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

描述（由申请人提供）：本研究的长期目标是确定胰腺β细胞功能障碍在糖尿病发展中的早期机制。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）的关键组成部分。在T1D中，目前的共识是免疫细胞在胰岛内以非常高的剂量局部产生的细胞因子在胰腺β细胞的破坏中起关键作用。在T2D中，由于低度全身性炎症，循环细胞因子水平在疾病发展早期升高。然而，与低级别全身性炎症相关的循环细胞因子水平比胰岛内与T1D相关的直接免疫细胞浸润时低约100-1000倍。迄今为止，这些低水平细胞因子对β细胞的影响还没有被系统地研究过，特别是在肥胖和糖尿病模型中。我们的初步数据首次表明，特定的细胞因子组合，存在于肥胖和糖尿病个体血液中的浓度，足以诱导过量的基底细胞内游离钙，减少内质网（ER）钙的储存，并损害胰岛的胰岛素分泌。此外，这些细胞因子的作用在糖尿病前期db/db小鼠（T2D小鼠模型）的胰岛中更为严重。该提议的假设是，循环细胞因子在低级别全身性炎症的典型浓度下，通过破坏易患糖尿病的个体的细胞内钙处理，直接导致β细胞功能障碍。利用分子、电生理学和基于成像的方法，我们将通过解决三个特定目标来验证这一假设：(1)比较低度炎症对正常小鼠和糖尿病易感小鼠胰岛钙处理和细胞应激标志物的影响；(2)确定细胞因子诱导β细胞功能障碍的细胞位点；(3)确定低度炎症对正常小鼠、糖尿病易感小鼠或肥胖小鼠的体内影响。总的来说，这些研究将阐明细胞因子在肥胖和糖尿病患者体循环中浓度作用的新方面。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 β细胞功能障碍的治疗干预开辟新的途径。

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.