<i>TCF7L2</i> Genotype and <i>α</i>-Cell Function in Humans Without Diabetes

Shah, Meera; Varghese, Ron T.; Miles, John M.; Piccinini, Francesca; Man, Chiara Dalla; Cobelli, Claudio; Bailey, Kent R.; Rizza, Robert A.; Vella, Adrian

doi:10.2337/db15-1233

Cited by 50 publications

(65 citation statements)

References 51 publications

(63 reference statements)

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“…Intriguingly, Daniele et al (20) recently reported that the T allele at rs7903146 was associated with lower glucagon concentrations and decreased systemic meal appearance. This contrasts with our recent findings (14) and suggests the need for further study of hepatic extraction of ingested glucose using techniques designed to minimize measurement error of meal appearance (21). …”

Section: Discussioncontrasting

confidence: 99%

“…Genotyping was performed using TaqMan (Applied Biosystems, Foster City, CA). The individuals genotyped were randomly selected from the Biobank cohort, as previously described (14). Subjects who were homozygous for the disease-causing allele (TT) were matched for age, gender, fasting glucose level, and body weight with subjects who were homozygous for the disease-protective allele (CC), and were invited in writing to participate in the study.…”

Section: Methodsmentioning

confidence: 99%

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Diabetes-Associated Variation in TCF7L2 Is Not Associated With Hepatic or Extrahepatic Insulin Resistance

et al. 2016

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A common genetic variation in TCF7L2 is associated with type 2 diabetes. However, the mechanism by which this occurs remains elusive. In addition to affecting insulin secretion, genetic variation at the TCF7L2 locus may alter insulin action or directly modify hepatic glucose metabolism. We sought to determine whether the diabetes-associated variant in this locus (the T allele of rs7903146) increases fasting endogenous glucose production (EGP), and impairs insulin-induced suppression of EGP and insulin-stimulated glucose disappearance. To address this, we studied individuals who were either homozygous for the diabetes-associated allele (TT) at rs7903146 or were homozygous for the protective allele (CC). Subjects were matched for other anthropometric characteristics and were studied using a euglycemic clamp. EGP and glucose uptake were measured using the tracer dilution technique, and the relative contribution of gluconeogenesis to EGP was quantitated using deuterated water corrected for transaldolase exchange. We report that the diabetes-associated variation in TCF7L2 did not associate with fasting EGP, insulin-induced suppression of EGP, and insulin-induced stimulation of glucose uptake. There was no association with the contribution of gluconeogenesis and glycogenolysis to EGP. These data indicate that genetic variation at TCF7L2 does not predispose an individual to type 2 diabetes by altering either hepatic or extrahepatic insulin action.

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Section: Discussioncontrasting

confidence: 99%

Section: Methodsmentioning

confidence: 99%

Diabetes-Associated Variation in TCF7L2 Is Not Associated With Hepatic or Extrahepatic Insulin Resistance

et al. 2016

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“…The design of this study has been previously reported [18]. In brief, this Mayo Clinic IRB approved protocol utilized the Mayo Clinic Biobank repository to genotype 4000 randomly selected individuals at rs7903146.…”

Section: Methodsmentioning

confidence: 99%

Glucose tolerance and free fatty acid metabolism in adults with variations in TCF7L2 rs7903146

et al. 2017

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Objective TCF7L2 variant rs7903146 is associated with increased risk for Type 2 diabetes. We investigated the effect of TCF7L2 variant rs7903146 and glucose tolerance on free fatty acid (FFA) metabolism. Research design and methods We recruited 120 individuals, half homozygous for the major CC allele and half homozygous for the minor TT allele at rs7903146; each underwent a 2-hour, 75g oral glucose tolerance test (OGTT). Plasma glucose, insulin and free fatty acid concentrations were measured on blood collected before and during the OGTT. Results Total FFA concentrations and percent FA species during OGTT were not different in CC and TT carriers when males and females were considered together. However, monounsaturated fatty acid (MUFA) concentrations and percentages were greater in TT than CC females during the OGTT. TT carriers with high HOMA-IR had significantly greater fasting FFA concentrations, lower disposition index (DI) and greater AUC of glucose than high HOMAIR CC carriers, whereas no such differences were observed in the low HOMA-IR group. We found that fasting (826 ± 25 vs. 634 ± 22 µmol/L, P < 0.0001) and OGTT plasma FFA concentrations were greater in IGT than NGT subjects, and the difference remained after adjusting for sex, age, BMI, and genotype. Finally, IGT subjects had greater MUFA concentrations and percentages than NGT subjects during OGTT. Conclusions Despite similar fasting insulin and glucose, fasting plasma FFA are greater in IGT than NGT adults. Insulin resistance and sex influence plasma FFA responses amongst carriers of the minor T allele of TCF7L2 rs7903146.

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“…However, b-cells would likely fail to respond to the concentration of glucose in the blood in a timely manner in individuals with T2DM. Shah et al [36] studied 120 individuals, of whom onehalf were homozygous for TT at rs7903146 and one-half were homozygous for CC. In their study, b-cell responsiveness was slightly impaired in the TT genotype group and differed significantly between genotypes, implying that a genetic variant of TCF7L2 impairs glucose tolerance through effects on glucagon and insulin secretion [36].…”

Section: B-cell Apoptosis Proinsulin Conversion and B-cell Responsivitymentioning

confidence: 99%

“…Shah et al [36] studied 120 individuals, of whom onehalf were homozygous for TT at rs7903146 and one-half were homozygous for CC. In their study, b-cell responsiveness was slightly impaired in the TT genotype group and differed significantly between genotypes, implying that a genetic variant of TCF7L2 impairs glucose tolerance through effects on glucagon and insulin secretion [36]. In Alibegovic's [37] study, a total of 38 healthy individuals were examined to identify the association between the T-allele of TCF7L2 rs7903146 and insulin compensatory secretion to compensate for insulin resistance induced by bed rest.…”

Section: B-cell Apoptosis Proinsulin Conversion and B-cell Responsivitymentioning

confidence: 99%

Possible role of TCF7L2 in the pathogenesis of type 2 diabetes mellitus

Huang

Liao

Huang

et al. 2018

Biotechnology & Biotechnological Equipment

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With people's changing life style and dietary habits, the prevalence of type 2 diabetes mellitus (T2DM) has become much more serious than ever before. T2DM is a polygenic metabolic disorder, resulting from the interaction of genetic and various environmental factors. Among all the T2DM related genes, the transcription factor 7 like 2 (TCF7L2) gene is one of the most relevant risk-related genes for T2DM. However, the role of TCF7L2 in T2DM pathogenesis has not yet been interpreted thoroughly. Based on the experimental studies in recent years, this review discusses several possible mechanisms of T2DM pathogenesis induced by TCF7L2.

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TCF7L2 Genotype and α-Cell Function in Humans Without Diabetes

Cited by 50 publications

References 51 publications

Diabetes-Associated Variation in TCF7L2 Is Not Associated With Hepatic or Extrahepatic Insulin Resistance

Diabetes-Associated Variation in TCF7L2 Is Not Associated With Hepatic or Extrahepatic Insulin Resistance

Glucose tolerance and free fatty acid metabolism in adults with variations in TCF7L2 rs7903146

Possible role of TCF7L2 in the pathogenesis of type 2 diabetes mellitus

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