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

Scott, Robert A; Fall, Tove; Pasko, Dorota; Barker, Adam; Sharp, Stephen J; Arriola, Larraitz; Balkau, Beverley; Barricarte, Aurelio; Barroso, Inês and Boeing, Heiner, et al. (2014) In Diabetes 63(12). p.4378-4387
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... (More)
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. (Less)
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type
Contribution to journal
publication status
published
subject
in
Diabetes
volume
63
issue
12
pages
4378 - 4387
publisher
American Diabetes Association Inc.
external identifiers
  • pmid:24947364
  • wos:000345335500046
  • scopus:84965094470
ISSN
1939-327X
DOI
10.2337/db14-0319
language
English
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yes
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01391ca7-6573-4058-a19f-2564accd2f00 (old id 4527891)
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http://www.ncbi.nlm.nih.gov/pubmed/24947364?dopt=Abstract
date added to LUP
2014-07-06 19:36:26
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2017-01-22 03:11:16
@article{01391ca7-6573-4058-a19f-2564accd2f00,
  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 Fall, Tove and Pasko, Dorota and Barker, Adam and Sharp, Stephen J and Arriola, Larraitz and Balkau, Beverley and Barricarte, Aurelio and Barroso, Inês and Boeing, Heiner and Clavel-Chapelon, Françoise and Crowe, Francesca L and Dekker, Jacqueline M and Fagherazzi, Guy and Ferraninini, Ele and Forouhi, Nita G and Franks, Paul and Gavrila, Diana and Giedraitis, Vilmantas and Grioni, Sara and Groop, Leif and Kaaks, Rudolf and Key, Timothy J and Kühn, Tilman and Lotta, Luca and Nilsson, Peter and Overvad, Kim and Palli, Domenico and Panico, Salvatore and Quirós, J Ramón and Rolandsson, Olov and Roswall, Nina and Sacerdote, Carlotta and Sala, Núria and Sánchez, María-José and Schulze, Matthias B and Siddiq, Afshan and Slimani, Nadia and Sluijs, Ivonne and Spijkerman, Annemieke Mw and Tjonneland, Anne and Tumino, Rosario and van der A, Daphne L and Yaghootkar, Hanieh and McCarthy, Mark I and Semple, Robert K and Riboli, Elio and Walker, Mark and Ingelsson, Erik and Frayling, Tim M and Savage, David B and Langenberg, Claudia and Wareham, Nicholas J},
  issn         = {1939-327X},
  language     = {eng},
  number       = {12},
  pages        = {4378--4387},
  publisher    = {American Diabetes Association Inc.},
  series       = {Diabetes},
  title        = {Common genetic variants highlight the role of insulin resistance and body fat distribution in type 2 diabetes, independently of obesity.},
  url          = {http://dx.doi.org/10.2337/db14-0319},
  volume       = {63},
  year         = {2014},
}