Impact of Type 2 Diabetes Susceptibility Variants on Quantitative Glycemic Traits Reveals Mechanistic Heterogeneity
| العنوان: | Impact of Type 2 Diabetes Susceptibility Variants on Quantitative Glycemic Traits Reveals Mechanistic Heterogeneity |
|---|---|
| المؤلفون: | J. Graessler, Ulf Smith, Marie-France Hivert, Antigone S. Dimas, Joshua W. Knowles, Stéphane Cauchi, Karen L. Mohlke, Michael Boehnke, David Meyre, Nicholas J. Wareham, Ci Song, Denis Rybin, Erik Ingelsson, Mario A. Morken, Anne U. Jackson, Michael R. Erdos, Peter Kovacs, Fahim Abbasi, Claudia Langenberg, Ke Hao, Andreas Pfeiffer, Thomas Quertemous, Lars Lind, Stefan R. Bornstein, Suzannah Bumpstead, Alena Stančáková, Lori L. Bonnycastle, Michael Stumvoll, Oluf Pedersen, Themistocles L. Assimes, Inês Barroso, Andrea Benazzo, Richard M. Watanabe, Magic Investigators, Josée Dupuis, Inga Prokopenko, Heather M. Stringham, Felicity Payne, Markku Laakso, Antje Fischer-Rosinsky, Francis S. Collins, Mark Walker, James B. Meigs, Torben Hansen, Peter Schwarz, Xia Yang, Yvonne Böttcher, Hans-Ulrich Häring, Anke Tönjes, Narisu Narisu, Cécile Lecoeur, Jaakko Tuomilehto, Reedik Mägi, Joachim Spranger, Amy J. Swift, Johanna Kuusisto, Jose C. Florez, Niels Grarup, Philippe Froguel, Vasiliki Lagou, Peter S. Chines, Mark I. McCarthy, Adam Barker, Trine Welløv Boesgaard, Richard N. Bergman |
| المصدر: | Diabetes 63, 2158-2171 (2013) Diabetes Diabetes, vol 63, iss 6 Dimas, A S, Lagou, V, Barker, A, Knowles, J W, Magi, R, Hivert, M F, Benazzo, A, Rybin, D, Jackson, A U, Stringham, H M, Song, C, Fischer-Rosinsky, A, Boesgaard, T W, Grarup, N, Abbasi, F A, Assimes, T L, Hao, K, Yang, X, Lecoeur, C, Barroso, I, Bonnycastle, L L, Bottcher, Y, Bumpstead, S, Chines, P S, Erdos, M R, Graessler, J, Kovacs, P, Morken, M A, Narisu, N, Payne, F, Stancakova, A, Swift, A J, Tonjes, A, Bornstein, S R, Cauchi, S, Froguel, P, Meyre, D, Schwarz, P E H, Haring, H U, Smith, U, Boehnke, M, Bergman, R N, Collins, F S, Mohlke, K L, Tuomilehto, J, Quertemous, T, Lind, L, Hansen, T, Pedersen, O, Walker, M, Pfeiffer, A F H, Spranger, J, Stumvoll, M, Meigs, J B, Wareham, N J, Kuusisto, J, Laakso, M, Langenberg, C, Dupuis, J, Watanabe, R M, Florez, J C, Ingelsson, E, McCarthy, M I, Prokopenko, I & Investigators, M 2014, ' Impact of Type 2 Diabetes Susceptibility Variants on Quantitative Glycemic Traits Reveals Mechanistic Heterogeneity ', Diabetes, vol. 63, no. 6, pp. 2158-2171 . https://doi.org/10.2337/db13-0949Test |
| بيانات النشر: | American Diabetes Association, 2014. |
| سنة النشر: | 2014 |
| مصطلحات موضوعية: | Male, Endocrinology, Diabetes and Metabolism, Insulin Resistance/genetics, Type 2 diabetes, Medical and Health Sciences, Endocrinology, 0302 clinical medicine, Gene Frequency, Risk Factors, Insulin-Secreting Cells, Insulin Secretion, 2.1 Biological and endogenous factors, Cluster Analysis, Insulin, Aetiology, 2. Zero hunger, Genetics, 0303 health sciences, SLC30A8, Medicine (all), Diabetes, Single Nucleotide, Diabetes and Metabolism, Diabetes Mellitus, Type 2/genetics, Female, Type 2, Insulin processing, medicine.medical_specialty, Insulin/metabolism, Quantitative Trait Loci, Socio-culturale, 030209 endocrinology & metabolism, Biology, Autoimmune Disease, Polymorphism, Single Nucleotide, MAGIC Investigators, Endocrinology & Metabolism, 03 medical and health sciences, Insulin-Secreting Cells/metabolism, Insulin resistance, Clinical Research, Alleles, Diabetes Mellitus, Type 2, Genetic Variation, Genome-Wide Association Study, Humans, Insulin Resistance, Transcription Factors, Genetic Predisposition to Disease, Internal Medicine, Diabetes mellitus, Internal medicine, Genetic model, Diabetes Mellitus, medicine, Transcription Factors/metabolism, Polymorphism, Metabolic and endocrine, 030304 developmental biology, Glycemic, Prevention, medicine.disease, biology.protein, Quantitative Trait Loci/genetics, TCF7L2 |
| الوصف: | Patients with established type 2 diabetes display both beta-cell dysfunction and insulin resistance. To define fundamental processes leading to the diabetic state, we examined the relationship between type 2 diabetes risk variants at 37 established susceptibility loci, and indices of proinsulin processing, insulin secretion, and insulin sensitivity. We included data from up to 58,614 nondiabetic subjects with basal measures and 17,327 with dynamic measures. We used additive genetic models with adjustment for sex, age, and BMI, followed by fixed-effects, inverse-variance meta-analyses. Cluster analyses grouped risk loci into five major categories based on their relationship to these continuous glycemic phenotypes. The first cluster (PPARG, KLF14, IRS1, GCKR) was characterized by primary effects on insulin sensitivity. The second cluster (MTNR1B, GCK) featured risk alleles associated with reduced insulin secretion and fasting hyperglycemia. ARAP1 constituted a third cluster characterized by defects in insulin processing. A fourth cluster (TCF712, SLC30A8, HHEX/IDE, CDKAL1, CDKN2A/2B) was defined by loci influencing insulin processing and secretion without a detectable change in fasting glucose levels. The final group contained 20 risk loci with no clear-cut associations to continuous glycemic traits. By assembling extensive data on continuous glycemic traits, we have exposed the diverse mechanisms whereby type 2 diabetes risk variants impact disease predisposition. Patients with established type 2 diabetes display both b-cell dysfunction and insulin resistance. To define fundamental processes leading to the diabetic state, we examined the relationship between type 2 diabetes risk variants at 37 established susceptibility loci, and indices of proinsulin processing, insulin secretion, and insulin sensitivity. We included data from up to 58,614 nondiabetic subjects with basal measures and 17,327 with dynamic measures. We used additive genetic models with adjustment for sex, age, and BMI, followed by fixed-effects, inverse-variance meta-analyses. Cluster analyses grouped risk loci into five major categories based on their relationship to these continuous glycemic phenotypes. The first cluster (PPARG, KLF14, IRS1, GCKR) was characterized by primary effects on insulin sensitivity. The second cluster (MTNR1B, GCK) featured risk alleles associated with reduced insulin secretion and fasting hyperglycemia. ARAP1 constituted a third cluster characterized by defects in insulin processing. A fourth cluster (TCF7L2, SLC30A8, HHEX/IDE, CDKAL1, CDKN2A/2B) was defined by loci influencing insulin processing and secretion without a detectable change in fasting glucose levels. The final group contained 20 risk loci with no clear-cut associations to continuous glycemic traits. By assembling extensive data on continuous glycemic traits, we have exposed the diverse mechanisms whereby type 2 diabetes risk variants impact disease predisposition. |
| وصف الملف: | application/pdf |
| تدمد: | 1939-327X 0012-1797 |
| الوصول الحر: | https://explore.openaire.eu/search/publication?articleId=doi_dedup___::6ec76408386665bb3ac65c80f7efd345Test https://doi.org/10.2337/db13-0949Test |
| حقوق: | OPEN |
| رقم الانضمام: | edsair.doi.dedup.....6ec76408386665bb3ac65c80f7efd345 |
| قاعدة البيانات: | OpenAIRE |
| تدمد: | 1939327X 00121797 |
|---|