The Skeletal Effects of Reducing Inflammation in Type 2 Diabetes Mellitus

描述（由申请方提供）：该辅助方案的母研究，即在2型糖尿病中使用水杨酸盐靶向炎症（TINSAL）试验，发现高剂量水杨酸盐，双水杨酸盐，改善了T2 D患者的血糖控制。这些结果支持炎症是2型糖尿病（T2 D）中重要的病理生理因素的概念。慢性炎症通过增加骨吸收和减少骨形成对骨重建产生负面影响。这些异常在T2 D受试者的骨骼中进行了描述，同时沿着新认识到骨骼是T2 DM并发症的靶器官。该建议的假设是，减少T2 D中的炎症将导致骨重建过程的再平衡。为了验证这一假设，我们将测量TINSAL研究储存样本中骨转换的生化标志物。在母研究中，108例T2 D受试者随机接受安慰剂或双水杨酯（3.0、3.5或4.0 g/d tid）治疗14周。所有3种双水杨酯剂量均显著改善了T2 D的血糖控制和其他代谢参数。本辅助提案将研究双水杨酸治疗是否能同样改善骨重建的生化标志物。我们还将确定是否减少炎症标志物和脂联素水平，已经在TINSAL中测量，预测骨重建的变化，以及骨重建的变化是否反过来预测血糖参数的改善。获得的数据将解决T2 DM中异常骨骼动力学的基本问题，因为它们可能直接与炎症过程相关。这项研究有望深入了解T2 D骨骼异常的病因，并可能提出T2 D骨骼并发症的治疗或机制方法。直到最近，骨骼在传统上还没有被认为是T2 D并发症的靶器官。然而，新出现的证据表明，T2 D和骨骼实际上可能彼此有重要的关系。成骨细胞（骨中指导与骨形成相关的过程的细胞）的关键细胞产物之一是骨钙素。最近研究表明，骨钙素通过向胰腺细胞和脂肪细胞发出信号参与葡萄糖稳态。这一发现可能与流行病学研究有关，该研究将T2 D与骨折风险增加相关联。因此，T2 D中骨形成减少的动态可能与骨钙素活性降低有关。骨钙素活性降低，反过来，可能与异常的葡萄糖稳态。炎症是T2 D发病机制的重要参与者，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，T2 D与骨折风险增加相关。这项研究将提供深入了解T2 D骨骼异常的病因，并可能提出T2 D骨骼并发症的治疗方法。

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.