Beta-Cell Exhaustion and Glucotoxicity in Diabetes

糖尿病中的β细胞耗竭和糖毒性

• 批准号: 10200803
• 负责人: Maria Sara Remedi
• 金额: $ 39.38万
• 依托单位: WASHINGTON UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-07-01 至 2024-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10200803
• 关键词: Address; Antidiabetic Drugs; Automobile Driving; Beta Cell; Blood Glucose; Calcium; Cell Death; Cell physiology; Cells; Cellular Stress; Chronic; Data; Diabetes Mellitus; Diabetic mouse; Dietary Intervention; Disease; Disease Progression; Event; Functional disorder; Glycolysis; Goals; Hand; Human; Hyperglycemia; Individual; Insulin; Lead; Light; Measures; Mitochondria; Molecular; Mus; Patients; Pharmacology; Pluripotent Stem Cells; Positioning Attribute; Process; Reactive Oxygen Species; Recovery; Structure of beta Cell of islet; Sulfonylurea Compounds; Testing; Transplantation; Work; World Health; cell injury; diabetes pathogenesis; diabetic; diabetic patient; endoplasmic reticulum stress; exhaustion; experimental study; glucose metabolism; human model; human stem cells; improved; in vivo; in vivo evaluation; induced pluripotent stem cell; insulin secretion; mitochondrial dysfunction; mouse model; neonatal diabetes mellitus; novel; novel strategies; prevent; response; stem cells; success; tool

Diabetes mellitus is one of the major world health problems. Reduced pancreatic β-cell function and loss of β-cell mass are key events in the pathogenesis of diabetes mellitus. In normal conditions, the pancreatic β-cell responds to elevated blood glucose with insulin secretion, and to persistently elevated blood glucose (hyperglycemia) with compensatory increase in insulin secretion and β-cell mass. Persistent hyperglycemia may also lead to glucotoxic β-cell dysfunction, with loss of insulin content and β-cell mass. We and others have recently demonstrated that loss of β-cell mass in diabetes is associated with loss of β-cell identity, rather than cell death, as frequently assumed. Strikingly, we have also shown that this process is reversible, with recovery of β-cell mass and therefore antidiabetic drug responsivity, after lowering of blood glucose with insulin therapy in experimental neonatal diabetes mellitus. These results, correlating with human studies of recovery of sulfonylurea responsivity following insulin therapy in diabetes, challenge the current understanding of permanent β-cell damage in diabetes, and prompt us to study the underlying mechanisms of loss- and recovery- of β-cell identity in vivo, which remain elusive. Chronic hyperglycemia will lead to increased reactive oxygen species (ROS) formation. Excessive ROS will lead to mitochondrial dysfunction, and increased oxidative and endoplasmic reticulum (ER) stress; likely to be major contributors to glucotoxic loss of β-cell identity in systemic diabetes. The main goal of this proposal seeks to address the question of what are the mechanisms underlying loss of β-cell mass and identity in diabetes in vivo. We will use novel mouse models of human neonatal diabetes driven by β-cell insulin secretory deficiency as well as other diabetic mouse models. We will specifically test what is the contribution of hyperglycemia vs lack of insulin in loss of β-cell identity in systemic diabetes, and if hyperglycemia-induced cellular stress and consequent mitochondrial dysfunction is driving it. We will also determine translatability of these features to human β-cells by using stem cell derived β-cells from diabetic patients. In seeking answers to these questions, the experiments proposed in this project represent a significant effort to understand mechanisms underlying diabetic glucotoxicity and loss of β-cell identity will be of direct relevance to the progression of human diabetes, potentially opening up the exciting possibility to restore or revent loss of β-cell mass in diabetes.

糖尿病是世界上主要的健康问题之一。胰腺β细胞功能降低和β细胞质量损失是糖尿病发病机制中的关键事件。在正常情况下，胰腺β-细胞对升高的血糖有胰岛素分泌的响应，对持续升高的血糖（高血糖症）有胰岛素分泌和β-细胞质量的代偿性增加的响应。持续性高血糖症还可能导致葡萄糖毒性β细胞功能障碍，伴随胰岛素含量和β细胞质量的损失。我们和其他人最近已经证明，糖尿病中β细胞质量的损失与β细胞身份的丧失有关，而不是通常认为的细胞死亡。令人惊讶的是，我们还表明，这一过程是可逆的，在实验性新生儿糖尿病中用胰岛素治疗降低血糖后，β细胞质量恢复，因此抗糖尿病药物反应性恢复。这些结果与糖尿病胰岛素治疗后磺酰脲类药物反应性恢复的人体研究相关，挑战了目前对糖尿病永久性β细胞损伤的理解，并促使我们研究体内β细胞身份丧失和恢复的潜在机制，这仍然是难以捉摸的。慢性高血糖会导致活性氧（ROS）形成增加。过量的ROS将导致线粒体功能障碍，以及氧化和内质网（ER）应激增加;可能是全身性糖尿病中β细胞特性的葡萄糖毒性丧失的主要原因。该提案的主要目标是解决体内糖尿病中β细胞质量和身份丧失的潜在机制是什么的问题。我们将使用由β细胞胰岛素分泌缺陷驱动的人类新生儿糖尿病的新型小鼠模型以及其他糖尿病小鼠模型。我们将特别测试高血糖与胰岛素缺乏在系统性糖尿病中β细胞身份丧失中的作用，以及高血糖诱导的细胞应激和随之而来的线粒体功能障碍是否是驱动它的因素。我们还将通过使用来自糖尿病患者的干细胞衍生的β细胞来确定这些特征对人类β细胞的可翻译性。在寻求这些问题的答案时，本项目中提出的实验代表了理解糖尿病葡萄糖毒性和β细胞身份丧失的潜在机制的重大努力，这些机制将与人类糖尿病的进展直接相关，可能为恢复或逆转糖尿病中β细胞质量的丧失开辟令人兴奋的可能性。