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 - 2010/4
Y1 - 2010/4
N2 - OBJECTIVE - Phosphoinositide 3-kinase (PI3K) is a major effector in insulin signaling. rs361072, located in the promoter of the gene (PIK3CB) for the p110β 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 p110β and p85α 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 p85α:p110β protein ratio (Padd = 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 p85α:p110β 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 p110β 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 p110β and p85α 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 p85α:p110β protein ratio (Padd = 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 p85α:p110β 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
SN - 0012-1797
VL - 59
SP - 1108
EP - 1112
JO - Diabetes
JF - Diabetes
IS - 4
ER -
