The Skeletal Effects of Reducing Inflammation in Type 2 Diabetes Mellitus

描述(申请人提供)：这项辅助建议的母公司研究，即使用水杨酸盐治疗2型糖尿病的靶向炎症(TINSAL)试验，发现高剂量的水杨酸盐，水杨酸盐，水杨酸盐可以改善T2D患者的血糖控制。这些结果支持炎症是2型糖尿病(T2D)的重要病理生理因素的观点。已有研究表明，慢性炎症通过增加骨吸收和减少骨形成而对骨重建产生负面影响。随着对骨骼是T2 DM并发症的靶器官的新认识，这些异常在T2D受试者的骨骼中被描述。这一建议的假设是，减少T2D的炎症将导致骨重建过程的重新平衡。为了验证这一假设，我们将测量TINSAL研究中储存的样本中骨转换的生化标记物。在母研究中，108名T2D受试者被随机分成两组，分别服用安慰剂或水杨酸盐(3.0、3.5或4.0g/d，tid)，为期14周。所有3种剂量的水杨酸盐均显著改善了T2D的血糖控制和其他代谢参数。这项辅助建议将调查骨重建的生化标记物是否与盐酸盐治疗有类似的改善。我们还将确定炎症标志物和脂联素水平的降低(已经在TINSAL中测量)是否可以预测骨重建的变化，以及骨重建的变化是否反过来预测观察到的血糖参数的改善。将获得的数据将解决T2 DM患者骨骼动力学异常的基本问题，因为它们可能与炎症过程直接相关。这项研究承诺为T2D骨骼异常的病因提供洞察力，并可能建议治疗或机制治疗T2D骨骼并发症的方法。直到最近，骨骼一直没有被认为是T2D并发症的靶器官。然而，新出现的证据表明，T2D和骨骼实际上可能彼此有重要的关系。成骨细胞的关键细胞产物之一是骨钙素，它是骨中指导骨形成相关过程的细胞。最近的研究表明，骨钙素通过向胰腺细胞和脂肪细胞发出信号来参与血糖的稳态。这一发现可能与流行病学研究有关，该研究将T2D与骨折风险增加联系起来。因此，T2D中骨形成减少的动态变化可能与骨钙素活性降低有关。骨钙素活性降低，反过来可能与糖稳态异常有关。炎症是T2D发病机制中的重要参与者，可能将这两个系统联系在一起。 公共卫生相关性：在最近的流行病学研究中，T2D与骨折风险增加有关。这项研究将为T2D的骨骼异常的病因提供洞察力，并可能为T2D的骨骼并发症提供治疗方法。

DESCRIPTION (provided by applicant): The parent study for this ancillary proposal, the Targeting INflammation using SALsalate in Type 2 Diabetes (TINSAL) trial, found that a high dose salicylate, salsalate, improved glycemic control in patients with T2D. These results support the concept that inflammation is an important pathophysiologic element in Type 2 Diabetes Mellitus (T2D). Chronic inflammation has been shown to negatively influence bone remodeling by increasing bone resorption and reducing bone formation. These abnormalities are being described in the skeleton of subjects with T2D along with the new recognition that the skeleton is a target organ for complications of T2DM. The hypothesis of this proposal is that reducing inflammation in T2D will lead to a rebalancing of the bone remodeling process. To test this hypothesis, we will measure biochemical markers of bone turnover in stored samples from the TINSAL study. In the parent study, 108 T2D subjects were randomized to placebo or salsalate (3.0, 3.5 or 4.0 g/d tid) for 14 weeks. All 3 salsalate doses significantly improved glycemic control and other metabolic parameters of T2D. This ancillary proposal will investigate whether biochemical markers of bone remodeling similarly improve with salsalate treatment. We will also determine whether reductions in inflammatory markers and adiponectin levels, already measured in TINSAL, predict changes in bone remodeling, and whether changes in bone remodeling in turn predict the observed improvements in the glycemic parameters. The data to be obtained will address fundamental issues of abnormal skeletal dynamics in T2DM as they may relate directly to the inflammatory process. This study promises to provide insight into the etiology of skeletal abnormalities in T2D and may suggest therapeutic, or mechanistic, approaches to the skeletal complications of T2D. Until recently, the skeleton has not been traditionally recognized as a target organ for complications in T2D. Newly emerging lines of evidence, however, suggest that T2D and the skeleton may, in fact have important relationships to each other. One of the key cellular products of the osteoblast, the cell in bone that directs processes associated with bone formation, is osteocalcin. It has been shown recently that osteocalcin participates in glucose homeostasis by signaling pancreatic cells as well as adipocytes. This finding may be related to epidemiologic studies which associate T2D with increased fracture risk. The dynamic of reduced bone formation in T2D thus may relate to reduced osteocalcin activity. Reduced osteocalcin activity, in turn, may be related to abnormal glucose homeostasis. Inflammation, which is an important participant in the pathogenesis of T2D, may link these two systems together. PUBLIC HEALTH RELEVANCE: T2D has been associated with increased fracture risk in recent epidemiologic studies. This study will provide insight into the etiology of skeletal abnormalities in T2D and may suggest therapeutic approaches to the skeletal complications of T2D.