Nitric Oxide Increases Glucose Uptake Through a Mechanism That Is Distinct From the Insulin and Contraction Pathways in Rat Skeletal Muscle

Abstract

Insulin, contraction, and the nitric oxide (NO) donor, sodium nitroprusside (SNP), all increase glucose transport in skeletal muscle. Some reports suggest that NO is a critical mediator of insulin-and/or contraction-stimulated transport. To determine if the mechanism leading to NO-stimulated glucose uptake is similar to the insulin-or contraction-dependent signaling pathways, isolated soleus and extensor digitorum longus (EDL) muscles from rats were treated with various combinations of SNP (maximum 10 mmol/l), insulin (maximum 50 mU/ml), electrical stimulation to produce contractions (maximum 10 min), wortmannin (100 nmol/l), and/or the NO synthase (NOS) inhibitor N G -monomethyl-L-arginine (L-NMMA) (0.1 mmol/l). The combinations of SNP plus insulin and SNP plus contraction both had fully additive effects on 2-deoxyglucose uptake. Wortmannin completely inhibited insulinstimulated glucose transport and only slightly inhibited SNP-stimulated 2-deoxyglucose uptake, whereas L-NMMA did not inhibit contraction-stimulated 2-deoxyglucose uptake. SNP significantly increased the activity of the ␣1 catalytic subunit of 5AMP-activated protein kinase (AMPK), a signaling molecule that has been implicated in mediating glucose transport in fuel-depleted cells. Addition of the NOS inhibitor N G -nitro-L-arginine methyl ester (L-NAME) (1 mg/ml) to the drinking water of rats for 2 days failed to affect the increase in muscle 2-deoxyglucose uptake in response to treadmill exercise. These data suggest that NO stimulates glucose uptake through a mechanism that is distinct from both the insulin and contraction signaling pathways.

Effects of the nitric oxide donor, sodium nitroprusside, on resting leg glucose uptake in patients with type 2 diabetes

“…Similarly, methacholine increased leg glucose uptake [38], but it was assumed that such effects were a consequence of NO-mediated endothelial-dependent vasodilation and increased glucose delivery. Consistent with animal data [13,[16][17][18][19]29] the current study suggests that SNP increased glucose uptake beyond the effects on blood flow via increasing translocation of the SLC2A4 glucose transporter.…”

“…SNP increases glucose transport in a number of cell culture models including human peripheral blood mononuclear cells [24], 3T3-L1 adipocytes [25], L929 fibroblasts [26], isolated rat cardiomyocytes [27] and human vascular smooth muscle cells [28]. SNP also increases glucose transport in isolated rat skeletal muscle preparations [13,[16][17][18][19]. The fact that SNP is able to increase glucose uptake in both cell culture and isolated muscle preparations suggests that NO has a direct action on glucose transport via SLC2A4 translocation, in addition to increasing glucose delivery via effects on blood flow.…”

“…While the evidence for a role of NO in glucose uptake is overwhelming, the specific involvement of NO in contraction-mediated glucose uptake is not without controversy. Two NOS inhibition studies in rats have failed to show any effect on contraction-stimulated glucose uptake [16,17], although both measured glucose uptake after completion of exercise or electrical stimulation, while the human studies displaying positive NOS inhibition results measured glucose uptake during exercise [20,21].…”

“…Electrical stimulation, eliciting muscle contraction causes release of NO [15]. Animal studies have demonstrated that NO donor drugs such as sodium nitroprusside (SNP) increase glucose transport in skeletal muscle [13,[16][17][18][19]. SNP also increases SLC2A4 translocation in isolated rat skeletal muscle preparations [16].…”

Potential upstream regulators and downstream targets of AMP-activated kinase signaling during oocyte maturation in a marine worm

“…One possible explanation involves the fact that AMPKs are heterotrimers that comprise varying combinations of a, b, and g subunits (Hardie 2007). Accordingly, disparate effects of AMPK on GVBD could be due to alternative types of AMPKs, given that in somatic cells AMPKs can exhibit isotype-specific responses to modulating stimuli (Salt et al 1998, Higaki et al 2001, Zierath 2002. In any case, data reported here and summarized in Fig.…”