Evidence for altered sensitivity of the nitric oxide/cGMP signalling cascade in insulin-resistant skeletal muscle

Abstract

Nitric oxide activates guanylate cyclase to form cGMP, comprising a signalling system that is believed to be a distinct mechanism for increasing glucose transport and metabolism in skeletal muscle. The effects of a selective cGMP phosphodiesterase inhibitor, zaprinast, on basal glucose utilization was investigated in incubated rat soleus muscle preparations isolated from both insulin-sensitive (lean Zucker; Fa/?) and insulin-resistant (obese Zucker; fa/fa) rats. Zaprinast at 27 μM significantly increased cGMP levels in incubated soleus muscle isolated from lean, but not obese, Zucker rats. Muscles were incubated with 14C-labelled glucose and various concentrations of zaprinast (3, 27 and 243 μM). Zaprinast (at 27 and 243 μM) significantly increased rates of net and 14C-labelled lactate release and of glycogen synthesis in lean Zucker rat soleus muscle; glucose oxidation was also increased by 27 μM zaprinast. In addition, regardless of concentration, the phosphodiesterase inhibitor failed to increase any aspect of 14C-labelled glucose utilization in soleus muscles isolated from obese Zucker rats. The maximal activity of nitric oxide synthase (NOS) was significantly decreased in insulin-resistant obese Zucker muscles. Thus the lack of effect of zaprinast in insulin-resistant skeletal muscle is consistent with decreased NOS activity. To test whether there is a defect in insulin-resistant skeletal muscle for endogenous activation of guanylate cyclase, soleus muscles were isolated from both insulin-sensitive and insulin-resistant Zucker rats and incubated with various concentrations of the NO donor sodium nitroprusside (SNP; 0.1, 1, 5 and 15 mM). SNP significantly increased rates of net and 14C-labelled lactate release, as well as glucose oxidation in muscles isolated from both insulin-sensitive and insulin-resistant rats. A decreased response to SNP was observed in the dose-dependent generation of cGMP within isolated soleus muscles from insulin-resistant rats. A possible link between impaired NO/cGMP signalling and abnormal glucose utilization by skeletal muscle is discussed.

Nitric Oxide Synthase Inhibition Reduces Glucose Uptake During Exercise in Individuals With Type 2 Diabetes More Than in Control Subjects

“…Although NO seems to be important for glucose uptake in individuals with type 2 diabetes, there is evidence in humans to suggest that individuals with type 2 diabetes have impaired resting NO-dependent vascular responses (48) and in animals that resting skeletal muscle NOS expression and activity are lower than in relevant control subjects (49,50). These results suggest that NOS protein and activity at rest may be reduced in humans with type 2 diabetes.…”

“…It is likely that NO mediates its effects via stimulation of soluble guanylate cyclase and production of cGMP. Inhibition of cGMP breakdown with Zaprinast, a specific inhibitor of cGMP type 5 phosphodiesterase in incubated rat soleus muscle, raised skeletal muscle cGMP levels by ϳ90% and substantially increased glucose uptake (49). This finding, together with the known stimulatory effect of NO donors such as sodium nitroprusside on skeletal muscle glucose uptake (12,14), highlights the NO-glucose uptake mechanism as a potential therapeutic target in patients with type 2 diabetes.…”

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

“…Both muscle contraction [42] and SNP [18,42] increase cGMP formation. Furthermore pharmacological manipulation of both soluble guanylate cyclase and cGMP modulates the effect of SNP on glucose uptake [18,43].…”

Long-Term Oral l-Arginine Administration Improves Peripheral and Hepatic Insulin Sensitivity in Type 2 Diabetic Patients

“…In support of this hypothesis, recent studies have shown that NO synthase (NOS) is expressed in skeletal muscle (26) and that NO per se could influence muscle glucose metabolism in studies in animals and in vitro (27). In fact, NOS inhibition by Nmonomethyl-L-arginine inhibits glucose transport in incubated skeletal muscle preparations (28), and it has been shown that sodium nitroprusside, an NO donor, increases glucose transport both in the absence and presence of insulin in rat extensor digitorum longus muscle in vitro (29). Insulin-resistant obese Zucker fa/fa rats were found to have a defect in the metabolic pathway of NO, and the administration of Zaprinast, a selective cGMP phosphodiesterase inhibitor, increased both cGMP levels and glucose uptake in skeletal muscle (28).…”