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Common genetic variants highlight the role of insulin resistance and body fat distribution in type 2 diabetes, independent of obesity

Authors :
Núria Sala
Nina Roswall
Tilman Kühn
Larraitz Arriola
Dorota Pasko
Elio Riboli
Mark I. McCarthy
Afshan Siddiq
María José Sánchez
Luca A. Lotta
Francesca L. Crowe
Timothy J. Key
Peter M. Nilsson
Anne Tjønneland
Inês Barroso
Guy Fagherazzi
Nita G. Forouhi
Carlotta Sacerdote
Kim Overvad
Aurelio Barricarte
Nicholas J. Wareham
Sara Grioni
Tove Fall
Françoise Clavel-Chapelon
Olov Rolandsson
Heiner Boeing
Jacqueline M. Dekker
Mark Walker
Adam Barker
Vilmantas Giedraitis
Daphne L. van der A
Claudia Langenberg
Diana Gavrila
David B. Savage
Ele Ferrannini
Matthias B. Schulze
Hanieh Yaghootkar
Nadia Slimani
Paul W. Franks
Erik Ingelsson
Annemieke M.W. Spijkerman
Robert A. Scott
Ivonne Sluijs
Rosario Tumino
Stephen J. Sharp
Salvatore Panico
Robert K. Semple
Beverley Balkau
Leif Groop
Domenico Palli
Timothy M. Frayling
J. Ramón Quirós
Rudolf Kaaks
Scott, Ra
Fall, T
Pasko, D
Barker, A
Sharp, Sj
Arriola, L
Balkau, B
Barricarte, A
Barroso, I
Boeing, H
Clavel Chapelon, F
Crowe, Fl
Dekker, Jm
Fagherazzi, G
Ferrannini, E
Forouhi, Ng
Franks, Pw
Gavrila, D
Giedraitis, V
Grioni, S
Groop, Lc
Kaaks, R
Key, Tj
K?hn, T
Lotta, La
Nilsson, Pm
Overvad, K
Palli, D
Panico, Salvatore
Quir?s, Jr
Rolandsson, O
Roswall, N
Sacerdote, C
Sala, N
S?nchez, Mj
Schulze, Mb
Siddiq, A
Slimani, N
Sluijs, I
Spijkerman, Am
Tjonneland, A
Tumino, R
van der A., Dl
Yaghootkar, H
Mccarthy, Mi
Semple, Rk
Riboli, E
Walker, M
Ingelsson, E
Frayling, Tm
Savage, Db
Langenberg, C
Wareham, Nj
The RISC The study group InterAct, Consortium
Epidemiology and Data Science
EMGO - Lifestyle, overweight and diabetes
Source :
Scott, R A, Fall, T, Pasko, D, Barker, A, Sharp, S J, Arriola, L, Balkau, B, Barricarte, A, Barroso, I, Boeing, H, Clavel-Chapelon, F, Crowe, F L, Dekker, J M, Fagherazzi, G, Ferrannini, E, Forouhi, N G, Franks, P W, Gavrila, D, Giedraitis, V, Grioni, S, Groop, L C, Kaaks, R, Key, T J, Kuhn, T, Lotta, L A, Nilsson, P M, Overvad, K, Palli, D, Panico, S, Quiros, J R, Rolandsson, O, Roswall, N, Sacerdote, C, Sala, N, Sanchez, MJ, Schulze, M B, Siddiq, A, Slimani, N, Sluijs, I, Spijkerman, A M W, Tjonneland, A, Tumino, R, van der A, D L, Yaghootkar, H, McCarthy, M I, Semple, R K, Riboli, E, Walker, M, Ingelsson, E, Frayling, T M, Savage, D B, Langenberg, C & Wareham, N J 2014, ' Common Genetic Variants Highlight the Role of Insulin Resistance and Body Fat Distribution in Type 2 Diabetes, Independent of Obesity ', Diabetes, vol. 63, no. 12, pp. 4378-4387 . https://doi.org/10.2337/db14-0319, Scott, R A, Fall, T, Pasko, D, Barker, A, Sharp, S J, Arriola, L, Balkau, B, Barricarte, A, Barroso, I, Boeing, H, Clavel-Chapelon, F, Crowe, F L, Dekker, J M, Fagherazzi, G, Ferraninini, E, Forouhi, N G, Franks, P W, Gavrila, D, Giedraitis, V, Grioni, S, Groop, L C, Kaaks, R, Key, T J, Kühn, T, Lotta, L, Nilsson, P M, Overvad, K, Palli, D, Panico, S, Quirós, J R, Rolandsson, O, Roswall, N, Sacerdote, C, Sala, N, Sánchez, M-J, Schulze, M B, Siddiq, A, Slimani, N, Sluijs, I, Spijkerman, A M, Tjonneland, A, Tumino, R, van der A, D L, Yaghootkar, H, McCarthy, M I, Semple, R K, Riboli, E, Walker, M, Ingelsson, E, Frayling, T M & The RISC study group 2014, ' Common genetic variants highlight the role of insulin resistance and body fat distribution in type 2 diabetes, independently of obesity ', Diabetes, vol. 63, no. 12, pp. 4378-4387 . https://doi.org/10.2337/db14-0319, Scott, R A, Fall, T, Pasko, D, Barker, A, Sharp, S J, Arriola, L, Balkau, B, Barricarte, A, Barroso, I, Boeing, H, Clavel-Chapelon, F, Crowe, F L, Dekker, J M, Fagherazzi, G, Ferraninini, E, Forouhi, N G, Franks, P W, Gavrila, D, Giedraitis, V, Grioni, S, Groop, L C, Kaaks, R, Key, T J, Kühn, T, Lotta, L, Nilsson, P M, Overvad, K, Palli, D, Panico, S, Quirós, J R, Rolandsson, O, Roswall, N, Sacerdote, C, Sala, N, Sánchez, M-J, Schulze, M B, Siddiq, A, Slimani, N, Sluijs, I, Spijkerman, A M, Tjonneland, A, Tumino, R, van der A, D L, Yaghootkar, H, McCarthy, M I, Semple, R K, Riboli, E, Walker, M, Ingelsson, E, Frayling, T M & The RISC study group 2014, ' Common genetic variants highlight the role of insulin resistance and body fat distribution in type 2 diabetes, independently of obesity ', Diabetes, vol. 63, no. 12, pp. 4378-87 . https://doi.org/10.2337/db14-0319, Diabetes, 63(12), 4378-4387. American Diabetes Association Inc.
Publication Year :
2016

Abstract

We aimed to validate genetic variants as instruments for insulin resistance and secretion, to characterize their association with intermediate phenotypes, and to investigate their role in type 2 diabetes (T2D) risk among normal-weight, overweight, and obese individuals. We investigated the association of genetic scores with euglycemic-hyperinsulinemic clamp– and oral glucose tolerance test–based measures of insulin resistance and secretion and a range of metabolic measures in up to 18,565 individuals. We also studied their association with T2D risk among normal-weight, overweight, and obese individuals in up to 8,124 incident T2D cases. The insulin resistance score was associated with lower insulin sensitivity measured by M/I value (β in SDs per allele [95% CI], −0.03 [−0.04, −0.01]; P = 0.004). This score was associated with lower BMI (−0.01 [−0.01, −0.0]; P = 0.02) and gluteofemoral fat mass (−0.03 [−0.05, −0.02; P = 1.4 × 10−6) and with higher alanine transaminase (0.02 [0.01, 0.03]; P = 0.002) and γ-glutamyl transferase (0.02 [0.01, 0.03]; P = 0.001). While the secretion score had a stronger association with T2D in leaner individuals (Pinteraction = 0.001), we saw no difference in the association of the insulin resistance score with T2D among BMI or waist strata (Pinteraction > 0.31). While insulin resistance is often considered secondary to obesity, the association of the insulin resistance score with lower BMI and adiposity and with incident T2D even among individuals of normal weight highlights the role of insulin resistance and ectopic fat distribution in T2D, independently of body size.

Details

Language :
English
ISSN :
00121797
Database :
OpenAIRE
Journal :
Scott, R A, Fall, T, Pasko, D, Barker, A, Sharp, S J, Arriola, L, Balkau, B, Barricarte, A, Barroso, I, Boeing, H, Clavel-Chapelon, F, Crowe, F L, Dekker, J M, Fagherazzi, G, Ferrannini, E, Forouhi, N G, Franks, P W, Gavrila, D, Giedraitis, V, Grioni, S, Groop, L C, Kaaks, R, Key, T J, Kuhn, T, Lotta, L A, Nilsson, P M, Overvad, K, Palli, D, Panico, S, Quiros, J R, Rolandsson, O, Roswall, N, Sacerdote, C, Sala, N, Sanchez, MJ, Schulze, M B, Siddiq, A, Slimani, N, Sluijs, I, Spijkerman, A M W, Tjonneland, A, Tumino, R, van der A, D L, Yaghootkar, H, McCarthy, M I, Semple, R K, Riboli, E, Walker, M, Ingelsson, E, Frayling, T M, Savage, D B, Langenberg, C & Wareham, N J 2014, ' Common Genetic Variants Highlight the Role of Insulin Resistance and Body Fat Distribution in Type 2 Diabetes, Independent of Obesity ', Diabetes, vol. 63, no. 12, pp. 4378-4387 . https://doi.org/10.2337/db14-0319, Scott, R A, Fall, T, Pasko, D, Barker, A, Sharp, S J, Arriola, L, Balkau, B, Barricarte, A, Barroso, I, Boeing, H, Clavel-Chapelon, F, Crowe, F L, Dekker, J M, Fagherazzi, G, Ferraninini, E, Forouhi, N G, Franks, P W, Gavrila, D, Giedraitis, V, Grioni, S, Groop, L C, Kaaks, R, Key, T J, Kühn, T, Lotta, L, Nilsson, P M, Overvad, K, Palli, D, Panico, S, Quirós, J R, Rolandsson, O, Roswall, N, Sacerdote, C, Sala, N, Sánchez, M-J, Schulze, M B, Siddiq, A, Slimani, N, Sluijs, I, Spijkerman, A M, Tjonneland, A, Tumino, R, van der A, D L, Yaghootkar, H, McCarthy, M I, Semple, R K, Riboli, E, Walker, M, Ingelsson, E, Frayling, T M & The RISC study group 2014, ' Common genetic variants highlight the role of insulin resistance and body fat distribution in type 2 diabetes, independently of obesity ', Diabetes, vol. 63, no. 12, pp. 4378-4387 . https://doi.org/10.2337/db14-0319, Scott, R A, Fall, T, Pasko, D, Barker, A, Sharp, S J, Arriola, L, Balkau, B, Barricarte, A, Barroso, I, Boeing, H, Clavel-Chapelon, F, Crowe, F L, Dekker, J M, Fagherazzi, G, Ferraninini, E, Forouhi, N G, Franks, P W, Gavrila, D, Giedraitis, V, Grioni, S, Groop, L C, Kaaks, R, Key, T J, Kühn, T, Lotta, L, Nilsson, P M, Overvad, K, Palli, D, Panico, S, Quirós, J R, Rolandsson, O, Roswall, N, Sacerdote, C, Sala, N, Sánchez, M-J, Schulze, M B, Siddiq, A, Slimani, N, Sluijs, I, Spijkerman, A M, Tjonneland, A, Tumino, R, van der A, D L, Yaghootkar, H, McCarthy, M I, Semple, R K, Riboli, E, Walker, M, Ingelsson, E, Frayling, T M & The RISC study group 2014, ' Common genetic variants highlight the role of insulin resistance and body fat distribution in type 2 diabetes, independently of obesity ', Diabetes, vol. 63, no. 12, pp. 4378-87 . https://doi.org/10.2337/db14-0319, Diabetes, 63(12), 4378-4387. American Diabetes Association Inc.
Accession number :
edsair.doi.dedup.....3c8ee2f66cc5ddfced99ae870e2bac31
Full Text :
https://doi.org/10.2337/db14-0319