Mechanisms of antihyperglycemic effects of moxonidine in the obese spontaneously hypertensive Koletsky rat (SHROB)

Increased activity of the sympathetic nervous system may be a critical fact or in the development of impaired insulin secretion and insulin resistance. We studied the chronic effects of sympathetic inhibition with moxonidine o n glucose metabolism in the spontaneously hypertensive genetically obese ra t (SHROB). This unique animal model closely resembles human syndrome X, exp ressing insulin resistance, genetic obesity, spontaneous hypertension, and hyperlipoproteinemia. Moxonidine, a selective imidazoline receptor agonist, was administered to lean spontaneous hypertensive rats (SHR) and SHROBs fo r 90 days in food at 8 mg/kg/day and significantly reduced mean blood press ure. Moxonidine treatment reduced fasting insulin revels by 71 % in SHROB a nd lowered plasma free fatty acids by 25%. In SHR, moxonidine treatment dec reased free fatty acids by 17% compared with controls. During an oral gluco se tolerance test, blood glucose levels in moxonidine-treated SHROB were re duced relative to untreated controls from 60 min onwards. Insulin secretion was facilitated at 30 min (83% greater) and 60 min (67% greater) postchall enge compared with control SHROB. In skeletal muscle, moxonidine treatment increased the expression of the insulin receptor beta subunit by 19% in SHR OB but was without effect in SHR. The level of insulin receptor substrate-1 (IRS-1) protein was decreased by 60% in control SHROB compared with lean S HR. Moxonidine treatment enhanced the expression and insulin-stimulated pho sphorylation of IRS-I protein in skeletal muscle in SHROB by 74 and 27%, re spectively, and in SHR by 40 and 56%, respectively. Moxonidine increased th e levels of expression of IRS-1 protein in liver in SHR by 275% and in SHRO B by 260%. These findings indicate that chronic inhibition of sympathetic a ctivity with moxonidine therapy can lower free fatty acids and significantl y improve insulin secretion, glucose disposal, and expression of key insuli n signaling intermediates in an animal model of obese hypertension.