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Impact of rs361072 in the Phosphoinositide 3-Kinase p110 beta Gene on Whole-Body Glucose Metabolism and Subunit Protein Expression in Skeletal Muscle

Ribel-Madsen, Rasmus; Poulsen, Pernille; Holmkvist, Johan; Mortensen, Brynjulf; Grarup, Niels; Friedrichsen, Martin; Jorgensen, Torben; Lauritzen, Torsten; Wojtaszewski, Jorgen F. P. and Pedersen, Oluf, et al. (2010) In Diabetes 59(4). p.1108-1112
Abstract
OBJECTIVE-Phosphoinositide 3-kinase (PI3K) is a major effector in insulin signaling. rs361072, located in the promoter of the gene (PIK3CB) for the p110 beta 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 p110... (More)
OBJECTIVE-Phosphoinositide 3-kinase (PI3K) is a major effector in insulin signaling. rs361072, located in the promoter of the gene (PIK3CB) for the p110 beta 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 p110 beta and p85 alpha 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 p85 alpha:p110 beta 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 p85 alpha:p110 beta ratio and lower hepatic glucose production at high plasma insulin levels. However, no impact on type 2 diabetes prevalence was found. Diabetes 59:1108-1112, 2010 (Less)
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Contribution to journal
publication status
published
subject
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Diabetes
volume
59
issue
4
pages
1108 - 1112
publisher
American Diabetes Association Inc.
external identifiers
  • wos:000276601200038
  • scopus:77951172610
ISSN
1939-327X
DOI
10.2337/db09-1359
language
English
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yes
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b94e76ac-78a3-4e7d-8f6f-85f241abba51 (old id 1603172)
date added to LUP
2010-05-19 09:48:10
date last changed
2018-05-29 10:46:12
@article{b94e76ac-78a3-4e7d-8f6f-85f241abba51,
  abstract     = {OBJECTIVE-Phosphoinositide 3-kinase (PI3K) is a major effector in insulin signaling. rs361072, located in the promoter of the gene (PIK3CB) for the p110 beta 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 p110 beta and p85 alpha 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 p85 alpha:p110 beta 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 p85 alpha:p110 beta ratio and lower hepatic glucose production at high plasma insulin levels. However, no impact on type 2 diabetes prevalence was found. Diabetes 59:1108-1112, 2010},
  author       = {Ribel-Madsen, Rasmus and Poulsen, Pernille and Holmkvist, Johan and Mortensen, Brynjulf and Grarup, Niels and Friedrichsen, Martin and Jorgensen, Torben and Lauritzen, Torsten and Wojtaszewski, Jorgen F. P. and Pedersen, Oluf and Hansen, Torben and Vaag, Allan},
  issn         = {1939-327X},
  language     = {eng},
  number       = {4},
  pages        = {1108--1112},
  publisher    = {American Diabetes Association Inc.},
  series       = {Diabetes},
  title        = {Impact of rs361072 in the Phosphoinositide 3-Kinase p110 beta Gene on Whole-Body Glucose Metabolism and Subunit Protein Expression in Skeletal Muscle},
  url          = {http://dx.doi.org/10.2337/db09-1359},
  volume       = {59},
  year         = {2010},
}