487 in all participants. There were significant linear interactions between rs7903146 and BMI/WC and elevated blood glucose (P < 0.001); rs290487 and BMI/WC also showed a linear interaction with blood glucose levels (P < 0.001). The interaction was stronger at higher BMI (>21.02) and higher WC (>66.77 cm). The additive interaction of rs 290487 and overweight/obesity variables yielded a significant increase in the risk for T2D. RERI (relative excess risk of interaction) was 2.949 (95%CI: 1.700–4.198), AP (attributable proportion due to interaction) was 0.391 (95%CI: 2.281–0.502), and SI (synergy index) was 1.822 (95%CI: 1.463–2.268). Additionally, there was a significant interaction between rs 290487 and abdominal obesity on the risk of T2D (RERI: 2.642, 95%CI: 1.384–3.900; AP: 0.350, 95%CI: 0.231–0.468; SI: 1.675, 95%CI: 1.348–2.083). These results show that a TCF7L2 gene-BMI interaction or gene–WC interaction may play an important role in the risk for T2D in the Chinese population. [ABSTRACT FROM AUTHOR]

Background: The transcription factor 7-like 2 (TCF7L2) gene confers one of the strongest genetic predispositions to type 2 diabetes, but diabetes development can be modified by diet.Objective: The aim of our study was to evaluate postprandial metabolic alterations in healthy men with a high genetic risk of diabetes, after two meals with varying macronutrient content.Methods: The study was conducted in 21 homozygous nondiabetic men carrying the high-risk (HR, n = 8, age: 31.2 ± 6.3 y, body mass index (BMI, kg/m2) 28.5 ± 8.1) or low-risk (LR, n = 13, age: 35.2 ± 10.3 y, BMI: 28.1 ± 6.4) genotypes at the rs7901695 locus. During two meal challenge test visits subjects received standardized isocaloric (450 kcal) liquid meals: high-carbohydrate (HC, carbohydrates: 89% of energy) and normo-carbohydrate (NC, carbohydrates: 45% of energy). Fasting (0 min) and postprandial (30, 60, 120, 180 min) plasma samples were analyzed for metabolite profiles through untargeted metabolomics. Metabolic fingerprinting was performed on an ultra-high-performance liquid chromatography (UHPLC) system connected to an iFunnel quadrupole-time-of-flight (Q-TOF) mass spectrometer.Results: In HR-genotype men, after the intake of an HC-meal, we noted a significantly lower area under the curves (AUCs) of postprandial plasma concentrations of most of the phospholipids (-37% to -53%, variable importance in the projection (VIP) = 1.2-1.5), lysophospholipids (-29% to -86%, VIP = 1.1-2.6), sphingolipids (-32% to -47%, VIP = 1.1-1.3), as well as arachidonic (-36%, VIP = 1.4) and oleic (-63%, VIP = 1.3) acids, their metabolites: keto- and hydoxy-fatty acids (-38% to -78%, VIP = 1.3-2.5), leukotrienes (-65% to -83%, VIP = 1.4-2.2), uric acid (-59%, VIP = 1.5), and pyroglutamic acid (-65%, VIP = 1.8). The AUCs of postprandial sphingosine concentrations were higher (125-832%, VIP = 1.9-3.2) after the NC-meal, AUCs of acylcarnitines were lower (-21% to -61%, VIP = 1.1-2.4), and AUCs of fatty acid amides were higher (51-508%, VIP = 1.7-3.1) after the intake of both meals.Conclusions: In nondiabetic men carrying the TCF7L2 HR genotype, subtle but detectable modifications in intermediate lipid metabolism are induced by an HC-meal. This trial was registered at www.clinicaltrials.gov as NCT03792685. [ABSTRACT FROM AUTHOR]

Introduction: Interaction between obesity and genetic factors involved in the regulatory pathways of glucose homeostasis may play a significant role in diabetes development in the obese. The aim of this study was to investigate the associations between the TCF7L2 rs7903146 polymorphism, adiponectin levels, age at onset of obesity and the occurrence of type 2 diabetes (T2D) in a sample of obese Polish adults.Material and Methods: A total of 474 unrelated obese subjects were included in this study. Real-time PCR was used to detect the TCF7L2 rs7903146 polymorphism. Serum level of adiponectin was determined by the ELISA method. Standard assays were used to measure total cholesterol, HDL cholesterol, triglycerides, glucose and HbA1c concentrations. We used multiple logistic regression to identify factors associated with type 2 diabetes.Results: We found that the T allele of rs7903146 was significantly associated with T2D risk (odds ratio of 1.59 for T allele, p = 0.005). This association persisted after adjusting for confounders in the recessive model (odds ratio of 3.54 for TT genotype, p = 0.011). Serum adiponectin levels were significantly lower in diabetic subjects than in nondiabetic individuals (3.6 vs. 5.6 µg/ml, p < 0.001). Participants who were obese at age ≥ 20 years had significantly higher odds of having T2D (OR = 4.94) than those with the onset of obesity before 20 years (p < 0.001).Conclusions: Our study highlights the significance of the relationship between the TCF7L2 polymorphism, a person's age at onset of obesity and the prevalence of T2D, and confirms lower adiponectin levels in obese diabetics in comparison to obese nondiabetics. [ABSTRACT FROM AUTHOR]

BACKGROUND The prevalence of type-2 diabetes mellitus (T2DM) has been increasing rapidly in developed and developing countries. Many new loci associated with T2DM have been uncovered by genetic and genome-wide association studies, eg. the transcription factor 7-like 2 (TCF7L2) gene variant rs7895340 has been associated with type-2 diabetes mellitus. The aim of this research was to find an association between polymorphisms of TCF7L2 gene variant rs7895340 with T2DM in ethnic Minangkabau. METHODS This was a case-control study using a consecutive sampling technique among ethnic Minangkabau patients who came for treatment to the Metabolic Endocrinology Polyclinic at Dr. M. Jamil Hospital. Analysis was performed on 132 subjects (66 T2DM patients and 66 controls). DNA was isolated from venous blood samples and amplified using the amplification refractory mutation system - polymerase chain reaction (ARMS-PCR) method to detect single nucleotide polymorphisms (SNPs) of TCF7L2 gene variant rs7895340. To determine the significance of association of SNPs of rs7895340 with T2DM in ethnic Minangkabau, data analysis was performed using chi-square test. RESULTS The ARMS - PCR for TCF7L2 gene variant rs7895340 found polymorphisms in 28 (42.42%) subjects with type 2 diabetes mellitus and in 15 (22.72%) non-diabetic subjects.There was a significant association between rs7895340 SNPs with the probability of T2DM in ethnic Minangkabau (OR=2.505, p=0.026). CONCLUSIONS Single nucleotide polymorphism rs7895340 of TCF7L2 gene can be used as genetic marker of type-2 diabetes mellitus in ethnic Minangkabau.

In various populations worldwide, common variants of the TCF7L2 (Transcription factor 7-like 2) gene are associated with the risk of type 2 diabetes mellitus (T2DM). The aim was to investigate the association between rs12255372 (G/T) polymorphism in the TCF7L2 gene and T2DM in an Iranian population. 236 unrelated patients with T2DM, and 255 normoglycemic controls without diabetes were studied. The PCR-RFLP method was used for genotyping rs12255372 (G/T) polymorphism, and the SPSS version 18.0 for Windows for statistical analysis. The minor T allele of TCF7L2 rs12255372 was found to significantly increase the risk of T2DM, with an allelic odds ratio (OR) of 1.458 (95% CI 1.108-1.918, p = 0.007). A significant difference in TT genotype was observed between T2DM patients and normoglycemic controls (OR 2.038, 95% CI 1.147-3.623; p = 0.014). On assuming dominant and recessive models, ORs of 1.52 [95% CI (1.05-2.21) p = 0.026)] and 1.74 [95% CI (1.01-3.00) p = 0.043] were obtained, respectively, thereby implying that the co-dominant model would best fit the susceptible gene effect. This study further confirms the TCF7L2 gene as enhancing susceptibility to the development of T2DM.

Background/aim: Type 2 diabetes (T2D) is a multifactorial disease, determined by environmental and genetic factors. Currently, the transcription factor 7-like 2 (TCF7L2) gene shows the strongest association with T2D. In this study, we investigated whether TCF7L2 gene polymorphisms are associated with T2D in a Turkish population. Materials and methods: Using PCR-RFLP and PCR-SSCP, we genotyped six intronic polymorphisms in the TCF7L2 gene, commonly associated with T2D, in 169 individuals with diabetes and 119 healthy controls. Results: We found that rs7903146 C → T substitution in intron 3 (OR: 1.9, P = 0.005) and rs12255372 G → T substitution in intron 4 (OR: 2.1, P = 0.002) were significantly associated with T2D while other SNPs were not associated (P > 0.05). We determined no association between TCF7L2 gene polymorphisms and fasting glucose, fasting insulin, HbA1c, or HOMA-IR levels (P > 0.05), except for rs7903146 C → T substitution, which was significantly associated with the fasting glucose level (P = 0.003). Conclusion: Our results indicate that, in the Turkish population, the T allele of the rs7903146 (C → T) and rs12255372 (G → T) polymorphisms in the TCF7L2 gene is an independent risk factor for the development of T2D. [ABSTRACT FROM AUTHOR]

Background: Genetic variations of the TCF7L2 gene are associated with the development of Type 2 diabetes (T2D). The associated mutations have demonstrated an adaptive role in some human populations, but no studies have determined the impact of evolutionary forces on genetic diversity in indigenous populations from Mexico. Here, we sequenced and analyzed the variation of the TCF7L2 gene in three Amerindian populations and compared the results with whole-exon-sequencing of Mestizo populations from Sigma and the 1000 Genomes Project to assess the roles of selection and recombination in diversity. Results: The diversity in the indigenous populations was biased to intronic regions. Most of the variation was low frequency. Only mutations rs77961654 and rs61724286 were located on exon 15. We did not observe variation in intronic region 4-6 in any of the three indigenous populations. In addition, we identified peaks of selective sweeps in the mestizo samples from the Sigma Project within this region. By replicating the analysis of association with T2D between case-controls from the Sigma Project, we determined that T2D was most highly associated with the rs7903146 risk allele and to a lesser extent with the other six variants. All associated markers were located in intronic region 4-6, and their r2 values of linkage disequilibrium were significantly higher in the Mexican population than in Africans from the 1000 Genomes Project. We observed reticulations in both the haplotypes network analysis from seven marker associates and the neighborNet tree based on 6061 markers in the TCF7L2 gene identified from all samples of the 1000 Genomes Project. Finally, we identified two recombination hotspots in the upstream region and 3' end of the TCF7L2 gene. Conclusions: The lack of diversity in intronic region 4-6 in Indigenous populations could be an effect of selective sweeps generated by the selection of neighboring rare variants at T2D-associated mutations. The survivors' variants make the intronic region 4-6 the area of the greatest population differentiation within the TCF7L2 gene. The abundance of selective peak sweeps in the downstream region of the TCF7L2 gene suggests that the TCF7L2 gene is part of a region that is in constant recombination between populations. [ABSTRACT FROM AUTHOR]

The transcription factor 7-like 2 ( TCF7L2) gene plays a significant role in the development of type 2 diabetes and diabetic nephropathy. The aim of this study was to investigate the association of TCF7L2 rs12255372 (G/T)polymorphism with type 2 diabetic nephropathy in the South Indian population. A total of 2102 subjects, 927 normal glucose tolerant (NGT) subjects, 598 type 2 diabetic subjects without nephropathy (DM), and 577 type 2 diabetic subjects with nephropathy (DN) were genotyped by MassARRAY. As compared to the NGT group, the odds ratio (adjusted for age, sex, BMI, HbA1c, and systolic BP) computed for the GT/TT genotype taking the GG genotype as reference was found to be 2.02 (95% CI: 1.16-3.51, p = 0.013) for DN and 1.94 (95% CI: 1.36-2.78, p = 0.0002) for DM. The genotype frequency was not significantly different between the DM and DN groups. In conclusion, the rs12255372 polymorphism in the TCF7L2 gene is associated with type 2 diabetes and DN but its association with DN is mediated through diabetes. [ABSTRACT FROM AUTHOR]

Type 2 diabetes (T2DM) is a complex disease resulting from the contribution of both environmental and genetic factors. Recently, the list of genes implicated in the susceptibility to T2DM has substantially grown, also as a consequence of the great development of the genome-wide association studies in the last decade. Common polymorphisms in TCF7L2 gene have shown to have a strong effect with respect to many other involved genes. The aims of our study were to confirm the role of TCF7L2 in the susceptibility to T2DM in the Italian population and to investigate whether TCF7L2 genotypes also contribute to the clinical phenotypes variability and to diabetic complications development. Three TCF7L2 polymorphisms (rs7903146, rs7901695 and rs12255372) have been analyzed by allelic discrimination assays in a cohort of 154 Italian patients with T2DM and 171 healthy controls. A case-control association study and a genotype-phenotype correlation study have been carried out. Consistent with previous studies, all three SNPs showed a strong association with susceptibility to T2DM, both at genotypic ( P = 0.003, P = 0.004 and P = 0.012) and at allelic level ( P = 0.0004, P = 0.0004 and P = 0.003). Moreover, we observed associations between TCF7L2 variants and the following diabetic complications: diabetic retinopathy, cardiovascular disease and coronary artery disease. We also found a strong correlation between the rs7903146 and the presence of cardiovascular autonomic neuropathy ( P = 0.02 with a high OR = 8.28). In conclusion, our study, in addition to confirming the involvement of TCF7L2 gene in the T2DM susceptibility, has shown that TCF7L2 genetic variability also contributes to the development of diabetic complications such as retinopathy and cardiovascular autonomic neuropathy. [ABSTRACT FROM AUTHOR]

Abstract: Genetic variants in the transcription factor 7-like 2(Tcf7l2) gene have been found to confer a significant risk of type 2 diabetes and attenuated insulin secretion. Based on its genomic wide association Tcf7l2 is considered the single most important predictor of diabetes to date. Previous studies of Tcf7l2 mRNA localization in the adult brain suggest a putative role of Tcf7l2 in the CNS regulation of energy homeostasis. The present study further characterizes the immunophenotypic distribution of peptide expression in the brains of Tcf7l2 progeny during developmental time periods between E12.5 and P1. Tcf7l2−/− is lethal beyond P1. Results show that while negligible TCF7L2 expression is found in the developing brains of Tcf7l2−/−mice, TCF7L2 protein is relatively widespread and robustly expressed in the brain by E18.5 and exhibits specific expression within neuronal populations and regions of the brain in Tcf7l2 +/− and Tcf7l2 +/+ progeny. Strong immunophenotypic labeling was found in the diencephalic structure of the thalamus that suggests a role of Tcf7l2 in the development and maintenance of thalamic activity. Strongly expressed TCF7L2 was localized in select hypothalamic and preoptic nuclei indicative of Tcf7l2 function within neurons controlling energy balance. Definitive neuronal staining for TCF7L2 within nuclei of the brain stem and circumventricular organs extends TCF7L2 localization within autonomic neurons and its potential integration with autonomic function. In addition robust TCF7L2 expression was found in the tectal and tegmental structures of the superior and inferior colliculi as well as transient expression in neuroepithelium of the cerebral and hippocampal cortices of E16 and E18.5. Patterns of TCF7L2 peptide localization when compared to the adult protein synthetic chemical/anatomical landscape of glucose sensing exhibit a good correlational fit between its expression and regions, nuclei, and pathways regulating energy homeostasis via integration and response to peripheral endocrine, metabolic and neuronal signaling. TCF was also found co-localized with peptides that regulate energy homeostasis including AgRP, POMC and NPY. TCF7l2, some variants of which have been shown to impair GLP-1-induced insulin secretion, was also found co-localize with GLP-1 in adult TCF wild type progeny. Impaired Tcf7l2-mediated neural regulation may contribute to the risk and/or underlying pathophysiology of type 2 diabetes that has found high expression in genomic studies of Tcf7l2 variants. [Copyright &y& Elsevier]