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Essential hypertension is associated with an increased incidence of insulin resistance of skeletal muscle glucose transport. The present study determined if celiprolol, an antihypertensive agent with selective beta1-adrenoceptor antagonist and additional beta2-agonistic properties, administered by gavage either acutely (3 hr) or chronically (14 d), had a direct effect on improving glucose tolerance and insulin-stimulated glucose transport activity (using 2-deoxyglucose (2-DG) uptake) in isolated epitrochlearis muscles of the insulin-resistant obese Zucker rat. The effects of a selective beta1-blocker, metoprolol, were also assessed. Acute administration of celiprolol, but not metoprolol, increased insulin-stimulated 2-DG uptake in muscle by 22% (p<0.05). Chronic celiprolol treatment significantly lowered fasting plasma insulin (22%) and free fatty acids (40%) in comparison to obese control values. Moreover, chronic celiprolol administration decreased the glucose-insulin index (calculated as the product of the glucose and insulin areas under the curve during an oral glucose tolerance test), by 32% (p<0.05) compared to obese controls, indicating that peripheral insulin action was increased. Indeed, insulin-stimulated skeletal muscle 2-DG uptake was enhanced by 49% (p<0.05) in these celiprolol-treated obese animals. Metoprolol was without significant effect on any of these variables following chronic administration. These findings indicate that, in this animal model of insulin resistance, the beta1-antagonist/beta2-agonist celiprolol has a specific effect of improving insulin-stimulated skeletal muscle glucose transport that is independent of any hemodynamic alterations.

Alpha-lipoic acid (ALA), a potent biological antioxidant, improves insulin action of skeletal muscle glucose transport and metabolism in both human and animal models of insulin resistance. In order to obtain further insight into the potential intracellular mechanisms for the action of ALA on insulin-stimulated glucose transport in skeletal muscle, we investigated the effects of direct incubation with ALA (2 mM) on 2-deoxyglucose (2-DG) uptake by epitrochlearis muscle from either insulin-sensitive lean (Fa/-) or insulin-resistant obese (fa/fa) Zucker rats. ALA stimulated 2-DG uptake in muscle of lean animals by 76%, whereas ALA stimulated 2-DG uptake by only 48% in muscle from obese animals. The stimulation of 2-DG uptake due to ALA was enhanced 30-55% in the presence of insulin. In contrast, ALA action on 2-DG uptake was not additive with the effects of electrically-stimulated muscle contractions in either insulin-sensitive or insulin-resistant muscle. Wortmannin (1 microM), an inhibitor of phosphotidylinositol-3-kinase, completely inhibited insulin action on 2-DG uptake, but inhibited ALA action by only 25%. Collectively, these results indicate that although a portion of ALA action on glucose transport in mammalian skeletal muscle is mediated via the insulin signal transduction pathway, the majority of the direct effect of ALA on skeletal muscle glucose transport is insulin-independent.

In rat adipocytes, palmitate: a) increases basal 2-deoxyglucose transport 129 +/- 27% (p less than 0.02), b) decreases the insulin sensitive glucose transporter (GLUT4) in low density microsomes and increases GLUT4 in plasma membranes and c) increases the activity of the insulin receptor tyrosine kinase. Palmitate-stimulated glucose transport is not additive with the effect of insulin and is not inhibited by the protein kinase C inhibitors staurosporine and sphingosine. In rat muscle, palmitate: a) does not affect basal glucose transport in either the soleus or epitrochlearis and b) inhibits insulin-stimulated glucose transport by 28% (p less than 0.005) in soleus but not in epitrochlearis muscle. These studies demonstrate a potentially important differential role for fatty acids in the regulation of glucose transport in different insulin target tissues.