Beneficial effect of salicylates: insulin action, secretion or clearance?

水杨酸盐的有益作用：胰岛素作用、分泌或清除？

• 批准号: 7863404
• 负责人: GERALD M. REAVEN
• 金额: $ 36万
• 依托单位: STANFORD UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2010
• 资助国家: 美国
• 起止时间: 2010-07-20 至 2013-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7863404
• 关键词: Accounting; Agreement; Consensus; Data; Diabetes Mellitus; Enrollment; Glucose; Goals; Individual; Inflammation; Inflammatory; Infusion Technique; Infusion procedures; Insulin; Insulin Resistance; Intervention; Link; Measurement; Measures; Mediating; Metabolism; Methods; Non-Insulin-Dependent Diabetes Mellitus; Obesity; Overweight; Participant; Pathogenesis; Patients; Placebos; Play; Prevalence; Qualifying; Randomized; Research Proposals; Role; Testing; Time; glucose metabolism; glucose tolerance; glucose uptake; glycemic control; improved; insulin secretion; interest; non-diabetic; public health relevance; salicylate; salicylsalicylic acid; volunteer

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.

描述（由申请人提供）：肥胖相关的炎症变化可能在 2 型糖尿病 (2DM) 的发病机制中发挥作用的可能性引起了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 2DM 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，既有积极的信息，也有消极的信息。缺乏共识可能是因为这些研究都没有使用与替代估计相反的特定方法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，对肥胖、非糖尿病个体的研究并未考虑到大约三分之一的肥胖个体对胰岛素敏感这一事实，并且很难证明对此类受试者的 IMGU 进行任何干预具有有益效果。本研究提案旨在通过使用特定方法量化超重/肥胖、非糖尿病、胰岛素抵抗个体的 IMGU、GS-ISR 和 I-Cl 来克服这些混杂因素。我们将使用胰岛素抑制试验 (IST) 来量化非糖尿病、超重/肥胖志愿者的 IMGU，以确定那些具有足够胰岛素抵抗性的个体，可以参加这项研究。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 的具体测量值。在这些基线测量之后，将给参与者服用水杨酸或安慰剂一个月，之后将重复 IST 和分级葡萄糖输注，以量化和比较 IMGU、GS-ISR 和 I-Cl 的变化。水杨酸与安慰剂的结果。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。 公共健康相关性：尽管有证据表明水杨酸盐给药可能有助于治疗糖尿病患者，但对于如何产生这种有益效果尚未达成普遍共识。在这项研究中，我们将尝试通过使用特定方法来比较超重/肥胖、胰岛素抵抗、非糖尿病个体中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，从而提供这些缺失的信息。