ABSTRACT
OBJECTIVE: Evaluate the safety and tolerability of beloranib, a fumagillin-class methionine aminopetidase-2 (MetAP2) inhibitor, in obese women over 4 weeks. DESIGN AND METHODS: Thirty-one obese (mean BMI 38 kg/m2) women were randomized to intravenous 0.1, 0.3, or 0.9 mg/m2 beloranib or placebo twice weekly for 4 weeks (N = 7, 6, 9, and 9). RESULTS: The most frequent AEs were headache, infusion site injury, nausea, and diarrhea. Nausea and infusion site injury occurred more with beloranib than placebo. The most common reason for discontinuation was loss of venous access. There were no clinically significant abnormal laboratory findings. In subjects completing 4 weeks, median weight loss with 0.9 mg/m2 beloranib was -3.8 kg (95% CI -5.1, -0.9; N = 8) versus -0.6 kg with placebo (-4.5, -0.1; N = 6). Weight change for 0.1 and 0.3 mg/m2 beloranib was similar to placebo. Beloranib (0.9 mg/m2) was associated with a significant 42 and 18% reduction in triglycerides and LDL-cholesterol, as well as improvement in C-reactive protein and reduced sense of hunger. Changes in ß-hydroxybutyrate, adiponectin, leptin, and fibroblast growth factor-21 were consistent with the putative mechanism of MetAP2 inhibition. Glucose and blood pressure were unchanged. CONCLUSIONS: Beloranib treatment was well tolerated and associated with rapid weight loss and improvements in lipids, C-reactive protein, and adiponectin.
Subject(s)
Adiponectin/blood , Aminopeptidases/antagonists & inhibitors , Anti-Obesity Agents/therapeutic use , Cyclohexanes/therapeutic use , Fatty Acids, Unsaturated/therapeutic use , Glycoproteins/antagonists & inhibitors , Lipids/blood , Obesity/drug therapy , Weight Loss/drug effects , 3-Hydroxybutyric Acid/blood , Anti-Obesity Agents/adverse effects , Anti-Obesity Agents/pharmacology , Aspergillus/chemistry , Biological Products/adverse effects , Biological Products/pharmacology , Biological Products/therapeutic use , Blood Glucose/metabolism , Blood Pressure , C-Reactive Protein/metabolism , Cholesterol, LDL/blood , Cyclohexanes/adverse effects , Cyclohexanes/pharmacology , Double-Blind Method , Fatty Acids, Unsaturated/adverse effects , Fatty Acids, Unsaturated/pharmacology , Female , Fibroblast Growth Factors/blood , Humans , Hunger/drug effects , Infusions, Intravenous , Leptin/blood , Methionyl Aminopeptidases , Middle Aged , Obesity/blood , Sesquiterpenes/adverse effects , Sesquiterpenes/pharmacology , Sesquiterpenes/therapeutic use , Triglycerides/bloodABSTRACT
AIM: To test the hypothesis that ascorbic acid (AA) and thiazolidinedione (TZD) would have additive effects on HMW adiponectin secretion by virtue of different modes of action. METHODS: We determined the effects of supplementation of AA and/or TZD on expression and secretion of total and HMW adiponectin from human Simpson-Golabi-Behmel syndrome (SGBS) adipocytes in the absence or presence of the proinflammatory cytokine TNFα. RESULTS: AA supplementation significantly increased secretion of HMW adiponectin (1.7-fold) without altering adiponectin expression or total adiponectin secretion. TZD significantly increased expression (3-fold) and secretion of total (1.4-fold) but not HMW adiponectin. Combined supplementation resulted in a significant increase in expression (3-fold) and secretion of total (1.8-fold) and HMW (5-fold) adiponectin. Similar results were seen in cells co-treated with TNFα. CONCLUSIONS: These data show that AA and TZD have synergistic rather than simple additive effects on secretion of HMW adiponectin from human adipocytes and raise the possibility that differences in AA levels may contribute to the variability in adiponectin multimer profiles and efficacy of TZD in humans. Our results also provide a rationale for longitudinal clinical trials investigating the effects of AA supplementation with or without TZD on adiponectin and metabolic profiles.