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


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.
Ribel-Madsen
Rasmus
R
Steno Diabetes Center, Gentofte, Denmark. rrma@steno.dk
Poulsen
Pernille
P
Holmkvist
Johan
J
Mortensen
Brynjulf
B
Grarup
Niels
N
Friedrichsen
Martin
M
Jørgensen
Torben
T
Lauritzen
Torsten
T
Wojtaszewski
Jørgen F P
JF
Pedersen
Oluf
O
Hansen
Torben
T
Vaag
Allan
A
D000328:Adult; D015992:Body Mass Index; D058534:Class I Phosphatidylinositol 3-Kinases; D003924:Diabetes Mellitus, Type 2 / Q000235:genetics; D005260:Female; D015971:Gene Expression Regulation, Enzymologic; D005838:Genotype; D005947:Glucose / Q000378:metabolism*; D018149:Glucose Intolerance / Q000235:genetics*; D006801:Humans; D018482:Muscle, Skeletal / Q000187:drug effects / Q000502:physiology*; D019869:Phosphatidylinositol 3-Kinases / Q000235:genetics*; D021122:Protein Subunits / Q000235:genetics; D012016:Reference Values; D014429:Twins, Dizygotic; D014430:Twins, Monozygotic
D021122:Protein Subunits; D019869:Phosphatidylinositol 3-Kinases; D058534:Class I Phosphatidylinositol 3-Kinases; C497132:PIK3CB protein, human; D005947:Glucose