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ENDOCRINE AND REPRODUCTIVE

Therapeutic Actions of an Insulin Receptor Activator and a Novel Peroxisome Proliferator-Activated Receptor Agonist in the Spontaneously Hypertensive Obese Rat Model of Metabolic Syndrome X

Department of Nutrition, Case Western Reserve University School of Medicine, Cleveland, Ohio (R.A.V., J.E.F., J.S., P.E.); Department of Pediatrics, University of Colorado Heath Sciences Center, Aurora, Colorado (J.E.F.); and Department of Molecular Endocrinology and Metabolic Disorders, Merck Research Labs, Rahway, New Jersey (B.B.Z.)

Insulin resistance clusters with hyperlipidemia, impaired glucose tolerance, and hypertension as metabolic syndrome X. We tested a low molecular weight insulin receptor activator, demethylasterriquinone B-1 (DMAQ-B1), and a novel indole peroxisome proliferator-activated receptor agonist, 2-(2-(4-phenoxy-2-propylphenoxy)ethyl)indole-5-acetic acid (PPEIA), in spontaneously hypertensive obese rats (SHROB), a genetic model of syndrome X. Agents were given orally for 19 days. SHROB showed fasting normoglycemia but impaired glucose tolerance after an oral load, as shown by increased glucose area under the curve (AUC) [20,700 mg · min/ml versus 8100 in lean spontaneously hypertensive rats (SHR)]. Insulin resistance was indicated by 20-fold excess fasting insulin and increased insulin AUC (6300 ng · min/ml versus 990 in SHR). DMAQ-B1 did not affect glucose tolerance (glucose AUC = 21,300) but reduced fasting insulin 2-fold and insulin AUC (insulin AUC = 4300). PPEIA normalized glucose tolerance (glucose AUC = 9100) and reduced insulin AUC (to 3180) without affecting fasting insulin. PPEIA also increased food intake, fat mass, and body weight gain (81 ± 12 versus 45 ± 8 g in untreated controls), whereas DMAQ-B1 had no effect on body weight but reduced subscapular fat mass. PPEIA but not DMAQ-B1 reduced blood pressure. In skeletal muscle, insulin-stimulated phosphorylation of the insulin receptor and insulin receptor substrate protein 1-associated phosphatidylinositol 3-kinase activity were decreased by 40 to 55% in SHROB relative to lean SHR. PPEIA, but not DMAQ-B1, enhanced both insulin actions. SHROB also showed severe hypertriglyceridemia (355 ± 42 mg/dl versus 65 ± 3 in SHR) attenuated by both agents (DMAQ-B1, 228 ± 18; PPEIA, 79 ± 3). Both these novel antidiabetic agents attenuate insulin resistance and hypertriglyceridemia associated with metabolic syndrome but via distinct mechanisms.

Address correspondence to: Dr. Paul Ernsberger, Department of Nutrition, Case Western Reserve University School of Medicine, Cleveland, OH 44106-4906. E-mail: pre{at}po.cwru.edu

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