The
sympatholytic antihypertensive agent moxonidine, a centrally acting selective I1-imidazoline receptor modulator (putative agonist), may be beneficial in hypertensive patients with
insulin resistance. In the present study, the effects of chronic in vivo
moxonidine treatment of obese Zucker rats--a model of severe
glucose intolerance,
hyperinsulinemia and
insulin resistance, and
dyslipidemia--on whole-body
glucose tolerance, plasma
lipids, and
insulin-stimulated skeletal muscle
glucose transport activity (2-deoxyglucose uptake) were investigated.
Moxonidine was administered by gavage for 21 consecutive days at 2, 6, or 10 mg/kg
body weight.
Body weights in control and
moxonidine-treated groups were matched, except at the highest dose, at which final
body weight was 17% lower in the
moxonidine-treated animals compared with controls. The
moxonidine-treated (6 and 10 mg/kg) obese animals had significantly lower fasting plasma levels of
insulin (17% and 19%, respectively) and
free fatty acids (36% and 28%, respectively), whereas plasma
glucose was not altered. During an oral
glucose tolerance test, the
glucose response (area under the curve) was 47% and 67% lower, respectively, in the two highest
moxonidine-treated obese groups. Moreover,
glucose transport activity in the isolated epitrochlearis muscle stimulated by a maximally effective
insulin dose (13.3 nmol/L) was 39% and 70% greater in the 6 and 10 mg/kg
moxonidine-treated groups, respectively (P<.05 for all effects). No significant alterations in muscle
glucose transport were elicited by 2 mg/kg
moxonidine. These findings indicate that in the severely
insulin-resistant and dyslipidemic obese Zucker rat, chronic in vivo treatment with
moxonidine can significantly improve, in a dose-dependent manner, whole-body
glucose tolerance, possibly as a result of enhanced
insulin-stimulated skeletal muscle
glucose transport activity and reduced circulating
free fatty acids.