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

Martin Friedrichsen; P. Poulsen; Erik Richter; B. F. Hansen; Jesper Bratz Birk; R. Ribel-Madsen; K. Stender-Petersen; E. Nilsson; H. Beck-Nielsen; A. Vaag; Jørgen Wojtaszewski

doi:10.1007/s00125-010-1795-8

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

Martin Friedrichsen, P. Poulsen, Erik Richter, B. F. Hansen, Jesper Bratz Birk, R. Ribel-Madsen, K. Stender-Petersen, E. Nilsson, H. Beck-Nielsen, A. Vaag, Jørgen Wojtaszewski

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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 ( VO_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 ( VO_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.

Original language	English
Journal	Diabetologia
Volume	53
Issue number	9
Pages (from-to)	1998-2007
Number of pages	10
ISSN	0012-186X
DOIs	https://doi.org/10.1007/s00125-010-1795-8
Publication status	Published - Sept 2010

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Friedrichsen, M., Poulsen, P., Richter, E., Hansen, B. F., Birk, J. B., Ribel-Madsen, R., Stender-Petersen, K., Nilsson, E., Beck-Nielsen, H., Vaag, A., & Wojtaszewski, J. (2010). Differential aetiology and impact of phosphoinositide 3-kinase (PI3K) and Akt signalling in skeletal muscle on in vivo insulin action. Diabetologia, 53(9), 1998-2007. https://doi.org/10.1007/s00125-010-1795-8

Friedrichsen, M, Poulsen, P, Richter, E, Hansen, BF, Birk, JB, Ribel-Madsen, R, Stender-Petersen, K, Nilsson, E, Beck-Nielsen, H, Vaag, A & Wojtaszewski, J 2010, 'Differential aetiology and impact of phosphoinositide 3-kinase (PI3K) and Akt signalling in skeletal muscle on in vivo insulin action', Diabetologia, vol. 53, no. 9, pp. 1998-2007. https://doi.org/10.1007/s00125-010-1795-8

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

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 ( VO2max) , 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 ( VO2max), 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 = "Martin Friedrichsen and P. Poulsen and Erik Richter and Hansen, {B. F.} and Birk, {Jesper Bratz} and R. Ribel-Madsen and K. Stender-Petersen and E. Nilsson and H. Beck-Nielsen and A. Vaag and J{\o}rgen Wojtaszewski",

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T1 - Differential aetiology and impact of phosphoinositide 3-kinase (PI3K) and Akt signalling in skeletal muscle on in vivo insulin action

AU - Friedrichsen, Martin

AU - Poulsen, P.

AU - Richter, Erik

AU - Hansen, B. F.

AU - Birk, Jesper Bratz

AU - Ribel-Madsen, R.

AU - Stender-Petersen, K.

AU - Nilsson, E.

AU - Beck-Nielsen, H.

AU - Vaag, A.

AU - Wojtaszewski, Jørgen

N1 - CURIS 2010 5200 085

PY - 2010/9

Y1 - 2010/9

N2 - 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 ( VO2max) , 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 ( VO2max), 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.

AB - 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 ( VO2max) , 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 ( VO2max), 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.

U2 - 10.1007/s00125-010-1795-8

DO - 10.1007/s00125-010-1795-8

M3 - Journal article

C2 - 20512309

SN - 0012-186X

VL - 53

SP - 1998

EP - 2007

JO - Diabetologia

JF - Diabetologia

IS - 9

ER -

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

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