The beta2-adrenergic modulator celiprolol reduces insulin resistance in obese Zucker rats

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.