TY - JOUR

T1 - Impact of rs361072 in the phosphoinositide 3-kinase p110beta gene on whole-body glucose metabolism and subunit protein expression in skeletal muscle

AU - Ribel-Madsen, Rasmus

AU - Poulsen, Pernille

AU - Holmkvist, Johan

AU - Mortensen, Brynjulf

AU - Grarup, Niels

AU - Friedrichsen, Martin

AU - Jørgensen, Torben

AU - Lauritzen, Torsten

AU - Wojtaszewski, Jørgen

AU - Pedersen, Oluf

AU - Hansen, Torben

AU - Vaag, Allan

N1 - Keywords: 1-Phosphatidylinositol 3-Kinase; Adult; Body Mass Index; Diabetes Mellitus, Type 2; Female; Gene Expression Regulation, Enzymologic; Genotype; Glucose; Glucose Intolerance; Humans; Muscle, Skeletal; Protein Subunits; Reference Values; Twins, Dizygotic; Twins, Monozygotic

PY - 2010

Y1 - 2010

N2 - OBJECTIVE: Phosphoinositide 3-kinase (PI3K) is a major effector in insulin signaling. rs361072, located in the promoter of the gene (PIK3CB) for the p110beta subunit, has previously been found to be associated with homeostasis model assessment for insulin resistance (HOMA-IR) in obese subjects. The aim was to investigate the influence of rs361072 on in vivo glucose metabolism, skeletal muscle PI3K subunit protein levels, and type 2 diabetes. RESEARCH DESIGN AND METHODS: The functional role of rs361072 was studied in 196 Danish healthy adult twins. Peripheral and hepatic insulin sensitivity was assessed by a euglycemic-hyperinsulinemic clamp. Basal and insulin-stimulated biopsies were taken from the vastus lateralis muscle, and tissue p110beta and p85alpha proteins were measured by Western blotting. The genetic association with type 2 diabetes and quantitative metabolic traits was investigated in 9,316 Danes with glucose tolerance ranging from normal to overt type 2 diabetes. RESULTS: While hepatic insulin resistance was similar in the fasting state, carriers of the minor G allele had lower hepatic glucose output (per-allele effect: -16%, P(add) = 0.004) during high physiological insulin infusion. rs361072 did not associate with insulin-stimulated peripheral glucose disposal despite a decreased muscle p85alpha:p110beta protein ratio (P(add) = 0.03) in G allele carriers. No association with HOMA-IR or type 2 diabetes (odds ratio 1.07, P = 0.5) was identified, and obesity did not interact with rs361072 on these traits. CONCLUSIONS: Our study suggests that the minor G allele of PIK3CB rs361072 associates with decreased muscle p85alpha:p110beta ratio and lower hepatic glucose production at high plasma insulin levels. However, no impact on type 2 diabetes prevalence was found.

AB - OBJECTIVE: Phosphoinositide 3-kinase (PI3K) is a major effector in insulin signaling. rs361072, located in the promoter of the gene (PIK3CB) for the p110beta subunit, has previously been found to be associated with homeostasis model assessment for insulin resistance (HOMA-IR) in obese subjects. The aim was to investigate the influence of rs361072 on in vivo glucose metabolism, skeletal muscle PI3K subunit protein levels, and type 2 diabetes. RESEARCH DESIGN AND METHODS: The functional role of rs361072 was studied in 196 Danish healthy adult twins. Peripheral and hepatic insulin sensitivity was assessed by a euglycemic-hyperinsulinemic clamp. Basal and insulin-stimulated biopsies were taken from the vastus lateralis muscle, and tissue p110beta and p85alpha proteins were measured by Western blotting. The genetic association with type 2 diabetes and quantitative metabolic traits was investigated in 9,316 Danes with glucose tolerance ranging from normal to overt type 2 diabetes. RESULTS: While hepatic insulin resistance was similar in the fasting state, carriers of the minor G allele had lower hepatic glucose output (per-allele effect: -16%, P(add) = 0.004) during high physiological insulin infusion. rs361072 did not associate with insulin-stimulated peripheral glucose disposal despite a decreased muscle p85alpha:p110beta protein ratio (P(add) = 0.03) in G allele carriers. No association with HOMA-IR or type 2 diabetes (odds ratio 1.07, P = 0.5) was identified, and obesity did not interact with rs361072 on these traits. CONCLUSIONS: Our study suggests that the minor G allele of PIK3CB rs361072 associates with decreased muscle p85alpha:p110beta ratio and lower hepatic glucose production at high plasma insulin levels. However, no impact on type 2 diabetes prevalence was found.

U2 - 10.2337/db09-1359

DO - 10.2337/db09-1359

M3 - Journal article

C2 - 20107106

VL - 59

SP - 1108

EP - 1112

JO - Diabetes

JF - Diabetes

SN - 0012-1797

IS - 4

ER -