title: Distinct mechanisms of glucose lowering by specific agonists for peroxisomal proliferator activated receptor gamma and retinoic acid X receptors.
abstract: Agonists for the nuclear receptor peroxisomal proliferator-activated receptor-gamma (PPARgamma) and its heterodimeric partner, retinoid X receptor (RXR), are effective agents for the treatment of type 2 diabetes. To gain insight into the antidiabetic action of these compounds, we treated female Zucker diabetic rats (ZFF) with AGN194204, which we show to be a homodimer-specific RXR agonist, or the PPARgamma agonist, troglitazone. Hyperinsulinemic-euglycemic clamps in ZFF showed that troglitazone and AGN194204 reduced basal endogenous glucose production (EGP) approximately 30% and doubled the insulin suppression of EGP. AGN194204 had no effect on peripheral glucose utilization, whereas troglitazone increased insulin-stimulated glucose utilization by 50%, glucose uptake into skeletal muscle by 85%, and de novo skeletal muscle glycogen synthesis by 300%. Troglitazone increased skeletal muscle Irs-1 and phospho-Akt levels following in vivo insulin treatment, whereas AGN194204 increased hepatic Irs-2 and insulin stimulated phospho-Akt in liver. Gene profiles of AGN194204-treated mouse liver analyzed by Ingenuity Pathway Analysis identified increases in fatty acid synthetic genes, including Srebp-1 and fatty acid synthase, a pathway previously shown to be induced by RXR agonists. A network of down-regulated genes containing Foxa2, Foxa3, and G-protein subunits was identified, and decreases in these mRNA levels were confirmed by quantitative reverse transcription-PCR. Treatment of HepG2 cells with AGN194204 resulted in inhibition of glucagon-stimulated cAMP accumulation suggesting the G-protein down-regulation may provide an additional mechanism for hepatic insulin sensitization by RXR. These studies demonstrate distinct molecular events lead to insulin sensitization by high affinity RXR and PPARgamma agonists.
authors.affiliation: Division of Endocrinology and Metabolism, Department of Internal Medicine, University of Michigan, Ann Arbor, Michigan 48109-0354, USA.
authors.forename: Xiangquan
authors.initials: X
authors.lastname: Li
authors.forename: Polly A
authors.initials: PA
authors.lastname: Hansen
authors.forename: Li
authors.initials: L
authors.lastname: Xi
authors.forename: Roshantha A S
authors.initials: RA
authors.lastname: Chandraratna
authors.forename: Charles F
authors.initials: CF
authors.lastname: Burant
mesh_terms: D000818:Animals; D001786:Blood Glucose / Q000378:metabolism*; D002460:Cell Line; D003921:Diabetes Mellitus, Experimental / Q000097:blood / Q000188:drug therapy; D015536:Down-Regulation / Q000187:drug effects; D005231:Fatty Acids, Unsaturated / Q000494:pharmacology*; D005260:Female; D047495:PPAR gamma / Q000819:agonists* / Q000378:metabolism*; D051381:Rats; D011924:Rats, Zucker; D047488:Retinoid X Receptors / Q000819:agonists* / Q000378:metabolism*; D013764:Tetrahydronaphthalenes / Q000494:pharmacology*; D000077288:Troglitazone / Q000494:pharmacology*
chemical_list: C430898:AGN 194204; D001786:Blood Glucose; D005231:Fatty Acids, Unsaturated; D047495:PPAR gamma; D047488:Retinoid X Receptors; D013764:Tetrahydronaphthalenes; D000077288:Troglitazone