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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 (? 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 ?-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.

SUBMITTER: Scott RA

PROVIDER: S-EPMC4241116 | biostudies-literature | 2014 Dec

REPOSITORIES: biostudies-literature

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

Scott Robert A RA Fall Tove T Pasko Dorota D Barker Adam A Sharp Stephen J SJ Arriola Larraitz L Balkau Beverley B Barricarte Aurelio A Barroso Inês I Boeing Heiner H Clavel-Chapelon Françoise F Crowe Francesca L FL Dekker Jacqueline M JM Fagherazzi Guy G Ferrannini Ele E Forouhi Nita G NG Franks Paul W PW Gavrila Diana D Giedraitis Vilmantas V Grioni Sara S Groop Leif C LC Kaaks Rudolf R Key Timothy J TJ Kühn Tilman T Lotta Luca A LA Nilsson Peter M PM Overvad Kim K Palli Domenico D Panico Salvatore S Quirós J Ramón JR Rolandsson Olov O Roswall Nina N Sacerdote Carlotta C Sala Núria N Sánchez María-José MJ Schulze Matthias B MB Siddiq Afshan A Slimani Nadia N Sluijs Ivonne I Spijkerman Annemieke Mw AM Tjonneland Anne A Tumino Rosario R van der A Daphne L DL Yaghootkar Hanieh H McCarthy Mark I MI Semple Robert K RK Riboli Elio E Walker Mark M Ingelsson Erik E Frayling Tim M TM Savage David B DB Langenberg Claudia C Wareham Nicholas J NJ

Diabetes 20140619 12

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 indivi ...[more]

PMID: 24947364

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Project description:Tetrahydrobiopterin (BH4) is an essential cofactor for several metabolic enzymes, including the aromatic amino acid hydroxylases, alkylglycerol mono-oxygenase and NO synthases. BH4 deficiency due to an autosomal recessive defect in its biosynthetic enzyme 6-pyruvoyltetrahydropterin synthase (PTPS, encoded by the PTS gene) leads to a variant form of hyperphenylalaninemia concomitant with severe deficiency of brain monoamine neurotransmitters. In contrast, augmentation of BH4 by pharmacological supplementation or stimulation of its biosynthesis is thought to correct eNOS dysfunction, to protect from (cardio) vascular disease and/or to prevent from abdominal obesity and development of the metabolic syndrome. We have previously reported that complete Pts knock-out (ko) mice die after birth (Elzaouk et al JBC 2003). Here we generated a murine Pts-knock-in (ki) allele expressing a PTPS-p.Arg15Cys mutant enzyme with low residual activity (12% of wild-type in vitro) and investigated heterozygous Pts-ko/wt, homozygous Pts-ki/ki and compound heterozygous Pts-ki/ko mutant mice. All mice were viable and, depending on the severity of the Pts alleles, exhibited up to 90% reduction of PTPS activity in liver and brain tissues concomitant with high neopterin, but neither an elevation of blood L-Phe, nor a decrease in brain monoamine neurotransmitters dopamine or serotonin. Upon a standard systemic and comprehensive phenotyping of Pts-ki/ki mice, we found alterations in energy metabolites with reduced body mass, higher fat content, lower lean mass, and increased blood glucose and cholesterol in mutant animals. Furthermore, heterozygous Pts-ko/wt and/or homozygous Pts-ki/ki mice exhibited increased body weight and elevated intra-abdominal fat tissue when fed with normal chow or high fat diet. We conclude that a reduced BH4-biosynthetic activity in mice leads to abnormal body fat distribution and abdominal obesity potentially through a mildly compromised eNOS function.

Dataset Information

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

Publications

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

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