title: Effects of selective and non-selective glucocorticoid receptor II antagonists on rapid-onset diabetes in young rats.
abstract: The blockade of glucocorticoid (GC) action through antagonism of the glucocorticoid receptor II (GRII) has been used to minimize the undesirable effects of chronically elevated GC levels. Mifepristone (RU486) is known to competitively block GRII action, but not exclusively, as it antagonizes the progesterone receptor. A number of new selective GRII antagonists have been developed, but limited testing has been completed in animal models of overt type 2 diabetes mellitus. Therefore, two selective GRII antagonists (C113176 and C108297) were tested to determine their effects in our model of GC-induced rapid-onset diabetes (ROD). Male Sprague-Dawley rats (∼ six weeks of age) were placed on a high-fat diet (60%), surgically implanted with pellets containing corticosterone (CORT) or wax (control) and divided into five treatment groups. Each group was treated with either a GRII antagonist or vehicle for 14 days after surgery: CORT pellets (400 mg/rat) + antagonists (80 mg/kg/day); CORT pellets + drug vehicle; and wax pellets (control) + drug vehicle. After 10 days of CORT treatment, body mass gain was increased with RU486 (by ∼20% from baseline) and maintained with C113176 administration, whereas rats given C108297 had similar body mass loss (∼15%) to ROD animals. Fasting glycemia was elevated in the ROD animals (>20 mM), normalized completely in animals treated with RU486 (6.2±0.1 mM, p<0.05) and improved in animals treated with C108297 and C113176 (14.0±1.6 and 8.8±1.6 mM, p<0.05 respectively). Glucose intolerance was normalized with RU486 treatment, whereas acute insulin response was improved with RU486 and C113176 treatment. Also, peripheral insulin resistance was attenuated with C113176 treatment along with improved levels of β-cell function while C108297 antagonism only provided modest improvements. In summary, C113176 is an effective agent that minimized some GC-induced detrimental metabolic effects and may provide an alternative to the effective, but non-selective, GRII antagonist RU486.
authors.affiliation: School of Kinesiology and Health Science, Faculty of Health, Muscle Health Research Center and Physical Activity and Chronic Disease Unit, York University, Toronto, Ontario, Canada.
authors.forename: Jacqueline L
authors.initials: JL
authors.lastname: Beaudry
authors.affiliation: School of Kinesiology and Health Science, Faculty of Health, Muscle Health Research Center and Physical Activity and Chronic Disease Unit, York University, Toronto, Ontario, Canada.
authors.forename: Emily C
authors.initials: EC
authors.lastname: Dunford
authors.affiliation: School of Kinesiology and Health Science, Faculty of Health, Muscle Health Research Center and Physical Activity and Chronic Disease Unit, York University, Toronto, Ontario, Canada.
authors.forename: Trevor
authors.initials: T
authors.lastname: Teich
authors.affiliation: School of Kinesiology and Health Science, Faculty of Health, Muscle Health Research Center and Physical Activity and Chronic Disease Unit, York University, Toronto, Ontario, Canada.
authors.forename: Dessi
authors.initials: D
authors.lastname: Zaharieva
authors.affiliation: Corcept Therapeutics, Menlo Park, California, United States of America.
authors.forename: Hazel
authors.initials: H
authors.lastname: Hunt
authors.affiliation: Corcept Therapeutics, Menlo Park, California, United States of America.
authors.forename: Joseph K
authors.initials: JK
authors.lastname: Belanoff
authors.affiliation: School of Kinesiology and Health Science, Faculty of Health, Muscle Health Research Center and Physical Activity and Chronic Disease Unit, York University, Toronto, Ontario, Canada.
authors.forename: Michael C
authors.initials: MC
authors.lastname: Riddell
mesh_terms: D000818:Animals; D001786:Blood Glucose / Q000378:metabolism; D001835:Body Weight / Q000187:drug effects; D003345:Corticosterone; D003921:Diabetes Mellitus, Experimental / Q000097:blood / Q000139:chemically induced / Q000188:drug therapy*; D059305:Diet, High-Fat; D006727:Hormone Antagonists / Q000494:pharmacology; D007328:Insulin / Q000378:metabolism; D007333:Insulin Resistance; D008297:Male; D015735:Mifepristone / Q000494:pharmacology; D051381:Rats; D017207:Rats, Sprague-Dawley; D011965:Receptors, Glucocorticoid / Q000037:antagonists & inhibitors* / Q000378:metabolism; D054852:Small Molecule Libraries / Q000494:pharmacology*
chemical_list: D001786:Blood Glucose; D006727:Hormone Antagonists; D007328:Insulin; D011965:Receptors, Glucocorticoid; D054852:Small Molecule Libraries; D015735:Mifepristone; D003345:Corticosterone