Beneficial Effect of Salicylates: Insulin action, Secretion or Clearance?

描述（由申请人提供）：肥胖相关炎症变化可能在2型糖尿病（2DM）的发病机制中发挥作用，这一可能性导致人们对水杨酸盐可能代表改善葡萄糖耐量的有用治疗的可能性的兴趣增加。在2型糖尿病患者以及非糖尿病肥胖个体中进行的几项研究表明，水杨酸盐对葡萄糖和胰岛素代谢具有有益作用，但尚未就所涉及的机制得出一致的观点。因此，关于水杨酸盐对胰岛素作用、胰岛素分泌和胰岛素清除的影响，已经提出了积极和消极的信息。缺乏共识可能是由于这些研究均未使用特定方法（与替代估计相反）来量化水杨酸盐给药对同一研究中所有三个相关变量的影响;胰岛素介导的葡萄糖摄取（IMGU）、葡萄糖刺激的胰岛素分泌率（GS-ISR）和胰岛素清除率（I-Cl）。此外，在肥胖、非糖尿病个体中的研究没有考虑到大约三分之一的肥胖个体是胰岛素敏感的这一事实，并且难以证明任何干预对这些受试者的IMGU的有益效果。本研究提案代表了通过使用特定方法量化超重/肥胖、非糖尿病、胰岛素抵抗个体中的IMGU、GS-ISR和I-Cl来克服这些混杂因素的努力。我们将使用胰岛素抑制试验（IST）对非糖尿病、超重/肥胖志愿者的IMGU进行定量，以确定是否有足够的胰岛素抵抗可入组本研究。然后，我们将在这些胰岛素抵抗受试者中使用分级葡萄糖输注技术，以生成GS-IS和I-Cl的特定测量值。在这些基线测量后，将对受试者给予双水杨酯或安慰剂一个月，之后将重复IST和分级葡萄糖输注，以量化和比较双水杨酯与安慰剂导致的IMGU、GS-ISR和I-Cl的变化。这些结果将首次提供水杨酸盐对超重/肥胖、胰岛素抵抗、非糖尿病个体的IMGU、GS-ISR和I-Cl影响的定量数据。 公共卫生相关性：虽然有证据表明水杨酸盐给药可能对糖尿病患者的治疗有用，但对于这种有益作用是如何发生的还没有普遍的共识。在这项研究中，我们将尝试使用特定的方法来提供这一缺失的信息，在超重/肥胖、胰岛素抵抗、非糖尿病个体中比较水杨酸盐与安慰剂给药对胰岛素作用、胰岛素分泌和胰岛素清除的影响。

DESCRIPTION (provided by applicant): The possibility that obesity-associated inflammatory changes may play a role in the pathogenesis of type 2 diabetes (2DM) has led to increased interest in the possibility that salicylates might represent a useful treatment to improve glucose tolerance. Several studies, performed in patients with 2DM, as well as in nondiabetic, obese individuals, have demonstrated that salicylates have beneficial effects on glucose and insulin metabolism, but have not led to a coherent view as to the mechanism(s) involved. Thus, both positive and negative information has been presented as to the effect of salicylates on insulin action, insulin secretion, and insulin clearance. The lack of consensus may result from the fact that none of these studies have used specific methods, in contrast to surrogate estimates, to quantify the effect of salicylate administration on all three relevant variables in the same study; insulin-mediated glucose uptake (IMGU), glucose-stimulated insulin secretion rate (GS-ISR), and insulin clearance (I-Cl). Furthermore, studies in obese, nondiabetic individuals have not taken into account the fact that approximately one-third of obese individuals are insulin sensitive, and it is difficult to demonstrate a benefice effect of any intervention on IMGU in such subjects. This research proposal represents an effort to overcome these confounders by using specific methods to quantify IMGU, GS- ISR, and I-Cl in overweight/obese, nondiabetic, insulin resistant individuals. We will use the insulin suppression test (IST) to quantify IMGU in nondiabetic, overweight/obese volunteers to identify those individuals who are sufficiently insulin resistant to be enrolled in this study. We will then use the graded glucose infusion technique in these insulin resistant subjects to generate specific measures of both GS-IS and I-Cl. Following these baseline measurements, salsalate or placebo will be administered for one month to the participants, after which time the IST and the graded glucose infusion will be repeated to quantify and compare the changes in IMGU, GS-ISR, and I-Cl that have resulted from salsalate versus placebo. These results will provide for the first time quantitative data of the effect of salicylates on IMGU, GS-ISR, and I-Cl in overweight/obese, insulin resistant, nondiabetic individuals. PUBLIC HEALTH RELEVANCE: Although there is evidence that salicylate administration may be useful in the treatment of patients with diabetes, there is no general agreement as how this beneficial effect occurs. In this study we will try to supply this missing information by using specific methods to compare in overweight/obese, insulin resistant, nondiabetic individuals the effects of salicylate versus placebo administration on insulin action, insulin secretion, and insulin clearance.