The effect of dipeptidyl peptidase-IV inhibition on bone in a mouse model of type 2 diabetes.
The effect of dipeptidyl peptidase-IV inhibition on bone in a mouse model of type 2 diabetes.
复制标题
DOI：
10.1002/dmrr.2466
复制
发表时间：
2014-03
期刊：
影响因子：
--
通讯作者：
LeRoith D
中科院分区：
文献类型：
--
作者：
Gallagher EJ;Sun H;Kornhauser C;Tobin-Hess A;Epstein S;Yakar S;LeRoith D
患有2型糖尿病（T2 D）的人比没有糖尿病的人骨折的风险更大。某些口服糖尿病药物可能会进一步增加骨折的风险。二肽基肽酶-IV（DPP-IV）抑制剂是一种基于肠促胰岛素的疗法，越来越多地用于T2 D的管理。据推测，这些药物可能会降低T2 D患者的骨折风险。在这项研究中，我们使用T2 D小鼠模型来检查DPP-IV抑制剂MK-0626对骨的影响。雄性野生型（WT）和糖尿病肌肉-赖氨酸-精氨酸（MKR）小鼠接受MK-0626、吡格列酮、阿仑膦酸盐或溶剂给药。将MK-0626给药对骨微结构和转换的影响与吡格列酮、阿仑膦酸盐和溶剂给药进行了比较。通过吡格列酮、MK-0626或磷酸盐缓冲液处理后WT和MKR小鼠骨髓细胞的碱性磷酸酶染色测定成骨细胞分化。我们发现MK-0626对糖尿病小鼠的皮质骨和松质骨具有中性作用。吡格列酮对WT小鼠的骨小梁有不良影响，但对糖尿病小鼠无不良影响。阿仑膦酸钠可改善糖尿病小鼠和野生型小鼠的皮质骨和骨小梁结构。MK-0626没有改变成骨细胞分化，但吡格列酮在体外损害成骨细胞分化。总体而言，DPP-IV抑制剂MK-0626对T2 D动物模型中的骨骼或直接对培养物中的成骨细胞没有不良影响。这些发现令人放心，因为DPP-IV抑制剂正被广泛用于治疗骨折风险增加的T2 D患者。
Individuals with type 2 diabetes (T2D) are at greater risk of bone fractures than those without diabetes. Certain oral diabetic medications may further increase the risk of fracture. Dipeptidyl peptidase-IV (DPP-IV) inhibitors are incretin-based therapies that are being increasingly used for the management of T2D. It has been hypothesized that these agents may reduce fracture risk in those with T2D. In this study, we used a mouse model of T2D to examine the effects of the DPP-IV inhibitor, MK-0626, on bone. Male wild type (WT) and diabetic muscle-lysine-arginine (MKR) mice were treated with MK-0626, pioglitazone, alendronate or vehicle. The effects of treatment with MK-0626 on bone microarchitecture and turnover were compared with treatment with pioglitazone, alendronate and vehicle. Osteoblast differentiation was determined by alkaline phosphatase staining of bone marrow cells from WT and MKR mice after treatment with pioglitazone, MK-0626 or phosphate buffered saline. We found that MK-0626 had neutral effects on cortical and trabecular bone in diabetic mice. Pioglitazone had detrimental effects on the trabecular bone of WT but not of diabetic mice. Alendronate caused improvements in cortical and trabecular bone architecture in diabetic and WT mice. MK-0626 did not alter osteoblast differentiation, but pioglitazone impaired osteoblast differentiation in vitro. Overall, the DPP-IV inhibitor, MK-0626, had no adverse effects on bone in an animal model of T2D or directly on osteoblasts in culture. These findings are reassuring as DPP-IV inhibitors are being widely used to treat patients with T2D who are already at an increased risk of fractures.