Nitric oxide increases cyclic GMP levels, AMP-activated protein kinase (AMPK)alpha1-specific activity and glucose transport in human skeletal muscle
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Nitric oxide increases cyclic GMP levels, AMP-activated protein kinase (AMPK)alpha1-specific activity and glucose transport in human skeletal muscle. / Deshmukh, A S; Long, Y C; de Castro Barbosa, T; Karlsson, H K R; Glund, S; Zavadoski, W J; Gibbs, E M; Koistinen, H A; Wallberg-Henriksson, H; Zierath, J R.
In: Diabetologia, Vol. 53, No. 6, 06.2010, p. 1142-50.Research output: Contribution to journal › Journal article › Research › peer-review
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TY - JOUR
T1 - Nitric oxide increases cyclic GMP levels, AMP-activated protein kinase (AMPK)alpha1-specific activity and glucose transport in human skeletal muscle
AU - Deshmukh, A S
AU - Long, Y C
AU - de Castro Barbosa, T
AU - Karlsson, H K R
AU - Glund, S
AU - Zavadoski, W J
AU - Gibbs, E M
AU - Koistinen, H A
AU - Wallberg-Henriksson, H
AU - Zierath, J R
PY - 2010/6
Y1 - 2010/6
N2 - AIMS/HYPOTHESIS: We investigated the direct effect of a nitric oxide donor (spermine NONOate) on glucose transport in isolated human skeletal muscle and L6 skeletal muscle cells. We hypothesised that pharmacological treatment of human skeletal muscle with N-(2-aminoethyl)-N-(2-hydroxy-2-nitrosohydrazino)-1,2-ethylenediamine (spermine NONOate) would increase intracellular cyclic GMP (cGMP) levels and promote glucose transport.METHODS: Skeletal muscle strips were prepared from vastus lateralis muscle biopsies obtained from seven healthy men. Muscle strips were incubated in the absence or presence of 5 mmol/l spermine NONOate or 120 nmol/l insulin. The L6 muscle cells were treated with spermine NONOate (20 micromol/l) and incubated in the absence or presence of insulin (120 nmol/l). The direct effect of spermine NONOate and insulin on glucose transport, cGMP levels and signal transduction was determined.RESULTS: In human skeletal muscle, spermine NONOate increased glucose transport 2.4-fold (p < 0.05), concomitant with increased cGMP levels (80-fold, p < 0.001). Phosphorylation of components of the canonical insulin signalling cascade was unaltered by spermine NONOate exposure, implicating an insulin-independent signalling mechanism. Consistent with this, spermine NONOate increased AMP-activated protein kinase (AMPK)-alpha1-associated activity (1.7-fold, p < 0.05). In L6 muscle cells, spermine NONOate increased glucose uptake (p < 0.01) and glycogen synthesis (p < 0.001), an effect that was in addition to that of insulin. Spermine NONOate also elicited a concomitant increase in AMPK and acetyl-CoA carboxylase phosphorylation. In the presence of the guanylate cyclase inhibitor LY-83583 (10 micromol/l), spermine NONOate had no effect on glycogen synthesis and AMPK-alpha1 phosphorylation.CONCLUSIONS/INTERPRETATION: Pharmacological treatment of skeletal muscle with spermine NONOate increases glucose transport via insulin-independent signalling pathways involving increased intracellular cGMP levels and AMPK-alpha1-associated activity.
AB - AIMS/HYPOTHESIS: We investigated the direct effect of a nitric oxide donor (spermine NONOate) on glucose transport in isolated human skeletal muscle and L6 skeletal muscle cells. We hypothesised that pharmacological treatment of human skeletal muscle with N-(2-aminoethyl)-N-(2-hydroxy-2-nitrosohydrazino)-1,2-ethylenediamine (spermine NONOate) would increase intracellular cyclic GMP (cGMP) levels and promote glucose transport.METHODS: Skeletal muscle strips were prepared from vastus lateralis muscle biopsies obtained from seven healthy men. Muscle strips were incubated in the absence or presence of 5 mmol/l spermine NONOate or 120 nmol/l insulin. The L6 muscle cells were treated with spermine NONOate (20 micromol/l) and incubated in the absence or presence of insulin (120 nmol/l). The direct effect of spermine NONOate and insulin on glucose transport, cGMP levels and signal transduction was determined.RESULTS: In human skeletal muscle, spermine NONOate increased glucose transport 2.4-fold (p < 0.05), concomitant with increased cGMP levels (80-fold, p < 0.001). Phosphorylation of components of the canonical insulin signalling cascade was unaltered by spermine NONOate exposure, implicating an insulin-independent signalling mechanism. Consistent with this, spermine NONOate increased AMP-activated protein kinase (AMPK)-alpha1-associated activity (1.7-fold, p < 0.05). In L6 muscle cells, spermine NONOate increased glucose uptake (p < 0.01) and glycogen synthesis (p < 0.001), an effect that was in addition to that of insulin. Spermine NONOate also elicited a concomitant increase in AMPK and acetyl-CoA carboxylase phosphorylation. In the presence of the guanylate cyclase inhibitor LY-83583 (10 micromol/l), spermine NONOate had no effect on glycogen synthesis and AMPK-alpha1 phosphorylation.CONCLUSIONS/INTERPRETATION: Pharmacological treatment of skeletal muscle with spermine NONOate increases glucose transport via insulin-independent signalling pathways involving increased intracellular cGMP levels and AMPK-alpha1-associated activity.
KW - AMP-Activated Protein Kinases
KW - Analysis of Variance
KW - Biological Transport
KW - Blotting, Western
KW - Cells, Cultured
KW - Cyclic GMP
KW - Glucose
KW - Humans
KW - Insulin
KW - Male
KW - Middle Aged
KW - Muscle, Skeletal
KW - Nitric Oxide
KW - Nitric Oxide Donors
KW - Phosphorylation
KW - Signal Transduction
KW - Spermine
KW - Journal Article
KW - Research Support, Non-U.S. Gov't
U2 - 10.1007/s00125-010-1716-x
DO - 10.1007/s00125-010-1716-x
M3 - Journal article
C2 - 20349036
VL - 53
SP - 1142
EP - 1150
JO - Diabetologia
JF - Diabetologia
SN - 0012-186X
IS - 6
ER -
ID: 170597608