AIMS/HYPOTHESIS: A recent genome-wide association study identified the SLC30A8 rs13266634 polymorphism encoding an Arg325Trp polymorphism in the zinc transporter protein member 8 (ZnT-8) to be associated with type 2 diabetes. Here, we investigate whether the polymorphism is related to altered insulin release in response to intravenous and oral glucose loads in non-diabetic offspring of type 2 diabetic patients. METHODS: We genotyped SLC30A8 rs13266634 in 846 non-diabetic offspring of type 2 diabetic patients from five different white populations: Danish (n = 271), Finnish (n = 217), German (n = 149), Italian (n = 109) and Swedish (n = 100). Participants were subjected to both IVGTTs and OGTTs, and measurements of insulin sensitivity. RESULTS: Homozygous carriers of the major type 2 diabetes C risk-allele showed a 19% decrease in first-phase insulin release (0-10 min) measured during the IVGTT (CC 3,624 +/- 3,197; CT 3,763 +/- 2,674; TT 4,478 +/- 3,032 pmol l(-1) min(-1), mean +/- SD; p = 0.007). We found no significant genotype effect on insulin release measured during the OGTT or on estimates of insulin sensitivity. CONCLUSIONS/ INTERPRETATION: Of European non-diabetic offspring of type 2 diabetes patients, 46% are homozygous carriers of the Arg325Trp polymorphism in ZnT-8, which is known to associate with type 2 diabetes. These diabetes-prone offspring are characterised by a 19% decrease in first-phase insulin release following an intravenous glucose load, suggesting a role for this variant in the pathogenesis of pancreatic beta cell dysfunction.
AIMS/HYPOTHESIS: A recent genome-wide association study identified the SLC30A8rs13266634 polymorphism encoding an Arg325Trp polymorphism in the zinc transporter protein member 8 (ZnT-8) to be associated with type 2 diabetes. Here, we investigate whether the polymorphism is related to altered insulin release in response to intravenous and oral glucose loads in non-diabetic offspring of type 2 diabeticpatients. METHODS: We genotyped SLC30A8rs13266634 in 846 non-diabetic offspring of type 2 diabeticpatients from five different white populations: Danish (n = 271), Finnish (n = 217), German (n = 149), Italian (n = 109) and Swedish (n = 100). Participants were subjected to both IVGTTs and OGTTs, and measurements of insulin sensitivity. RESULTS: Homozygous carriers of the major type 2 diabetes C risk-allele showed a 19% decrease in first-phase insulin release (0-10 min) measured during the IVGTT (CC 3,624 +/- 3,197; CT 3,763 +/- 2,674; TT 4,478 +/- 3,032 pmol l(-1) min(-1), mean +/- SD; p = 0.007). We found no significant genotype effect on insulin release measured during the OGTT or on estimates of insulin sensitivity. CONCLUSIONS/ INTERPRETATION: Of European non-diabetic offspring of type 2 diabetespatients, 46% are homozygous carriers of the Arg325Trp polymorphism in ZnT-8, which is known to associate with type 2 diabetes. These diabetes-prone offspring are characterised by a 19% decrease in first-phase insulin release following an intravenous glucose load, suggesting a role for this variant in the pathogenesis of pancreatic beta cell dysfunction.
Authors: Richa Saxena; Benjamin F Voight; Valeriya Lyssenko; Noël P Burtt; Paul I W de Bakker; Hong Chen; Jeffrey J Roix; Sekar Kathiresan; Joel N Hirschhorn; Mark J Daly; Thomas E Hughes; Leif Groop; David Altshuler; Peter Almgren; Jose C Florez; Joanne Meyer; Kristin Ardlie; Kristina Bengtsson Boström; Bo Isomaa; Guillaume Lettre; Ulf Lindblad; Helen N Lyon; Olle Melander; Christopher Newton-Cheh; Peter Nilsson; Marju Orho-Melander; Lennart Råstam; Elizabeth K Speliotes; Marja-Riitta Taskinen; Tiinamaija Tuomi; Candace Guiducci; Anna Berglund; Joyce Carlson; Lauren Gianniny; Rachel Hackett; Liselotte Hall; Johan Holmkvist; Esa Laurila; Marketa Sjögren; Maria Sterner; Aarti Surti; Margareta Svensson; Malin Svensson; Ryan Tewhey; Brendan Blumenstiel; Melissa Parkin; Matthew Defelice; Rachel Barry; Wendy Brodeur; Jody Camarata; Nancy Chia; Mary Fava; John Gibbons; Bob Handsaker; Claire Healy; Kieu Nguyen; Casey Gates; Carrie Sougnez; Diane Gage; Marcia Nizzari; Stacey B Gabriel; Gung-Wei Chirn; Qicheng Ma; Hemang Parikh; Delwood Richardson; Darrell Ricke; Shaun Purcell Journal: Science Date: 2007-04-26 Impact factor: 47.728
Authors: Valgerdur Steinthorsdottir; Gudmar Thorleifsson; Inga Reynisdottir; Rafn Benediktsson; Thorbjorg Jonsdottir; G Bragi Walters; Unnur Styrkarsdottir; Solveig Gretarsdottir; Valur Emilsson; Shyamali Ghosh; Adam Baker; Steinunn Snorradottir; Hjordis Bjarnason; Maggie C Y Ng; Torben Hansen; Yu Bagger; Robert L Wilensky; Muredach P Reilly; Adebowale Adeyemo; Yuanxiu Chen; Jie Zhou; Vilmundur Gudnason; Guanjie Chen; Hanxia Huang; Kerrie Lashley; Ayo Doumatey; Wing-Yee So; Ronald C Y Ma; Gitte Andersen; Knut Borch-Johnsen; Torben Jorgensen; Jana V van Vliet-Ostaptchouk; Marten H Hofker; Cisca Wijmenga; Claus Christiansen; Daniel J Rader; Charles Rotimi; Mark Gurney; Juliana C N Chan; Oluf Pedersen; Gunnar Sigurdsson; Jeffrey R Gulcher; Unnur Thorsteinsdottir; Augustine Kong; Kari Stefansson Journal: Nat Genet Date: 2007-04-26 Impact factor: 38.330
Authors: Eleftheria Zeggini; Michael N Weedon; Cecilia M Lindgren; Timothy M Frayling; Katherine S Elliott; Hana Lango; Nicholas J Timpson; John R B Perry; Nigel W Rayner; Rachel M Freathy; Jeffrey C Barrett; Beverley Shields; Andrew P Morris; Sian Ellard; Christopher J Groves; Lorna W Harries; Jonathan L Marchini; Katharine R Owen; Beatrice Knight; Lon R Cardon; Mark Walker; Graham A Hitman; Andrew D Morris; Alex S F Doney; Mark I McCarthy; Andrew T Hattersley Journal: Science Date: 2007-04-26 Impact factor: 47.728
Authors: Malek El Muayed; Liana K Billings; Meera R Raja; Xiaomin Zhang; Paul J Park; Marsha V Newman; Dixon B Kaufman; Thomas V O'Halloran; William L Lowe Journal: J Endocrinol Date: 2010-05-27 Impact factor: 4.286
Authors: Julie Norseen; Tetsuya Hosooka; Ann Hammarstedt; Mark M Yore; Shashi Kant; Pratik Aryal; Urban A Kiernan; David A Phillips; Hiroshi Maruyama; Bettina J Kraus; Anny Usheva; Roger J Davis; Ulf Smith; Barbara B Kahn Journal: Mol Cell Biol Date: 2012-03-19 Impact factor: 4.272
Authors: A Haupt; H Staiger; S A Schäfer; K Kirchhoff; M Guthoff; F Machicao; B Gallwitz; N Stefan; H-U Häring; A Fritsche Journal: Diabetologia Date: 2009-01-27 Impact factor: 10.122
Authors: Kristen E Syring; Kayla A Boortz; James K Oeser; Alessandro Ustione; Kenneth A Platt; Melanie K Shadoan; Owen P McGuinness; David W Piston; David R Powell; Richard M O'Brien Journal: Endocrinology Date: 2016-10-18 Impact factor: 4.736