CONTEXT: Insulin resistance is an important feature of type 2 diabetes. Ectoenzyme nucleotide pyrophosphatase phosphodiesterase 1 (ENPP1) inhibits insulin signaling, and a recent meta-analysis reported a nominal association between the Q allele in the K121Q (rs1044498) single nucleotide polymorphism in its gene ENPP1 and type 2 diabetes. OBJECTIVE AND INTERVENTION: We examined the impact of this polymorphism on diabetes incidence as well as insulin secretion and sensitivity at baseline and after treatment with a lifestyle intervention or metformin vs. placebo in the Diabetes Prevention Program (DPP). DESIGN, SETTING, PARTICIPANTS, AND OUTCOME: We genotyped ENPP1 K121Q in 3548 DPP participants and performed Cox regression analyses using genotype, intervention, and interactions as predictors of diabetes incidence. RESULTS:Fasting glucose and glycated hemoglobin were higher in QQ homozygotes at baseline (P < 0.001 for both). There was a significant interaction between genotype at rs1044498 and intervention under the dominant model (P = 0.03). In analyses stratified by treatment arm, a positive association with diabetes incidence was found in Q allele carriers compared to KK homozygotes [hazard ratio (HR), 1.38; 95% confidence interval (CI), 1.08-1.76; P = 0.009] in the placebo arm (n = 996). Lifestyle modification eliminated this increased risk. These findings persisted after adjustment for body mass index and race/ethnicity. Association of ENPP1 K121Q genotype with diabetes incidence under the additive and recessive genetic models showed consistent trends [HR, 1.10 (95% CI, 0.99-1.23), P = 0.08; and HR, 1.16 (95% CI, 0.92-1.45), P = 0.20, respectively] but did not reach statistical significance. CONCLUSIONS: ENPP1 K121Q is associated with increased diabetes incidence; the DPP lifestyle intervention eliminates this increased risk.
RCT Entities:
CONTEXT: Insulin resistance is an important feature of type 2 diabetes. Ectoenzyme nucleotide pyrophosphatase phosphodiesterase 1 (ENPP1) inhibits insulin signaling, and a recent meta-analysis reported a nominal association between the Q allele in the K121Q (rs1044498) single nucleotide polymorphism in its gene ENPP1 and type 2 diabetes. OBJECTIVE AND INTERVENTION: We examined the impact of this polymorphism on diabetes incidence as well as insulin secretion and sensitivity at baseline and after treatment with a lifestyle intervention or metformin vs. placebo in the Diabetes Prevention Program (DPP). DESIGN, SETTING, PARTICIPANTS, AND OUTCOME: We genotyped ENPP1 K121Q in 3548 DPPparticipants and performed Cox regression analyses using genotype, intervention, and interactions as predictors of diabetes incidence. RESULTS: Fasting glucose and glycated hemoglobin were higher in QQ homozygotes at baseline (P < 0.001 for both). There was a significant interaction between genotype at rs1044498 and intervention under the dominant model (P = 0.03). In analyses stratified by treatment arm, a positive association with diabetes incidence was found in Q allele carriers compared to KK homozygotes [hazard ratio (HR), 1.38; 95% confidence interval (CI), 1.08-1.76; P = 0.009] in the placebo arm (n = 996). Lifestyle modification eliminated this increased risk. These findings persisted after adjustment for body mass index and race/ethnicity. Association of ENPP1 K121Q genotype with diabetes incidence under the additive and recessive genetic models showed consistent trends [HR, 1.10 (95% CI, 0.99-1.23), P = 0.08; and HR, 1.16 (95% CI, 0.92-1.45), P = 0.20, respectively] but did not reach statistical significance. CONCLUSIONS:ENPP1 K121Q is associated with increased diabetes incidence; the DPP lifestyle intervention eliminates this increased risk.
Authors: A Pizzuti; L Frittitta; A Argiolas; R Baratta; I D Goldfine; M Bozzali; T Ercolino; G Scarlato; L Iacoviello; R Vigneri; V Tassi; V Trischitta Journal: Diabetes Date: 1999-09 Impact factor: 9.461
Authors: B A Maddux; P Sbraccia; S Kumakura; S Sasson; J Youngren; A Fisher; S Spencer; A Grupe; W Henzel; T A Stewart Journal: Nature Date: 1995-02-02 Impact factor: 49.962
Authors: David Meyre; Nabila Bouatia-Naji; Agnès Tounian; Chantal Samson; Cécile Lecoeur; Vincent Vatin; Maya Ghoussaini; Christophe Wachter; Serge Hercberg; Guillaume Charpentier; Wolfgang Patsch; François Pattou; Marie-Aline Charles; Patrick Tounian; Karine Clément; Béatrice Jouret; Jacques Weill; Betty A Maddux; Ira D Goldfine; Andrew Walley; Philippe Boutin; Christian Dina; Philippe Froguel Journal: Nat Genet Date: 2005-07-17 Impact factor: 38.330
Authors: K Müssig; M Heni; C Thamer; K Kantartzis; F Machicao; N Stefan; A Fritsche; H-U Häring; H Staiger Journal: Diabetologia Date: 2009-11-29 Impact factor: 10.122
Authors: Yandiswa Y Yako; Jabulisile H Madubedube; Andre P Kengne; Rajiv T Erasmus; Tahir S Pillay; Tandi E Matsha Journal: Afr Health Sci Date: 2015-12 Impact factor: 0.927