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

2 型糖尿病中的低度炎症、细胞因子和 β 细胞功能障碍

• 批准号: 8668937
• 负责人: Craig S Nunemaker
• 金额: $ 33.5万
• 依托单位: UNIVERSITY OF VIRGINIA
• 依托单位国家: 美国
• 财政年份: 2011
• 资助国家: 美国
• 起止时间: 2011-07-29 至 2016-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8668937
• 关键词: Address; Affect; American; Beta Cell; Biological Markers; Blood; Blood Circulation; Calcium; Cell Death; Cell membrane; Cell physiology; Cells; Cellular Stress; Cessation of life; Chronic; Clinical Research; Consensus; Cytokine Signaling; Data; Development; Diabetes Mellitus; Diabetes prevention; Diet; Disease; Dose; Endoplasmic Reticulum; Failure; Functional disorder; Gene Expression; Goals; Image; Immune; In Vitro; Individual; Infiltration; Inflammation; Inflammatory; Inflammatory Response; Insulin; Insulin-Dependent Diabetes Mellitus; Ion Channel; Islets of Langerhans; Kinetics; Lead; Measures; Mediating; Metabolic Diseases; Metabolic stress; Mitochondria; Modeling; Molecular; Mus; Non-Insulin-Dependent Diabetes Mellitus; Obese Mice; Obesity; Pancreas; Patients; Physiological; Play; Process; Pump; Regulation; Research; Risk; Role; Serum; Severities; Signal Pathway; Site; Source; Staging; Structure of beta Cell of islet; Testing; Therapeutic Intervention; Time; Work; base; cytokine; db/db mouse; diabetic; endoplasmic reticulum stress; feeding; in vivo; insight; insulin secretion; islet; mitochondrial dysfunction; mouse model; novel; novel therapeutic intervention; prevent; protein expression

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.

描述（由申请人提供）：本研究的长期目标是确定糖尿病发展中胰腺β细胞功能障碍的早期机制。有证据表明，至少部分由细胞因子介导的炎症是1型糖尿病（T1 D）和2型糖尿病（T2 D）的关键组成部分。在T1 D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细胞的破坏中起着关键作用。在T2 D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，与低度全身性炎症相关的循环细胞因子水平比在与T1 D相关的直接免疫细胞浸润期间在胰岛内观察到的低约100- 1000倍。迄今为止，这些低水平细胞因子对β细胞的影响尚未得到系统性研究，特别是在肥胖和T2 D模型中。我们的初步数据首次表明，特定的细胞因子组合，目前在肥胖和糖尿病患者的血液中发现的浓度，足以诱导过量的基础细胞内游离钙，减少内质网（ER）钙储存，并损害胰岛中的胰岛素分泌。此外，这些细胞因子效应在来自糖尿病前期db/db小鼠（T2 D的小鼠模型）的胰岛中更严重。该建议的假设是，在低级别全身性炎症的典型浓度下的循环细胞因子通过破坏糖尿病易感个体中的细胞内钙处理而直接引起β细胞功能障碍。使用分子，电生理学和基于成像的方法，我们将通过解决三个具体目标来测试这一假设：（I）比较轻度炎症对正常和糖尿病易感小鼠胰岛中胰岛钙处理和细胞应激标志物的影响，（II）确定β-细胞中精氨酸诱导的功能障碍的细胞位点，（III）确定正常小鼠与糖尿病易感小鼠或肥胖小鼠中低度炎症的体内作用。总的来说，这些研究将阐明肥胖和糖尿病个体体循环中存在的浓度下细胞因子作用的新方面。鉴定马槟榔碱介导的β细胞功能障碍的早期阶段将开辟治疗干预的新途径，以预防早期T2 D中的β细胞功能障碍。