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

Robert A. Scott; Tove Fall; Dorota Pasko; Adam Barker; Stephen J. Sharp; Larraitz Arriola; Beverley Balkau; Aurelio Barricarte; Inês Barroso; Heiner Boeing; Franҫoise Clavel-Chapelon; Francesca L. Crowe; Jacqueline M. Dekker; Guy Fagherazzi; Ele Ferrannini; Nita G. Forouhi; Paul W. Franks; Diana Gavrila; Vilmantas Giedraitis; Sara Grioni; Leif C. Groop; Rudolf Kaaks; Timothy J. Key; Tilman Kühn; Luca A. Lotta; Peter M. Nilsson; Kim Overvad; Domenico Palli; Salvatore Panico; J. Ramón Quirós; Olov Rolandsson; Nina Roswall; Carlotta Sacerdote; Núria Sala; María José Sánchez; Matthias B. Schulze; Afshan Siddiq; Nadia Slimani; Ivonne Sluijs; Annemieke M.W. Spijkerman; Anne Tjonneland; Rosario Tumino; Daphne L. Van Der A; Hanieh Yaghootkar; Mark I. McCarthy; Robert K. Semple; Elio Riboli; Mark Walker; Erik Ingelsson; Tim M. Frayling; The RISC Study Group; The EPICInterAct Consortium

doi:10.2337/db14-0319

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

Robert A. Scott^*, Tove Fall, Dorota Pasko, Adam Barker, Stephen J. Sharp, Larraitz Arriola, Beverley Balkau, Aurelio Barricarte, Inês Barroso, Heiner Boeing, Franҫoise Clavel-Chapelon, Francesca L. Crowe, Jacqueline M. Dekker, Guy Fagherazzi, Ele Ferrannini, Nita G. Forouhi, Paul W. Franks, Diana Gavrila, Vilmantas Giedraitis, Sara GrioniLeif C. Groop, Rudolf Kaaks, Timothy J. Key, Tilman Kühn, Luca A. Lotta, Peter M. Nilsson, Kim Overvad, Domenico Palli, Salvatore Panico, J. Ramón Quirós, Olov Rolandsson, Nina Roswall, Carlotta Sacerdote, Núria Sala, María José Sánchez, Matthias B. Schulze, Afshan Siddiq, Nadia Slimani, Ivonne Sluijs, Annemieke M.W. Spijkerman, Anne Tjonneland, Rosario Tumino, Daphne L. Van Der A, Hanieh Yaghootkar, Mark I. McCarthy, Robert K. Semple, Elio Riboli, Mark Walker, Erik Ingelsson, Tim M. Frayling, The RISC Study Group, The EPICInterAct Consortium

^*Corresponding author for this work

Research output: Contribution to journal › Article › Research › peer-review

146 Citations (Scopus)

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], 20.03 [20.04, 20.01]; P = 0.004). This score was associated with lower BMI (20.01 [20.01, 20.0]; P = 0.02) and gluteofemoral fat mass (20.03 [20.05, 20.02; P = 1.4 3 1026 ) 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 (P_interaction = 0.001), we saw no difference in the association of the insulin resistance score with T2D among BMI or waist strata (P_interaction > 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.

Original language	English
Pages (from-to)	4378-4387
Number of pages	10
Journal	Diabetes
Volume	63
Issue number	12
DOIs	https://doi.org/10.2337/db14-0319
Publication status	Published - 1 Dec 2014
Externally published	Yes

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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., ... The EPICInterAct Consortium (2014). Common genetic variants highlight the role of insulin resistance and body fat distribution in type 2 diabetes, independent of obesity. Diabetes, 63(12), 4378-4387. https://doi.org/10.2337/db14-0319

@article{d69406d9f96f4bb3b87849c5546dc5c6,

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

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], 20.03 [20.04, 20.01]; P = 0.004). This score was associated with lower BMI (20.01 [20.01, 20.0]; P = 0.02) and gluteofemoral fat mass (20.03 [20.05, 20.02; P = 1.4 3 1026 ) 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.",

author = "Scott, {Robert A.} and Tove Fall and Dorota Pasko and Adam Barker and Sharp, {Stephen J.} and Larraitz Arriola and Beverley Balkau and Aurelio Barricarte and In{\^e}s Barroso and Heiner Boeing and Franҫoise Clavel-Chapelon and Crowe, {Francesca L.} and Dekker, {Jacqueline M.} and Guy Fagherazzi and Ele Ferrannini and Forouhi, {Nita G.} and Franks, {Paul W.} and Diana Gavrila and Vilmantas Giedraitis and Sara Grioni and Groop, {Leif C.} and Rudolf Kaaks and Key, {Timothy J.} and Tilman K{\"u}hn and Lotta, {Luca A.} and Nilsson, {Peter M.} and Kim Overvad and Domenico Palli and Salvatore Panico and {Ram{\'o}n Quir{\'o}s}, J. and Olov Rolandsson and Nina Roswall and Carlotta Sacerdote and N{\'u}ria Sala and S{\'a}nchez, {Mar{\'i}a Jos{\'e}} and Schulze, {Matthias B.} and Afshan Siddiq and Nadia Slimani and Ivonne Sluijs and Spijkerman, {Annemieke M.W.} and Anne Tjonneland and Rosario Tumino and {Van Der A}, {Daphne L.} and Hanieh Yaghootkar and McCarthy, {Mark I.} and Semple, {Robert K.} and Elio Riboli and Mark Walker and Erik Ingelsson and Frayling, {Tim M.} and {The RISC Study Group} and {The EPICInterAct Consortium}",

note = "Publisher Copyright: {\textcopyright} 2014 by the American Diabetes Association.",

year = "2014",

month = dec,

day = "1",

doi = "10.2337/db14-0319",

language = "English",

volume = "63",

pages = "4378--4387",

journal = "Diabetes",

issn = "0012-1797",

publisher = "American Diabetes Association Inc.",

number = "12",

}

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, Kühn, T, Lotta, LA, Nilsson, PM, Overvad, K, Palli, D, Panico, S, Ramón Quirós, J, Rolandsson, O, Roswall, N, Sacerdote, C, Sala, N, Sánchez, MJ, Schulze, MB, Siddiq, A, Slimani, N, Sluijs, I, Spijkerman, AMW, Tjonneland, A, Tumino, R, Van Der A, DL, Yaghootkar, H, McCarthy, MI, Semple, RK, Riboli, E, Walker, M, Ingelsson, E, Frayling, TM, The RISC Study Group & The EPICInterAct Consortium 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

TY - JOUR

T1 - Common genetic variants highlight the role of insulin resistance and body fat distribution in type 2 diabetes, independent of obesity

AU - Scott, Robert A.

AU - Fall, Tove

AU - Pasko, Dorota

AU - Barker, Adam

AU - Sharp, Stephen J.

AU - Arriola, Larraitz

AU - Balkau, Beverley

AU - Barricarte, Aurelio

AU - Barroso, Inês

AU - Boeing, Heiner

AU - Clavel-Chapelon, Franҫoise

AU - Crowe, Francesca L.

AU - Dekker, Jacqueline M.

AU - Fagherazzi, Guy

AU - Ferrannini, Ele

AU - Forouhi, Nita G.

AU - Franks, Paul W.

AU - Gavrila, Diana

AU - Giedraitis, Vilmantas

AU - Grioni, Sara

AU - Groop, Leif C.

AU - Kaaks, Rudolf

AU - Key, Timothy J.

AU - Kühn, Tilman

AU - Lotta, Luca A.

AU - Nilsson, Peter M.

AU - Overvad, Kim

AU - Palli, Domenico

AU - Panico, Salvatore

AU - Ramón Quirós, J.

AU - Rolandsson, Olov

AU - Roswall, Nina

AU - Sacerdote, Carlotta

AU - Sala, Núria

AU - Sánchez, María José

AU - Schulze, Matthias B.

AU - Siddiq, Afshan

AU - Slimani, Nadia

AU - Sluijs, Ivonne

AU - Spijkerman, Annemieke M.W.

AU - Tjonneland, Anne

AU - Tumino, Rosario

AU - Van Der A, Daphne L.

AU - Yaghootkar, Hanieh

AU - McCarthy, Mark I.

AU - Semple, Robert K.

AU - Riboli, Elio

AU - Walker, Mark

AU - Ingelsson, Erik

AU - Frayling, Tim M.

AU - The RISC Study Group

AU - The EPICInterAct Consortium

PY - 2014/12/1

Y1 - 2014/12/1

N2 - 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], 20.03 [20.04, 20.01]; P = 0.004). This score was associated with lower BMI (20.01 [20.01, 20.0]; P = 0.02) and gluteofemoral fat mass (20.03 [20.05, 20.02; P = 1.4 3 1026 ) 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.

AB - 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], 20.03 [20.04, 20.01]; P = 0.004). This score was associated with lower BMI (20.01 [20.01, 20.0]; P = 0.02) and gluteofemoral fat mass (20.03 [20.05, 20.02; P = 1.4 3 1026 ) 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.

UR - http://www.scopus.com/inward/record.url?scp=84911949202&partnerID=8YFLogxK

U2 - 10.2337/db14-0319

DO - 10.2337/db14-0319

M3 - Article

C2 - 24947364

AN - SCOPUS:84911949202

SN - 0012-1797

VL - 63

SP - 4378

EP - 4387

JO - Diabetes

JF - Diabetes

IS - 12

ER -

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

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