A common genetic variant in WFS1 determines impaired glucagon-like peptide-1-induced insulin secretion

Schäfer, Silke; Müssig, Karsten; Staiger, Harald; Machicao, Fausto; Stefan, Norbert; Gallwitz, Baptist; Häring, Hans Ulrich; Fritsche, Andreas

doi:10.1007/s00125-009-1344-5

Cited by 81 publications

(69 citation statements)

References 43 publications

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“…Therefore, carriage of the susceptibility WFS1 variant is related to impaired glucoseinduced insulin response resulting from β-cell dysfunction. These results are in accordance with findings in other populations reporting the relationship between the carriage of various diseaseassociated variants of WFS1 and altered insulin secretion in response to glucose stimulation [10,[19][20][21] and lower pancreatic β-cell function [22]. SNP rs734312 is a missense mutation that is situated in the last exon (exon 8) of WFS1, and leads to an amino acid (aa) substitution of histidine to arginine in codon 611 (H611R).…”

Section: Discussionsupporting

confidence: 90%

A WFS1 Haplotype Consisting of the Minor Alleles of rs752854, rs10010131, and rs734312 Shows a Protective Role Against Type 2 Diabetes in Russian Patients

Chistiakov

Ходырев²,

Сметанина³

et al. 2010

Rev Diabet Stud

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BACKGROUND: Rare variants of the WFS1 gene encoding wolframin cause Wolfram syndrome, a monogenic disease associated with diabetes insipidus, diabetes mellitus, optic atrophy, and deafness. In contrast, common variants of WFS1 showed association with type 2 diabetes (T2D) in numerous Caucasian populations. AIM: In this study, we tested whether the markers rs752854, rs10010131, and rs734312, located in the WFS1 gene, are related to the development of T2D in a Russian population. METHODS: The polymorphic markers were genotyped in Russian diabetic (n = 1,112) and non-diabetic (n = 1,097) patients using a Taqman allele discrimination assay. The correlation between the carriage of disease-associated WFS1 variants and the patients' clinical and metabolic characteristics was studied using ANOVA and ANCOVA. Adjustment for confounding variables such as gender, age, body mass index, obesity, HbA1c, and hypertension was made. RESULTS: Haplotype GAG, consisting of the minor alleles of rs752854, rs10010131, and rs734312, respectively, showed association with decreased risk of T2D (OR = 0.44, 95% CI = 0.32-0.61, p = 4.3 x 10 -7 ). Compared to other WFS1 variants, non-diabetic individuals homozygous for GAG/CAG had significantly increased fasting insulin (p adjusted = 0.047) and homeostasis model assessment of β-cell function (HOMA-β) index (p adjusted = 0.006). Diabetic patients homozygous for GAG/GAG showed significantly elevated levels of 2-h insulin (p adjusted = 0.029) and HOMA-β = 0.011. CONCLUSIONS: Diseaseassociated variants of WFS1 contribute to the pathogenesis of T2D through impaired insulin response to glucose stimulation and altered β-cell function.

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Section: Discussionsupporting

confidence: 90%

A WFS1 Haplotype Consisting of the Minor Alleles of rs752854, rs10010131, and rs734312 Shows a Protective Role Against Type 2 Diabetes in Russian Patients

Chistiakov

Ходырев²,

Сметанина³

et al. 2010

Rev Diabet Stud

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“…Most notably, all previous studies that used a hyperglycaemic clamp procedure comparable to the one used here confirm the independence of genetic effects on insulin secretion and insulin sensitivity. For instance, the risk variants of CDKAL1, IGF2BP2 [36], TCF7L2 [37] or WFS1 [38] clearly impaired glucose-or GLP-1-induced insulin secretion, but did not impact on insulin sensitivity. It has often been suggested that beta cell dysfunction is uncovered only when insulin resistance creates a strongly increased insulin demand.…”

Section: Discussionmentioning

confidence: 98%

Genetic influences on the insulin response of the beta cell to different secretagogues

Simonis-Bik

Eekhoff

Moor³

et al. 2009

Diabetologia

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Aims/hypothesis The aim of the present study was to estimate the heritability of the beta cell insulin response to glucose and to glucose combined with glucagon-like peptide-1 (GLP-1) or with GLP-1 plus arginine. Methods This was a twin-family study that included 54 families from the Netherlands Twin Register. The participants were healthy twin pairs and their siblings of the same sex, aged 20 to 50 years. Insulin response of the beta cell was assessed by a modified hyperglycaemic clamp with additional GLP-1 and arginine. Insulin sensitivity index (ISI) was assessed by the euglycaemic-hyperinsulinaemic clamp. Multivariate structural equation modelling was used to obtain heritabilities and the genetic factors underlying individual differences in BMI, ISI and secretory responses of the beta cell. Results The heritability of insulin levels in response to glucose was 52% and 77% for the first and second phase, respectively, 53% in response to glucose+GLP-1 and 80% in response to an additional arginine bolus. Insulin responses to the administration of glucose, glucose+GLP-1 and glucose + GLP-1 + arginine were highly correlated (0.62

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“…Given that the glucose-lowering effect of metformin is so strong and is independent of incretin signalling, it might be difficult to detect the beneficial effect of metformin on the incretin axis in human studies. Nonetheless, it would be interesting to examine whether or not metformin is able to reverse the decreased sensitivity of pancreatic beta cells to the insulinotropic effects of incretins associated with genetic polymorphisms in TCF7L2 [28][29][30] and WFS1 [31]. It just may be that there are still unappreciated benefits to the old drug, metformin.…”

Section: Ampk Amp-activated Protein Kinase Dpp-4mentioning

confidence: 99%

New aspects of an old drug: metformin as a glucagon-like peptide 1 (GLP-1) enhancer and sensitiser

Cho

Kieffer

2010

Diabetologia

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The two major deficits in type 2 diabetes, insulin resistance and impaired beta cell function, are often treated with metformin and incretin-based drugs, respectively. However, there may be unappreciated benefits of this combination of therapies. In this issue of Diabetologia, Maida et al. (doi:10.1007Maida et al. (doi:10. /s00125-010-1937 report that metformin acutely increases plasma levels of glucagon-like peptide 1 (GLP-1) in mice. Moreover, they show that metformin enhances the expression of the genes encoding the receptors for both GLP-1 and glucose-dependent insulinotropic polypeptide (GIP) in mouse islets and also increases the effects of GIP and GLP-1 on insulin secretion from beta cells. Interestingly, these incretin-sensitising effects of metformin appear to be mediated by a peroxisome proliferator-activated receptor α-dependent pathway, as opposed to the more commonly ascribed pathway of metformin action involving AMP-activated protein kinase. These provocative findings by Maida et al. extend our understanding of the mechanism of action of metformin and provide further insights into the benefits of combining metformin with incretin-based drugs to combat diabetes.

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A common genetic variant in WFS1 determines impaired glucagon-like peptide-1-induced insulin secretion

Cited by 81 publications

References 43 publications

A WFS1 Haplotype Consisting of the Minor Alleles of rs752854, rs10010131, and rs734312 Shows a Protective Role Against Type 2 Diabetes in Russian Patients

A WFS1 Haplotype Consisting of the Minor Alleles of rs752854, rs10010131, and rs734312 Shows a Protective Role Against Type 2 Diabetes in Russian Patients

Genetic influences on the insulin response of the beta cell to different secretagogues

New aspects of an old drug: metformin as a glucagon-like peptide 1 (GLP-1) enhancer and sensitiser

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