TCF7L2 polymorphism associates with new-onset diabetes after transplantation.
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ABSTRACT:
SUBMITTER: Ghisdal L
PROVIDER: S-EPMC2799180 | biostudies-literature | 2009 Nov
REPOSITORIES: biostudies-literature
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TCF7L2 polymorphism associates with new-onset diabetes after transplantation.
Ghisdal Lidia L Baron Christophe C Le Meur Yannick Y Lionet Arnaud A Halimi Jean-Michel JM Rerolle Jean-Philippe JP Glowacki François F Lebranchu Yvon Y Drouet Mireille M Noël Christian C El Housni Hakim H Cochaux Pascale P Wissing Karl Martin KM Abramowicz Daniel D Abramowicz Marc M
Journal of the American Society of Nephrology : JASN 20090827 11
New-onset diabetes after transplantation (NODAT) is a serious and frequent complication in transplant recipients. Whether NODAT shares the same susceptibility genes as type 2 diabetes is unknown. In this multicenter study, we genotyped 1076 white patients without diabetes at transplantation for 11 polymorphisms that associate with type 2 diabetes. We defined NODAT as a fasting plasma glucose > or =126 mg/dl on at least two occasions or de novo hypoglycemic therapy. We compared clinical and genet ...[more]
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Project description:BackgroundNew-onset diabetes after transplantation (NODAT) is a serious complication in transplant recipients. Transcription factor-7-like 2 (TCF7L2) is a Wnt signaling-associated transcription factor that plays an important role in β-cell proliferation and insulin secretion. The association between TCF7L2 SNP rs7903146 and NODAT was documented in renal transplant patients.ObjectiveTo determine the association between TCF7L2 rs7903146 variants and the risk of NODAT after liver transplantation.MethodsThis study was conducted on 140 liver transplant recipients who had received tacrolimus-based immunosuppressive drugs. The patients were divided into NODAT (n=70) and non-NODAT (n=70) groups and were genotyped using PCR-RFLP. In addition, 100 normal subjects were considered as the comparison group.ResultsThere was a significant difference (p<0.05) between the two study groups regarding donor and recipient age, recipient body mass index, and recipient fasting plasma glucose before the transplantation. No significant relationship was observed between TCF7L2 rs7903146 genotypes and development of NODAT. No significant difference was also found between the two groups in terms of the tacrolimus and mycophenolate mofetil daily dosage as well as tacrolimus blood level. However, the prednisolone daily dosage was significantly (p=0.01) higher in the NODAT group compared to those without NODAT. The majority of the patients in the NODAT group also had an episode of acute rejection. Furthermore, a significant difference was found between the transplant recipients and the comparison subjects regarding T allele (p<0.001, OR=1.96) and TT genotype (p<0.001, OR=3.47) frequencies.ConclusionNo correlation was found between TCF7L2 genotypes and development of NODAT. Acute rejection and prednisolone pulse therapy predisposed the susceptible patients to NODAT.
| S-EPMC4346459 | biostudies-literature
Project description:New-onset diabetes after transplantation is a common complication that reduces recipient survival. Research in renal transplant recipients has suggested that pancreatic ?-cell dysfunction, as opposed to insulin resistance, may be the key pathologic process. In this study, clinical and genetic factors associated with new-onset diabetes after transplantation were identified in a white population. A joint analysis approach, with an initial genome-wide association study in a subset of cases followed by de novo genotyping in the complete case cohort, was implemented to identify single-nucleotide polymorphisms (SNPs) associated with the development of new-onset diabetes after transplantation. Clinical variables associated with the development of diabetes after renal transplantation included older recipient age, female sex, and percentage weight gain within 12 months of transplantation. The genome-wide association study identified 26 SNPs associated with new-onset diabetes after transplantation; this association was validated for eight SNPs (rs10484821, rs7533125, rs2861484, rs11580170, rs2020902, rs1836882, rs198372, and rs4394754) by de novo genotyping. These associations remained significant after multivariate adjustment for clinical variables. Seven of these SNPs are associated with genes implicated in ?-cell apoptosis. These results corroborate recent clinical evidence implicating ?-cell dysfunction in the pathophysiology of new-onset diabetes after transplantation and support the pursuit of therapeutic strategies to protect ? cells in the post-transplant period.
| S-EPMC4005297 | biostudies-literature
Project description:No effective interventions to reduce risk for new-onset diabetes after transplantation (NODAT), a condition associated with postoperative hyperglycemia and reduced patient and graft survival, have been established. In this 1-year, proof-of-concept clinical trial, we randomly assigned 50 renal transplant recipients to immediate-postoperative isophane insulin for evening blood glucose ≥140 mg/dl (treatment group) or short-acting insulin and/or oral antidiabetic agents for blood glucose ≥180-250 mg/dl (standard-of-care control group). We included only patients without a history of diabetes who received tacrolimus. By the third postoperative evening, all patients in the treatment group had blood glucose ≥140 mg/dl and were subsequently treated with basal insulin; during the first 3 weeks after transplantation, the mean ± SD daily insulin dosage was 17±11 IU/d. Among controls, 23 (92%) of 25 had blood glucose ≥200 mg/dl and 18 (72%) of 25 received standard-of-care antihyperglycemic treatment. Asymptomatic hypoglycemia occurred five times in the treatment group and once in the control group. Throughout follow-up, the treatment group had 73% lower odds of NODAT (odds ratio, 0.27) than the control group, and hemoglobin A1c was on average 0.38% lower in the treatment group than the control group. Twelve months after transplantation, all patients in the treatment group were insulin-independent, whereas 7 (28%) of 25 controls required antidiabetic agents. The groups did not differ for insulin sensitivity, but the treatment group showed better β-cell function throughout the 1-year follow-up. In conclusion, this study suggests regimens that include basal insulin significantly reduce the odds for NODAT after renal transplantation, presumably via insulin-mediated protection of β cells.
| S-EPMC3312499 | biostudies-literature
Project description:Several studies suggest a link between post-transplant hypomagnesemia and new-onset diabetes after transplantation (NODAT), but this relationship remains controversial. We conducted a retrospective cohort study of 948 nondiabetic kidney transplant recipients from January 1, 2000, to December 31, 2011, to examine the association between serum magnesium level and NODAT. Multivariable Cox proportional hazards models were fitted to evaluate the risk of NODAT as a function of baseline (at 1 month), time-varying (every 3 months), and rolling-average (i.e., mean for 3 months moving at 3-month intervals) serum magnesium levels while adjusting for potential confounders. A total of 182 NODAT events were observed over 2951.2 person-years of follow-up. Multivariable models showed an inverse relationship between baseline serum magnesium level and NODAT (hazard ratio [HR], 1.24 per 0.1 mmol/L decrease; 95% confidence interval [95% CI], 1.05 to 1.46; P=0.01). The association with the risk of NODAT persisted in conventional time-varying (HR, 1.32; 95% CI, 1.14 to 1.52; P<0.001) and rolling-average models (HR, 1.34; 95% CI, 1.13 to 1.57; P=0.001). Hypomagnesemia (serum magnesium <0.74 mmol/L) also significantly associated with increased risk of NODAT in baseline (HR, 1.58; 95% CI, 1.07 to 2.34; P=0.02), time-varying (HR, 1.78; 95% CI, 1.29 to 2.45; P<0.001), and rolling-average models (HR, 1.83; 95% CI, 1.30 to 2.57; P=0.001). Our results suggest that lower post-transplant serum magnesium level is an independent risk factor for NODAT in kidney transplant recipients. Interventions targeting serum magnesium to reduce the risk of NODAT should be evaluated.
| S-EPMC4884111 | biostudies-literature
Project description:New-onset diabetes after transplantation (NODAT) is associated with increased risk of allograft failure, cardiovascular disease and mortality, and therefore, jeopardizes the success of renal transplantation. Increased awareness of NODAT and the prediabetic states (impaired fasting glucose and impaired glucose tolerance, IGT) has fostered previous and present recommendations, based on the management of type 2 diabetes mellitus (T2DM). Unfortunately, the idea that NODAT merely resembles T2DM is potentially misleading, because the opportunity to initiate adequate anti-hyperglycaemic treatment early after transplantation might be given away for 'tailored' immunosuppression in patients who have developed NODAT or carry personal risk factors. Risk factor-independent mechanisms, however, seem to render postoperative hyperglycaemia with subsequent development of overt or 'full-blown' NODAT, the unavoidable consequence of the transplant and immunosuppressive process itself, at least in many cases. A proof of the concept that timely preventive intervention with exogenous insulin against post-transplant hyperglycaemia may decrease NODAT was recently provided by a small clinical trial, which is awaiting confirmation from a multicentre study. However, because early insulin therapy aimed at beta-cell protection seems to contrast the currently recommended, stepwise approach of 'watchful waiting' prior to pancreatic decompensation, we here aim at reviewing recent concepts regarding the development, prevention and treatment of NODAT, some of which seem to challenge the traditional view on T2DM and NODAT. In summary, we suggest a novel, risk factor-independent management approach to NODAT, which includes glycaemic monitoring and anti-hyperglycaemic treatment in virtually everybody after transplantation. This approach has widespread implications for future research and is intended to tackle NODAT and also ultimately cardiovascular disease.
| S-EPMC4375396 | biostudies-literature
Project description:Our aim was to identify serum microRNAs (miRNAs) in healthy humans which associate with future onset of both diabetes mellitus and cardiovascular disease. We performed global profiling of 753 mature human miRNAs in serum of 12 pilot subjects followed by measurement of 47 consistently expressed miRNAs in fasting serum of 553 healthy subjects from the baseline exam (1991-1994) of the population based Malmö Diet and Cancer Study Cardiovascular Cohort (MDC-CC), of whom 140 developed diabetes, and 169 cardiovascular diseases during follow-up. We used multivariate logistic regression to test individual miRNAs for association with incident diabetes and cardiovascular disease as compared to control subjects (n = 259). After Bonferroni correction and adjustment for age and sex, each SD increment of log-transformed miR-483-5p was significantly associated with both incident diabetes (OR = 1.48; 95% CI 1.18-1.84, P = 0.001) and cardiovascular disease (OR = 1.40; 95% CI 1.15, 1.72, P = 0.001). In cross sectional analysis, miR-483-5p was correlated with BMI (r = 0.162, P = 0.0001), fasting insulin (r = 0.156, P = 0.0002), HDL (r = -0.099, P = 0.02) and triglycerides (r = 0.11, P = 0.01). Adjustment for these metabolic risk factors, as well as traditional risk factors attenuated the miR-483-5p association with incident diabetes (OR = 1.28 95% CI 1.00-1.64, P = 0.049) whereas its association with incident cardiovascular disease remained virtually unchanged (OR = 1.46 95% CI, 1.18-1.81, P = 0.0005). In conclusion, miR-483-5p associates with both diabetes and cardiovascular disease. The association with diabetes seems partly mediated by obesity and insulin resistance, whereas the association with incident cardiovascular disease is independent of these metabolic factors and traditional cardiovascular disease risk factors.
| S-EPMC6224079 | biostudies-literature
Project description:BACKGROUND:A polymorphism in the transcription factor 7-like 2 (TCF7L2) gene has been found to be associated with type 2 diabetes in case-control studies. We aimed to estimate associations of the marker rs7903146 (C/T) polymorphism with fasting glucose, lipids, diabetes prevalence and complications in an older general population. METHODS:In total, 944 subjects aged > or = 65 years from the population representative InCHIANTI study were enrolled in this study. Those with fasting blood glucose of > or = 7 mmol/l or physician diagnosis were considered diabetic. Cut-off points for impaired fasting glucose (IFG) were > or = 5.6 mmol/l to < 7 mmol/l. RESULTS:In the general population sample, minor (T) allele carriers of rs7903146 had higher fasting blood glucose (FBG) (p = 0.028) but lower fasting insulin (p = 0.030) and HOMA2b scores (p = 0.001), suggesting poorer beta-cell function. T allele carriers also had smaller waist circumference (p = 0.009), lower triglyceride levels (p = 0.006), and higher high-density lipoprotein cholesterol (p = 0.008). The prevalence of diabetes or IFG was 32.4% in TT carriers and 23.3% in CC carriers; adjusted OR = 1.67 (95% confidence interval 1.05 to 2.65, p = 0.031). Within the diabetic and IFG groups, fewer T allele carriers had metabolic syndrome features (p = 0.047) or had experienced a myocardial infarction (p = 0.037). Conversely, T allele carriers with diabetes had poorer renal function (reduced 24-hour creatinine clearance, p = 0.013), and possibly more retinopathy (p = 0.067). Physician-diagnosed dementia was more common in the T carriers (in diabetes p = 0.05, with IFG p = 0.024). CONCLUSION:The TCF7L2 rs7903146 polymorphism is associated with lower insulin levels, smaller waist circumference, and lower risk lipid profiles in the general elderly population. Patients with diabetes who are carriers of the minor allele are less likely to have metabolic-syndrome features, but may experience more microvascular complications, although the number of cases was small. If replicated, these findings may have implications for developing treatment approaches tailored by genotype.
| S-EPMC1769391 | biostudies-literature
Project description:BACKGROUND:Large scale association studies have found a significant association between type 2 diabetes mellitus (T2DM) and transcription factor 7-like 2 (TCF7L2) polymorphism rs7903146. However, the quality of data varies greatly, as the studies report inconsistent results in different populations. Hence, we perform this meta-analysis to give a more convincing result. METHODS:The articles, published from January 1st, 2000 to April 1st, 2017, were identified by searching in PubMed and Google Scholar. A total of 56628 participants (34232 cases and 22396 controls) were included in the meta-analysis. A total of 28 studies were divided into 4 subgroups: Caucasian (10 studies), East Asian (5 studies), South Asian (5 studies) and Others (8 studies). All the data analyses were analyzed by the R package meta. RESULTS:The significant association was observed by using the dominant model (OR?=?1.41, CI?=?1.36?-?1.47, p?<?0.0001), recessive model (OR?=?1.58, CI?=?1.48?-?1.69, p?<?0.0001), additive model(CT vs CC) (OR?=?1.34, CI?=?1.28-1.39, p?<?0.0001), additive model(TT vs CC) (OR?=?1.81, CI?=?1.69-1.94, p?<?0.0001)and allele model (OR?=?1.35, CI?=?1.31-1.39, p?<?0.0001). CONCLUSION:The meta-analysis suggested that rs7903146 was significantly associated with T2DM in Caucasian, East Asian, South Asian and other ethnicities.
| S-EPMC5842570 | biostudies-literature
Project description:TCF7L2 variants have been associated with type 2 diabetes, body mass index (BMI), and deficits in proinsulin processing and insulin secretion. Here we sought to test whether these effects were apparent in high-risk individuals and modify treatment responses.We examined the potential role of the TCF7L2 rs7903146 variant in predicting resistance to weight loss or a lack of improvement of proinsulin processing during 2.5-years of follow-up participants (N?=?2,994) from the Diabetes Prevention Program (DPP), a randomized controlled trial designed to prevent or delay diabetes in high-risk adults.We observed no difference in the degree of weight loss by rs7903146 genotypes. However, the T allele (conferring higher risk of diabetes) at rs7903146 was associated with higher fasting proinsulin at baseline (P<0.001), higher baseline proinsulin:insulin ratio (p<0.0001) and increased proinsulin:insulin ratio over a median of 2.5 years of follow-up (P?=?0.003). Effects were comparable across treatment arms.The combination of a lack of impact of the TCF7L2 genotypes on the ability to lose weight, but the presence of a consistent effect on the proinsulin:insulin ratio over the course of DPP, suggests that high-risk genotype carriers at this locus can successfully lose weight to counter diabetes risk despite persistent deficits in insulin production.
| S-EPMC3144193 | biostudies-literature
Project description:BackgroundGlucagon-like peptide 1 (GLP-1) stimulates insulin secretion and reduces blood glucose in type 2 diabetes mellitus (T2DM). TCF7L2 rs7903146 polymorphism has been associated with decreased insulin secretion, reduced GLP-1 action, and possible impaired peripheral insulin sensitivity.ObjectivesTo evaluate the postprandial pancreatic hormone response in patients with T2DM carriers of the TCF7L2 variant rs7903146 (CT/TT) compared with noncarriers of this variant (CC) after treatment with the GLP-1 agonist exenatide.MethodsIntervention study. Patients with T2DM (n = 162) were genotyped for the TCF7L2 rs7903146 single nucleotide polymorphism (SNP). Individuals with CT/TT and CC genotypes were compared regarding basal serum levels of glucose, glycosylated hemoglobin A1C (HbA1c), HDL, uric acid, insulin, and C-peptide. A subset of 56 individuals was evaluated during a 500-calorie mixed-meal test with measurements of glucose, insulin, proinsulin, C-peptide and glucagon before and after treatment with exenatide for 8 weeks.ResultsPatients with genotypes CC and CT/TT presented similar glucose area under the curve (AUC) 0-180 min before treatment and a similar decrease after treatment (p < 0.001). Before exenatide, insulin levels at 30-120 min were higher in CT/TT versus CC subjects (p < 0.05). After treatment with exenatide, only CT/TT individuals demonstrated insulin reduction at 30-180 min during the meal test (p < 0.05). Patients with the CC genotype presented no differences in insulin concentrations before and after treatment. The areas under the glucagon curve between 0 and 180 min were similar before treatment and reduced after treatment in both groups (p < 0.001).ConclusionsThe presence of the TCF7L2 rs7903146 T allele in patients with T2DM was associated with increased secretion of insulin response to a mixed-meal test. Furthermore, after treatment with exenatide, only the carriers of the T allele showed significantly decreased postprandial plasma insulin peak levels comparing with non carriers.
| S-EPMC6347826 | biostudies-literature