AIMS/HYPOTHESIS: WFS1 type 2 diabetes risk variants appear to be associated with impaired beta cell function, although it is unclear whether insulin secretion is affected directly or secondarily via alteration of insulin sensitivity. We aimed to investigate the effect of a common WFS1 single-nucleotide polymorphism on several aspects of insulin secretion. METHODS: A total of 1,578 non-diabetic individuals (534 men and 1,044 women, aged 40 +/- 13 years, BMI 28.9 +/- 8.2 kg/m(2) [mean +/- SD]) at increased risk of type 2 diabetes were genotyped for rs10010131 within the WFS1 gene. All participants underwent an OGTT (and a subset additionally an IVGTT [n = 319]) and a hyperglycaemic clamp combined with glucagon-like peptide-1 (GLP-1) and arginine stimuli (n = 102). RESULTS: rs10010131 was associated with reduced OGTT-derived insulin secretion (p = 0.03). In contrast, insulin secretion induced by an i.v. glucose challenge in the IVGTT and hyperglycaemic clamp was not different between the genotypes. GLP-1 infusion combined with a hyperglycaemic clamp showed a significant reduction of the insulin secretion rate during the first and second phases of GLP-1-induced insulin secretion in carriers of the risk allele (reduction of 36% and 26%, respectively; p = 0.007 and p = 0.04, respectively). CONCLUSIONS/ INTERPRETATION: A common genetic variant in WFS1 specifically impairs GLP-1-induced insulin secretion independently of insulin sensitivity. This defect might explain the impaired insulin secretion in carriers of the risk allele and confer the increased risk of type 2 diabetes.
AIMS/HYPOTHESIS: WFS1 type 2 diabetes risk variants appear to be associated with impaired beta cell function, although it is unclear whether insulin secretion is affected directly or secondarily via alteration of insulin sensitivity. We aimed to investigate the effect of a common WFS1 single-nucleotide polymorphism on several aspects of insulin secretion. METHODS: A total of 1,578 non-diabetic individuals (534 men and 1,044 women, aged 40 +/- 13 years, BMI 28.9 +/- 8.2 kg/m(2) [mean +/- SD]) at increased risk of type 2 diabetes were genotyped for rs10010131 within the WFS1 gene. All participants underwent an OGTT (and a subset additionally an IVGTT [n = 319]) and a hyperglycaemic clamp combined with glucagon-like peptide-1 (GLP-1) and arginine stimuli (n = 102). RESULTS:rs10010131 was associated with reduced OGTT-derived insulin secretion (p = 0.03). In contrast, insulin secretion induced by an i.v. glucose challenge in the IVGTT and hyperglycaemic clamp was not different between the genotypes. GLP-1 infusion combined with a hyperglycaemic clamp showed a significant reduction of the insulin secretion rate during the first and second phases of GLP-1-induced insulin secretion in carriers of the risk allele (reduction of 36% and 26%, respectively; p = 0.007 and p = 0.04, respectively). CONCLUSIONS/ INTERPRETATION: A common genetic variant in WFS1 specifically impairs GLP-1-induced insulin secretion independently of insulin sensitivity. This defect might explain the impaired insulin secretion in carriers of the risk allele and confer the increased risk of type 2 diabetes.
Authors: Struan F A Grant; Gudmar Thorleifsson; Inga Reynisdottir; Rafn Benediktsson; Andrei Manolescu; Jesus Sainz; Agnar Helgason; Hreinn Stefansson; Valur Emilsson; Anna Helgadottir; Unnur Styrkarsdottir; Kristinn P Magnusson; G Bragi Walters; Ebba Palsdottir; Thorbjorg Jonsdottir; Thorunn Gudmundsdottir; Arnaldur Gylfason; Jona Saemundsdottir; Robert L Wilensky; Muredach P Reilly; Daniel J Rader; Yu Bagger; Claus Christiansen; Vilmundur Gudnason; Gunnar Sigurdsson; Unnur Thorsteinsdottir; Jeffrey R Gulcher; Augustine Kong; Kari Stefansson Journal: Nat Genet Date: 2006-01-15 Impact factor: 38.330
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Authors: S A Schäfer; O Tschritter; F Machicao; C Thamer; N Stefan; B Gallwitz; J J Holst; J M Dekker; L M 't Hart; L M t'Hart; G Nijpels; T W van Haeften; H U Häring; A Fritsche Journal: Diabetologia Date: 2007-07-28 Impact factor: 10.122
Authors: T D Müller; B Finan; S R Bloom; D D'Alessio; D J Drucker; P R Flatt; A Fritsche; F Gribble; H J Grill; J F Habener; J J Holst; W Langhans; J J Meier; M A Nauck; D Perez-Tilve; A Pocai; F Reimann; D A Sandoval; T W Schwartz; R J Seeley; K Stemmer; M Tang-Christensen; S C Woods; R D DiMarchi; M H Tschöp Journal: Mol Metab Date: 2019-09-30 Impact factor: 7.422
Authors: Annemarie M Simonis-Bik; Giel Nijpels; Timon W van Haeften; Jeanine J Houwing-Duistermaat; Dorret I Boomsma; Erwin Reiling; Els C van Hove; Michaela Diamant; Mark H H Kramer; Robert J Heine; J Antonie Maassen; P Eline Slagboom; Gonneke Willemsen; Jacqueline M Dekker; Elisabeth M Eekhoff; Eco J de Geus; Leen M 't Hart Journal: Diabetes Date: 2009-10-15 Impact factor: 9.461