title: Mechanisms of antihyperglycemic effects of moxonidine in the obese spontaneously hypertensive Koletsky rat (SHROB).
abstract: Increased activity of the sympathetic nervous system may be a critical factor in the development of impaired insulin secretion and insulin resistance. We studied the chronic effects of sympathetic inhibition with moxonidine on glucose metabolism in the spontaneously hypertensive genetically obese rat (SHROB). This unique animal model closely resembles human syndrome X, expressing insulin resistance, genetic obesity, spontaneous hypertension, and hyperlipoproteinemia. Moxonidine, a selective imidazoline receptor agonist, was administered to lean spontaneous hypertensive rats (SHR) and SHROBs for 90 days in food at 8 mg/kg/day and significantly reduced mean blood pressure. Moxonidine treatment reduced fasting insulin levels by 71% in SHROB and lowered plasma free fatty acids by 25%. In SHR, moxonidine treatment decreased free fatty acids by 17% compared with controls. During an oral glucose tolerance test, blood glucose levels in moxonidine-treated SHROB were reduced relative to untreated controls from 60 min onwards. Insulin secretion was facilitated at 30 min (83% greater) and 60 min (67% greater) postchallenge compared with control SHROB. In skeletal muscle, moxonidine treatment increased the expression of the insulin receptor beta subunit by 19% in SHROB 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 SHR. Moxonidine treatment enhanced the expression and insulin-stimulated phosphorylation of IRS-1 protein in skeletal muscle in SHROB by 74 and 27%, respectively, and in SHR by 40 and 56%, respectively. Moxonidine increased the levels of expression of IRS-1 protein in liver in SHR by 275% and in SHROB by 260%. These findings indicate that chronic inhibition of sympathetic activity with moxonidine therapy can lower free fatty acids and significantly improve insulin secretion, glucose disposal, and expression of key insulin signaling intermediates in an animal model of obese hypertension.
authors.affiliation: Department of Medicine, Division of Hypertension, Case Western Reserve University School of Medicine, Cleveland, Ohio, USA.
authors.forename: P
authors.initials: P
authors.lastname: Ernsberger
authors.forename: T
authors.initials: T
authors.lastname: Ishizuka
authors.forename: S
authors.initials: S
authors.lastname: Liu
authors.forename: C J
authors.initials: CJ
authors.lastname: Farrell
authors.forename: D
authors.initials: D
authors.lastname: Bedol
authors.forename: R J
authors.initials: RJ
authors.lastname: Koletsky
authors.forename: J E
authors.initials: JE
authors.lastname: Friedman
mesh_terms: D000818:Animals; D000959:Antihypertensive Agents / Q000494:pharmacology* / Q000627:therapeutic use; D005260:Female; D005951:Glucose Tolerance Test; D051275:Glucose Transporter Type 4; D006973:Hypertension / Q000150:complications / Q000188:drug therapy / Q000378:metabolism; D007004:Hypoglycemic Agents / Q000494:pharmacology* / Q000627:therapeutic use; D007093:Imidazoles / Q000494:pharmacology* / Q000627:therapeutic use; D007328:Insulin / Q000378:metabolism; D055504:Insulin Receptor Substrate Proteins; D008099:Liver / Q000187:drug effects / Q000378:metabolism; D008297:Male; D009004:Monosaccharide Transport Proteins / Q000096:biosynthesis; D009124:Muscle Proteins; D018482:Muscle, Skeletal / Q000378:metabolism; D009765:Obesity / Q000150:complications / Q000188:drug therapy / Q000378:metabolism; D010750:Phosphoproteins / Q000096:biosynthesis / Q000378:metabolism; D010766:Phosphorylation; D051381:Rats; D011918:Rats, Inbred SHR; D017207:Rats, Sprague-Dawley; D011972:Receptor, Insulin / Q000096:biosynthesis / Q000378:metabolism; D014443:Tyrosine / Q000378:metabolism
chemical_list: D000959:Antihypertensive Agents; D051275:Glucose Transporter Type 4; D007004:Hypoglycemic Agents; C526292:IRS1 protein, human; D007093:Imidazoles; D007328:Insulin; D055504:Insulin Receptor Substrate Proteins; C526296:Irs1 protein, rat; D009004:Monosaccharide Transport Proteins; D009124:Muscle Proteins; D010750:Phosphoproteins; C495694:Slc2a4 protein, rat; D014443:Tyrosine; C043482:moxonidine; D011972:Receptor, Insulin