Low-grade Inflammation, Cytokines, and Beta-Cell Dysfunction in Type 2 Diabetes

描述(由申请人提供)：这项研究的长期目标是确定糖尿病发展过程中胰岛β细胞功能障碍的早期机制。有证据表明，炎症至少部分由细胞因子介导，是1型糖尿病(T1D)和2型糖尿病(T2D)的关键成分。在T1D，目前的共识是免疫细胞以非常高的剂量在胰岛内局部产生的细胞因子在破坏胰岛β细胞方面起着关键作用。在T2D中，由于低度全身炎症，循环细胞因子水平在疾病发展的早期升高。然而，与低度全身炎症相关的循环细胞因子水平比与T1D相关的直接免疫细胞渗透期间胰岛内的水平低约100-1000倍。到目前为止，这些低水平的细胞因子对β细胞的影响还没有得到系统的研究，特别是在肥胖和T2D模型中。我们的初步数据首次表明，在肥胖和糖尿病患者的血液中发现的特定细胞因子组合足以诱导过量的基础细胞内游离钙，减少内质网(ER)钙存储，并损害胰岛的胰岛素分泌。此外，这些细胞因子效应在糖尿病前期db/db小鼠的胰岛中更为严重，db/db小鼠是t2d的小鼠模型。这一建议的假设是，循环中的细胞因子在低度全身炎症的典型浓度下，通过扰乱易患糖尿病的人的细胞内钙处理，直接导致β细胞功能障碍。我们将使用分子、电生理和基于成像的方法，通过三个具体目标来检验这一假说：(I)比较低度炎症对正常和易患糖尿病小鼠胰岛钙处理和细胞应激标志物的影响，(Ii)确定细胞因子诱导的β细胞功能障碍的细胞位置，(Iii)确定低度炎症对正常和易患糖尿病或肥胖小鼠的体内影响。总而言之，这些研究将阐明肥胖和糖尿病患者体内循环中存在的浓度下细胞因子作用的新方面。识别细胞因子介导的β细胞功能障碍的早期阶段将为预防早期T2D的β细胞功能障碍开辟新的治疗干预途径。

DESCRIPTION (provided by applicant): The long-term goal of this research is to identify the early mechanisms of pancreatic beta-cell dysfunction in development of diabetes. Evidence suggests that inflammation, mediated by at least in part by cytokines, is a key component in both type 1 diabetes (T1D) and type 2 diabetes (T2D). In T1D, the current consensus is that cytokines produced locally within the islets at very high doses by immune cells play a critical role in the destruction of pancreatic beta cells. In T2D, circulating cytokine levels are elevated early in the development of the disease due to low-grade systemic inflammation. However, circulating cytokine levels associated with low- grade systemic inflammation are ~100-1000x lower than seen within the islet during direct immune cell infiltration associated with T1D. To date, the effects of these low-level cytokines on beta-cells have not been systematically examined, particularly in models of obesity and T2D. Our preliminary data show for the first time that specific cytokine combinations, present at concentrations found in the blood of obese and diabetic individuals, are sufficient to induce excess basal intracellular free calcium, reduce endoplasmic reticulum (ER) calcium storage, and impair insulin secretion in pancreatic islets. Furthermore, these cytokine effects are more severe in islets from pre-diabetic db/db mice, a mouse model of T2D. The hypothesis for this proposal is that circulating cytokines at concentrations typical of low-grade systemic inflammation directly cause beta-cell dysfunction by disrupting intracellular calcium handling in diabetes-prone individuals. Using molecular, electrophysiological, and imaging-based approaches, we will test this hypothesis by addressing three specific aims: (I) Compare the effects of low-grade inflammation on islet calcium handling and markers of cell stress in islets from normal and diabetes-prone mice, (II) Determine the cellular sites of cytokine-induced dysfunction in beta-cells, (III) Determine the in vivo effects of low-grade inflammation in normal vs. diabetes-prone or obese mice. Collectively, these studies will elucidate novel aspects of cytokine action at concentrations present in the systemic circulation in obese and diabetic individuals. Identifying early stages in cytokine-mediated beta-cell dysfunction will open new avenues of therapeutic intervention to prevent beta-cell dysfunction in early T2D.