Amino acids are necessary for the insulin-induced activation of mTOR/S6K1 signaling and protein synthesis in healthy and insulin resistant human skeletal muscle

Micah J. Drummond, Jill A. Bell, Satoshi Fujita, Hans C. Dreyer, Erin L. Glynn, Elena Volpi, Blake Rasmussen

Research output: Contribution to journalArticle

42 Citations (Scopus)

Abstract

Background: Amino acids (AA) activate the mammalian target of rapamycin (mTOR) signaling pathway but overactivation has a negative feedback effect on insulin signaling which may lead to insulin resistance and type 2 diabetes (T2DM). Purpose: To determine the effect of reduced AA concentrations on mTOR and insulin signaling during increased nutrient and insulin availability. Methods: Six control and six T2DM subjects were studied at baseline and following a 5 h AA lowering high energy and insulin clamp. Stable isotopic techniques in combination with femoral catheterizations were used to measure AA kinetics across the leg while muscle biopsies were used to measure mTOR and insulin signaling proteins using immunoblotting techniques. Results: AA concentrations decreased by ∼30-60% in both groups (p < 0.05). Phospho-mTOR, S6K1, eEF2, and eIF2α were unchanged in both groups following the clamp (p > 0.05). In T2DM subjects, IRS-1 serine phosphorylation was unchanged while phospho-AMPKα decreased and phospho-Akt, phospho-AS160 and glucose uptake increased following the clamp (p < 0.05). In comparison, AA concentrations were maintained in a separate group during an insulin infusion. In this group, phospho-Akt, mTOR and S6K1 (n = 4) increased. Conclusion: Amino acids are necessary for insulin-induced activation of mTOR signaling and protein synthesis in both healthy and insulin resistant skeletal muscle.

Original languageEnglish (US)
Pages (from-to)447-456
Number of pages10
JournalClinical Nutrition
Volume27
Issue number3
DOIs
StatePublished - Jun 2008

Fingerprint

Sirolimus
Skeletal Muscle
Insulin
Amino Acids
Proteins
TOR Serine-Threonine Kinases
AMP-Activated Protein Kinases
Thigh
Immunoblotting
Catheterization
Serine
Type 2 Diabetes Mellitus
Insulin Resistance
Leg
Phosphorylation
Biopsy
Glucose
Food
Muscles

Keywords

  • Adenosine 5′-monophosphate-activated protein kinase
  • Amino acid availability
  • Mammalian target of rapamycin
  • Muscle protein synthesis

ASJC Scopus subject areas

  • Critical Care and Intensive Care Medicine
  • Endocrinology, Diabetes and Metabolism
  • Gastroenterology
  • Health Professions(all)
  • Medicine (miscellaneous)

Cite this

Amino acids are necessary for the insulin-induced activation of mTOR/S6K1 signaling and protein synthesis in healthy and insulin resistant human skeletal muscle. / Drummond, Micah J.; Bell, Jill A.; Fujita, Satoshi; Dreyer, Hans C.; Glynn, Erin L.; Volpi, Elena; Rasmussen, Blake.

In: Clinical Nutrition, Vol. 27, No. 3, 06.2008, p. 447-456.

Research output: Contribution to journalArticle

@article{4fde241a7f8343b181d6c0471dece7e1,
title = "Amino acids are necessary for the insulin-induced activation of mTOR/S6K1 signaling and protein synthesis in healthy and insulin resistant human skeletal muscle",
abstract = "Background: Amino acids (AA) activate the mammalian target of rapamycin (mTOR) signaling pathway but overactivation has a negative feedback effect on insulin signaling which may lead to insulin resistance and type 2 diabetes (T2DM). Purpose: To determine the effect of reduced AA concentrations on mTOR and insulin signaling during increased nutrient and insulin availability. Methods: Six control and six T2DM subjects were studied at baseline and following a 5 h AA lowering high energy and insulin clamp. Stable isotopic techniques in combination with femoral catheterizations were used to measure AA kinetics across the leg while muscle biopsies were used to measure mTOR and insulin signaling proteins using immunoblotting techniques. Results: AA concentrations decreased by ∼30-60{\%} in both groups (p < 0.05). Phospho-mTOR, S6K1, eEF2, and eIF2α were unchanged in both groups following the clamp (p > 0.05). In T2DM subjects, IRS-1 serine phosphorylation was unchanged while phospho-AMPKα decreased and phospho-Akt, phospho-AS160 and glucose uptake increased following the clamp (p < 0.05). In comparison, AA concentrations were maintained in a separate group during an insulin infusion. In this group, phospho-Akt, mTOR and S6K1 (n = 4) increased. Conclusion: Amino acids are necessary for insulin-induced activation of mTOR signaling and protein synthesis in both healthy and insulin resistant skeletal muscle.",
keywords = "Adenosine 5′-monophosphate-activated protein kinase, Amino acid availability, Mammalian target of rapamycin, Muscle protein synthesis",
author = "Drummond, {Micah J.} and Bell, {Jill A.} and Satoshi Fujita and Dreyer, {Hans C.} and Glynn, {Erin L.} and Elena Volpi and Blake Rasmussen",
year = "2008",
month = "6",
doi = "10.1016/j.clnu.2008.01.012",
language = "English (US)",
volume = "27",
pages = "447--456",
journal = "Clinical Nutrition",
issn = "0261-5614",
publisher = "Churchill Livingstone",
number = "3",

}

TY - JOUR

T1 - Amino acids are necessary for the insulin-induced activation of mTOR/S6K1 signaling and protein synthesis in healthy and insulin resistant human skeletal muscle

AU - Drummond, Micah J.

AU - Bell, Jill A.

AU - Fujita, Satoshi

AU - Dreyer, Hans C.

AU - Glynn, Erin L.

AU - Volpi, Elena

AU - Rasmussen, Blake

PY - 2008/6

Y1 - 2008/6

N2 - Background: Amino acids (AA) activate the mammalian target of rapamycin (mTOR) signaling pathway but overactivation has a negative feedback effect on insulin signaling which may lead to insulin resistance and type 2 diabetes (T2DM). Purpose: To determine the effect of reduced AA concentrations on mTOR and insulin signaling during increased nutrient and insulin availability. Methods: Six control and six T2DM subjects were studied at baseline and following a 5 h AA lowering high energy and insulin clamp. Stable isotopic techniques in combination with femoral catheterizations were used to measure AA kinetics across the leg while muscle biopsies were used to measure mTOR and insulin signaling proteins using immunoblotting techniques. Results: AA concentrations decreased by ∼30-60% in both groups (p < 0.05). Phospho-mTOR, S6K1, eEF2, and eIF2α were unchanged in both groups following the clamp (p > 0.05). In T2DM subjects, IRS-1 serine phosphorylation was unchanged while phospho-AMPKα decreased and phospho-Akt, phospho-AS160 and glucose uptake increased following the clamp (p < 0.05). In comparison, AA concentrations were maintained in a separate group during an insulin infusion. In this group, phospho-Akt, mTOR and S6K1 (n = 4) increased. Conclusion: Amino acids are necessary for insulin-induced activation of mTOR signaling and protein synthesis in both healthy and insulin resistant skeletal muscle.

AB - Background: Amino acids (AA) activate the mammalian target of rapamycin (mTOR) signaling pathway but overactivation has a negative feedback effect on insulin signaling which may lead to insulin resistance and type 2 diabetes (T2DM). Purpose: To determine the effect of reduced AA concentrations on mTOR and insulin signaling during increased nutrient and insulin availability. Methods: Six control and six T2DM subjects were studied at baseline and following a 5 h AA lowering high energy and insulin clamp. Stable isotopic techniques in combination with femoral catheterizations were used to measure AA kinetics across the leg while muscle biopsies were used to measure mTOR and insulin signaling proteins using immunoblotting techniques. Results: AA concentrations decreased by ∼30-60% in both groups (p < 0.05). Phospho-mTOR, S6K1, eEF2, and eIF2α were unchanged in both groups following the clamp (p > 0.05). In T2DM subjects, IRS-1 serine phosphorylation was unchanged while phospho-AMPKα decreased and phospho-Akt, phospho-AS160 and glucose uptake increased following the clamp (p < 0.05). In comparison, AA concentrations were maintained in a separate group during an insulin infusion. In this group, phospho-Akt, mTOR and S6K1 (n = 4) increased. Conclusion: Amino acids are necessary for insulin-induced activation of mTOR signaling and protein synthesis in both healthy and insulin resistant skeletal muscle.

KW - Adenosine 5′-monophosphate-activated protein kinase

KW - Amino acid availability

KW - Mammalian target of rapamycin

KW - Muscle protein synthesis

UR - http://www.scopus.com/inward/record.url?scp=46549084953&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=46549084953&partnerID=8YFLogxK

U2 - 10.1016/j.clnu.2008.01.012

DO - 10.1016/j.clnu.2008.01.012

M3 - Article

C2 - 18342407

AN - SCOPUS:46549084953

VL - 27

SP - 447

EP - 456

JO - Clinical Nutrition

JF - Clinical Nutrition

SN - 0261-5614

IS - 3

ER -