title: A novel EPO receptor agonist improves glucose tolerance via glucose uptake in skeletal muscle in a mouse model of diabetes.
abstract: Patients treated with recombinant human Epo demonstrate an improvement in insulin sensitivity. We aimed to investigate whether CNTO 530, a novel Epo receptor agonist, could affect glucose tolerance and insulin sensitivity. A single administration of CNTO 530 significantly and dose-dependently reduced the area under the curve in a glucose tolerance test in diet-induced obese and diabetic mice after 14, 21, and 28 days. HOMA analysis suggested an improvement in insulin sensitivity, and this effect was confirmed by a hyperinsulinemic-euglycemic clamp. Uptake of (14)C-2-deoxy-D-glucose indicated that animals dosed with CNTO 530 transported more glucose into skeletal muscle and heart relative to control animals. In conclusion, CNTO530 has a profound effect on glucose tolerance in insulin-resistant rodents likely because of improving peripheral insulin sensitivity. This effect was observed with epoetin-α and darbepoetin-α, suggesting this is a class effect, but the effect with these compounds relative to CNTO530 was decreased in duration and magnitude.
authors.affiliation: Discovery Research, Centocor R&D Inc., 145 King of Prussia Road, Radnor, PA 19087, USA.
authors.forename: Michael S
authors.initials: MS
authors.lastname: Scully
authors.forename: Tatiana A
authors.initials: TA
authors.lastname: Ort
authors.forename: Ian E
authors.initials: IE
authors.lastname: James
authors.forename: Peter J
authors.initials: PJ
authors.lastname: Bugelski
authors.forename: Dorie A
authors.initials: DA
authors.lastname: Makropoulos
authors.forename: Heather A
authors.initials: HA
authors.lastname: Deutsch
authors.forename: Elsbet J
authors.initials: EJ
authors.lastname: Pieterman
authors.forename: Anita M
authors.initials: AM
authors.lastname: van den Hoek
authors.forename: Louis M
authors.initials: LM
authors.lastname: Havekes
authors.forename: William H
authors.initials: WH
authors.lastname: Dubell
authors.forename: Joshua D
authors.initials: JD
authors.lastname: Wertheimer
authors.forename: Kristen M
authors.initials: KM
authors.lastname: Picha
mesh_terms: D000818:Animals; D000068256:Darbepoetin alfa; D003921:Diabetes Mellitus, Experimental / Q000209:etiology / Q000378:metabolism* / Q000503:physiopathology; D004041:Dietary Fats / Q000009:adverse effects; D004195:Disease Models, Animal; D004305:Dose-Response Relationship, Drug; D000068817:Epoetin Alfa; D004921:Erythropoietin / Q000031:analogs & derivatives / Q000494:pharmacology; D005947:Glucose / Q000378:metabolism*; D015309:Glucose Clamp Technique; D005951:Glucose Tolerance Test; D007333:Insulin Resistance / Q000502:physiology; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018482:Muscle, Skeletal / Q000187:drug effects* / Q000378:metabolism*; D009765:Obesity / Q000150:complications / Q000209:etiology / Q000378:metabolism; D017467:Receptors, Erythropoietin / Q000819:agonists*; D011993:Recombinant Fusion Proteins / Q000494:pharmacology*; D011994:Recombinant Proteins; D013997:Time Factors
chemical_list: C541126:CNTO 530; D004041:Dietary Fats; D017467:Receptors, Erythropoietin; D011993:Recombinant Fusion Proteins; D011994:Recombinant Proteins; D004921:Erythropoietin; D000068256:Darbepoetin alfa; D000068817:Epoetin Alfa; D005947:Glucose