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

Robert A Scott; Tove Fall; Dorota Pasko; Adam Barker; Stephen J Sharp; Larraitz Arriola; Beverley Balkau; Aurelio Barricarte; Inês Barroso; Heiner Boeing; Françoise Clavel-Chapelon; Francesca L Crowe; Jacqueline M Dekker; Guy Fagherazzi; Ele Ferraninini; Nita G Forouhi; Paul W Franks; Diana Gavrila; Vilmantas Giedraitis; Sara Grioni; Leif C Groop; Rudolf Kaaks; Timothy J Key; Tilman Kühn; Luca 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 Mw 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

doi:10.2337/db14-0319

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

Robert A Scott, Tove Fall, Dorota Pasko, Adam Barker, Stephen J Sharp, Larraitz Arriola, Beverley Balkau, Aurelio Barricarte, Inês Barroso, Heiner Boeing, Françoise Clavel-Chapelon, Francesca L Crowe, Jacqueline M Dekker, Guy Fagherazzi, Ele Ferraninini, Nita G Forouhi, Paul W Franks, Diana Gavrila, Vilmantas Giedraitis, Sara GrioniLeif C Groop, Rudolf Kaaks, Timothy J Key, Tilman Kühn, Luca 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 Mw 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

Research output: Contribution to journal › Journal article › Research › peer-review

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Abstract

We aimed to validate genetic variants as instruments for insulin resistance and secretion, to characterise their association with intermediate phenotypes, and to investigate their role in T2D risk among normal-weight, overweight and obese individuals.We investigated the association of genetic scores with euglycaemic-hyperinsulinaemic clamp- and OGTT-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=1.4x10(-6)), and with higher ALT (0.02[0.01,0.03];p=0.002) and gamma-GT (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.

Original language	English
Journal	Diabetes
Volume	63
Issue number	12
Pages (from-to)	4378-4387
Number of pages	10
ISSN	0012-1797
DOIs	https://doi.org/10.2337/db14-0319
Publication status	Published - 19 Jun 2014

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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., Ferraninini, E., Forouhi, N. G., Franks, P. W., Gavrila, D., Giedraitis, V., ... 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, 63(12), 4378-4387. https://doi.org/10.2337/db14-0319

@article{2bab4e10555a47d685866365d5a83ba8,

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

abstract = "We aimed to validate genetic variants as instruments for insulin resistance and secretion, to characterise their association with intermediate phenotypes, and to investigate their role in T2D risk among normal-weight, overweight and obese individuals.We investigated the association of genetic scores with euglycaemic-hyperinsulinaemic clamp- and OGTT-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=1.4x10(-6)), and with higher ALT (0.02[0.01,0.03];p=0.002) and gamma-GT (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 Fran{\c c}oise Clavel-Chapelon and Crowe, {Francesca L} and Dekker, {Jacqueline M} and Guy Fagherazzi and Ele Ferraninini 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 Luca Lotta and Nilsson, {Peter M} and Kim Overvad and Domenico Palli and Salvatore Panico and Quir{\'o}s, {J Ram{\'o}n} and Olov Rolandsson and Nina Roswall and Carlotta Sacerdote and N{\'u}ria Sala and Mar{\'i}a-Jos{\'e} S{\'a}nchez and Schulze, {Matthias B} and Afshan Siddiq and Nadia Slimani and Ivonne Sluijs and Spijkerman, {Annemieke Mw} 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}",

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

year = "2014",

month = jun,

day = "19",

doi = "10.2337/db14-0319",

language = "English",

volume = "63",

pages = "4378--4387",

journal = "Diabetes",

issn = "0012-1797",

publisher = "American Diabetes Association",

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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, Ferraninini, E, Forouhi, NG, Franks, PW, Gavrila, D, Giedraitis, V, Grioni, S, Groop, LC, Kaaks, R, Key, TJ, Kühn, T, Lotta, L, Nilsson, PM, Overvad, K, Palli, D, Panico, S, Quirós, JR, Rolandsson, O, Roswall, N, Sacerdote, C, Sala, N, Sánchez, M-J, 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 & 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

TY - JOUR

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

AU - Crowe, Francesca L

AU - Dekker, Jacqueline M

AU - Fagherazzi, Guy

AU - Ferraninini, 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

AU - Nilsson, Peter M

AU - Overvad, Kim

AU - Palli, Domenico

AU - Panico, Salvatore

AU - Quirós, J Ramón

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 Mw

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

PY - 2014/6/19

Y1 - 2014/6/19

N2 - We aimed to validate genetic variants as instruments for insulin resistance and secretion, to characterise their association with intermediate phenotypes, and to investigate their role in T2D risk among normal-weight, overweight and obese individuals.We investigated the association of genetic scores with euglycaemic-hyperinsulinaemic clamp- and OGTT-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=1.4x10(-6)), and with higher ALT (0.02[0.01,0.03];p=0.002) and gamma-GT (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 characterise their association with intermediate phenotypes, and to investigate their role in T2D risk among normal-weight, overweight and obese individuals.We investigated the association of genetic scores with euglycaemic-hyperinsulinaemic clamp- and OGTT-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=1.4x10(-6)), and with higher ALT (0.02[0.01,0.03];p=0.002) and gamma-GT (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.

U2 - 10.2337/db14-0319

DO - 10.2337/db14-0319

M3 - Journal article

C2 - 24947364

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, independently of obesity

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