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Differential aetiology and impact of phosphoinositide 3-kinase (PI3K) and Akt signalling in skeletal muscle on in vivo insulin action

Friedrichsen, M.; Poulsen, P.; Richter, E. A.; Hansen, B. F.; Birk, J. B.; Ribel-Madsen, R.; Stender-Petersen, K.; Nilsson, E.; Beck-Nielsen, H. and Vaag, Allan LU , et al. (2010) In Diabetologia 53(9). p.1998-2007
Abstract
Aims/hypothesis Insulin resistance in skeletal muscle is a key factor in the development of type 2 diabetes and although some studies indicate that this could be partly attributed to reduced content and activity of various proximal and distal insulin signalling molecules, consensus is lacking. We therefore aimed to investigate the regulation of proximal insulin signalling in skeletal muscle and its effect on glucose metabolism in a large non-diabetic population. Methods We examined 184 non-diabetic twins with gold-standard techniques including the euglycaemic-hyperinsulinaemic clamp. Insulin signalling was evaluated at three key levels, i.e. the insulin receptor, IRS-1 and V-akt murine thymoma viral oncogene (Akt) levels, employing kinase... (More)
Aims/hypothesis Insulin resistance in skeletal muscle is a key factor in the development of type 2 diabetes and although some studies indicate that this could be partly attributed to reduced content and activity of various proximal and distal insulin signalling molecules, consensus is lacking. We therefore aimed to investigate the regulation of proximal insulin signalling in skeletal muscle and its effect on glucose metabolism in a large non-diabetic population. Methods We examined 184 non-diabetic twins with gold-standard techniques including the euglycaemic-hyperinsulinaemic clamp. Insulin signalling was evaluated at three key levels, i.e. the insulin receptor, IRS-1 and V-akt murine thymoma viral oncogene (Akt) levels, employing kinase assays and phospho-specific western blotting. Results Proximal insulin signalling was not associated with obesity, age or sex. However, birthweight was positively associated with IRS-1-associated phosphoinositide 3-kinase (PI3K; IRS-1-PI3K) activity (p=0.04); maximal aerobic capacity ((V) over dotO(2max)), paradoxically, was negatively associated with IRS-1-PI3K (p=0.02) and Akt2 activity (p=0.01). Additionally, we found low heritability estimates for most measures of insulin signalling activity. Glucose disposal was positively associated with Akt-308 phosphorylation (p<0.001) and Akt2 activity (p=0.05), but not with insulin receptor tyrosine kinase or IRS-1-PI3K activity. Conclusions/interpretation With the exception of birthweight, 'classical' modifiers of insulin action, including genetics, age, sex, obesity and (V) over dotO(2max), do not seem to mediate their most central effects on whole-body insulin sensitivity through modulation of proximal insulin signalling in skeletal muscle. We also demonstrated an association between Akt activity and in vivo insulin sensitivity, suggesting a role of Akt in control of in vivo insulin resistance and potentially in type 2 diabetes. (Less)
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published
subject
keywords
Insulin, Insulin action, Human, Assay methods, Hormone receptors, Insulin sensitivity, resistance
in
Diabetologia
volume
53
issue
9
pages
1998 - 2007
publisher
Springer Verlag
external identifiers
  • wos:000281012200024
  • scopus:77955552494
ISSN
1432-0428
DOI
10.1007/s00125-010-1795-8
language
English
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yes
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467f9920-2b9b-4f1e-95f9-42ea7bf9ba3c (old id 1673908)
date added to LUP
2010-09-22 15:02:00
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2018-05-29 10:43:21
@article{467f9920-2b9b-4f1e-95f9-42ea7bf9ba3c,
  abstract     = {Aims/hypothesis Insulin resistance in skeletal muscle is a key factor in the development of type 2 diabetes and although some studies indicate that this could be partly attributed to reduced content and activity of various proximal and distal insulin signalling molecules, consensus is lacking. We therefore aimed to investigate the regulation of proximal insulin signalling in skeletal muscle and its effect on glucose metabolism in a large non-diabetic population. Methods We examined 184 non-diabetic twins with gold-standard techniques including the euglycaemic-hyperinsulinaemic clamp. Insulin signalling was evaluated at three key levels, i.e. the insulin receptor, IRS-1 and V-akt murine thymoma viral oncogene (Akt) levels, employing kinase assays and phospho-specific western blotting. Results Proximal insulin signalling was not associated with obesity, age or sex. However, birthweight was positively associated with IRS-1-associated phosphoinositide 3-kinase (PI3K; IRS-1-PI3K) activity (p=0.04); maximal aerobic capacity ((V) over dotO(2max)), paradoxically, was negatively associated with IRS-1-PI3K (p=0.02) and Akt2 activity (p=0.01). Additionally, we found low heritability estimates for most measures of insulin signalling activity. Glucose disposal was positively associated with Akt-308 phosphorylation (p&lt;0.001) and Akt2 activity (p=0.05), but not with insulin receptor tyrosine kinase or IRS-1-PI3K activity. Conclusions/interpretation With the exception of birthweight, 'classical' modifiers of insulin action, including genetics, age, sex, obesity and (V) over dotO(2max), do not seem to mediate their most central effects on whole-body insulin sensitivity through modulation of proximal insulin signalling in skeletal muscle. We also demonstrated an association between Akt activity and in vivo insulin sensitivity, suggesting a role of Akt in control of in vivo insulin resistance and potentially in type 2 diabetes.},
  author       = {Friedrichsen, M. and Poulsen, P. and Richter, E. A. and Hansen, B. F. and Birk, J. B. and Ribel-Madsen, R. and Stender-Petersen, K. and Nilsson, E. and Beck-Nielsen, H. and Vaag, Allan and Wojtaszewski, J. F. P.},
  issn         = {1432-0428},
  keyword      = {Insulin,Insulin action,Human,Assay methods,Hormone receptors,Insulin sensitivity,resistance},
  language     = {eng},
  number       = {9},
  pages        = {1998--2007},
  publisher    = {Springer Verlag},
  series       = {Diabetologia},
  title        = {Differential aetiology and impact of phosphoinositide 3-kinase (PI3K) and Akt signalling in skeletal muscle on in vivo insulin action},
  url          = {http://dx.doi.org/10.1007/s00125-010-1795-8},
  volume       = {53},
  year         = {2010},
}