Henriksen Kim, Byrjalsen Inger, Nielsen Rasmus H, Madsen Andreas N, Larsen Leif K, Christiansen Claus, Beck-Nielsen Henning, Karsdal Morten A
Nordic Bioscience A/S, Herlev, Denmark.
Eur J Pharmacol. 2009 Aug 15;616(1-3):340-5. doi: 10.1016/j.ejphar.2009.06.051. Epub 2009 Jul 10.
Agonists of Perioxisome Proliferator-Activator Receptor gamma (PPARgamma), which work as insulin sensitizers, are approved for type 2 diabetes. However, adverse effects, such as oedemas, infarctions, and increased fracture rates, limit their applicability. We performed a head-to-head comparison of equipotent glucose lowering concentrations of the partial PPARgamma agonist balaglitazone and the full agonist pioglitazone in male diet-induced obese rats, to investigate effects on bone formation, fluid retention and fat accumulation. Sixty male dio induced obese rats were divided into five categories: vehicle, pioglitazone 10 mg/kg, pioglitazone 30 mg/kg, balaglitazone 5 mg/kg, balaglitazone 10 mg/kg. At day -7, 21 and 42 fasting serum samples were collected and whole body tissue composition was evaluated by MR scanning. Food intake and bodyweights were monitored during the study period. At day 42, an oral glucose tolerance test was performed to evaluate glucose homeostasis in the rats. During oral glucose tolerance test both pioglitazone and balaglitazone lowered baseline glucose and maintained the suppression during the oral glucose tolerance test. Both lowered basal insulin, peak insulin secretion and total insulin during oral glucose tolerance test. Both drugs increased bodyweight, although this was more pronounced in the pioglitazone 30 group. MR scans of body fat and water showed that all treatment groups increased their fat mass, whereas only the pioglitazone 30 group accumulated water. Pioglitazone treatment led to reduction of the bone formation marker osteocalcin, whereas balaglitazone treatment did not affect it. Balaglitazone is a novel PPARgamma agonist, which potently lowers glucose levels, while it neither affects fluid retention nor bone formation parameters.
过氧化物酶体增殖物激活受体γ（PPARγ）激动剂作为胰岛素增敏剂，已被批准用于治疗2型糖尿病。然而，诸如水肿、梗死和骨折率增加等不良反应限制了它们的应用。我们在雄性饮食诱导肥胖大鼠中，对等效降糖浓度的部分PPARγ激动剂巴格列酮和完全激动剂吡格列酮进行了直接比较，以研究它们对骨形成、液体潴留和脂肪堆积的影响。60只雄性饮食诱导肥胖大鼠被分为五类：赋形剂组、吡格列酮10mg/kg组、吡格列酮30mg/kg组、巴格列酮5mg/kg组、巴格列酮10mg/kg组。在第-7天、21天和42天采集空腹血清样本，并通过磁共振扫描评估全身组织成分。在研究期间监测食物摄入量和体重。在第42天，进行口服葡萄糖耐量试验以评估大鼠的葡萄糖稳态。在口服葡萄糖耐量试验期间，吡格列酮和巴格列酮均降低了基线血糖，并在口服葡萄糖耐量试验期间维持了血糖抑制。两者均降低了基础胰岛素、口服葡萄糖耐量试验期间的胰岛素峰值分泌和总胰岛素分泌。两种药物均增加了体重，尽管在吡格列酮30mg/kg组中更为明显。身体脂肪和水分的磁共振扫描显示，所有治疗组的脂肪量均增加，而只有吡格列酮30mg/kg组出现了水分潴留。吡格列酮治疗导致骨形成标志物骨钙素减少，而巴格列酮治疗对其没有影响。巴格列酮是一种新型PPARγ激动剂，能有效降低血糖水平，同时既不影响液体潴留也不影响骨形成参数。
