Loss of the Exocrine Pancreas Improves Glucose Tolerance and Insulin Secretion

外分泌胰腺的丧失可改善葡萄糖耐量和胰岛素分泌

• 批准号: 10449695
• 负责人: Mohamed Saleh
• 金额: $ 16.47万
• 依托单位: UNIVERSITY OF PITTSBURGH AT PITTSBURGH
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-09-01 至 2027-07-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10449695
• 关键词: Ablation; Acetic Acids; Acinar Cell; Acinus organ component; Adult; Adverse effects; Affect; Anabolism; Animals; Attention; Beta Cell; Biphasic Pattern; Cause of Death; Cell membrane; Cell physiology; Cellular biology; Centers for Disease Control and Prevention (U.S.); Characteristics; Closure by clamp; Coculture Techniques; Communication; Cytoplasmic Granules; Data; Defect; Development; Diabetes Mellitus; Diagnosis; Diphtheria Toxin; Duct (organ) structure; Economic Burden; Elastases; Endothelial Cells; Enzymes; Excision; Exocrine pancreas; Exocytosis; Financial Hardship; Funding; Genetic Models; Genetic Transcription; Glucose; Glucose tolerance test; Goals; Health; High Fat Diet; Human; Hyperglycemia; Hypoglycemia; Image; In Situ; Infusion procedures; Institution; Insulin; Intercellular Fluid; Intervention; Islets of Langerhans; Lead; Mediating; Modeling; Molecular; Morbidity - disease rate; Mus; Non-Insulin-Dependent Diabetes Mellitus; Obesity; Operative Surgical Procedures; Pancreas; Pancreatic Ductal Adenocarcinoma; Pancreatic duct; Pancreatic enzyme; Pathway interactions; Patients; Peptide Hydrolases; Phase; Phenotype; Physiological; Physiology; Prediabetes syndrome; Preparation; Prevalence; Reporting; Research; Research Personnel; Resources; Reverse Transcriptase Polymerase Chain Reaction; Rodent; Serine Proteinase Inhibitors; Signal Transduction; Streptozocin; Supervision; Surgical Models; Testing; Tissues; Translations; Transplantation; United States; Universities; Viral; Viral Genes; Work; allotransplant; blood glucose regulation; cancer cell; design; diphtheria toxin receptor; economic cost; gene therapy; glucose tolerance; impaired glucose tolerance; improved; in vivo; insulin granule; insulin secretion; insulin sensitivity; islet; knock-down; mortality; mouse model; negative affect; nerve supply; nonhuman primate; novel therapeutics; peripheral blood; promoter; radiological imaging; response; selective expression; small hairpin RNA; therapeutic target; trafficking; transcriptome sequencing; tumor

Abstract Type 2 diabetes (T2D) is a major health problem in the US and worldwide, causing high morbidity and mortality. According to the CDC, in 2017, ~32.5 million had T2D, and an estimated 88 million adults in the United States had prediabetes. Diabetes is the seventh leading cause of death and has become the number one biomedical financial burden in the US, with an estimated national economic cost of $327 billion in 2017. Currently, there is no radical cure for T2D. Studies have demonstrated that glucose induces insulin secretion in a biphasic pattern: an initial first-phase, which develops rapidly but lasts only a few minutes, followed by a nadir, then a sustained second-phase. Loss of first-phase insulin secretion and reduced second-phase secretion are characteristic features of T2D. It is well known that a decrease in the first-phase insulin secretion is the earliest and detrimental defect detected in impaired glucose tolerance (prediabetes) and T2D. Although studies have highlighted the existence of two intra- pancreatic axes of communication between the endocrine and exocrine pancreas (the insular–acinar axis and the acinar–insular axis), little attention has been paid to any direct effect of the exocrine pancreas on β-cell function. We recently designed a surgical mouse model wherein a pancreatic ductal infusion of 1% acetic acid (AcA) led to complete ablation of the exocrine pancreas, but importantly with complete sparing of the islets. This model allows us to study β-cell function in-situ in the pancreas, with the islets retaining their native innervation and vasculature, but in the absence of the exocrine pancreas. We also established a genetic model that uses the diphtheria toxin receptor selectively expressed in acinar cells via the elastase promoter to quickly ablate acinar cells using diphtheria toxin. Our preliminary data in mice, and now in non-human primates, show a significant improvement in glucose tolerance and first-phase insulin secretion to supranormal levels following exocrine pancreas ablation. Observing a similar phenotype with both acinar-only ablation in the genetic model and global exocrine (acini and ducts) ablation in the surgical model supports our hypothesis that it is the acinar cells that are specifically detrimental to the β-cells. This proposal aims to understand the improvements in the physiology of glucose homeostasis in this model by performing the hyperglycemic clamp. It also aims to test the potential translatability of this study by examining the effect of exocrine pancreas loss in a mouse model of obesity-induced hyperglycemia and identifying the underlying causes of the improved insulin secretion following the loss of the exocrine tissue. Also, an important aim of this study is to try to identify the acinar-secreted factor that has an adverse effect on β-cell function. Successful completion of this project will provide the basis for the ultimate objective of this study of generating a therapeutic target for T2D that can physiologically increase insulin secretion, particularly the first-phase, without causing hypoglycemia.

抽象的 2型糖尿病（T2D）是美国和全球的主要健康问题，导致高发病和死亡率。 根据疾病预防控制中心的数据，2017年，约有3250万t2d，估计有880​​0万成年人在美国 有糖尿病。糖尿病是死亡的第七主要原因，已成为第一生物医学 美国的财务燃烧，估计在2017年的国家经济成本为3270亿美元。目前，有 没有对T2D的根本治疗。 研究表明，葡萄糖以双相模式诱导胰岛素分泌：初始第一阶段， 它迅速发展，但仅持续几分钟，然后是纳迪尔（Nadir），然后是持续的第二阶段。损失 第一阶段胰岛素分泌和减少的第二相分泌是T2D的特征。很好 知道第一阶段胰岛素分泌的减少是最早和有害的缺陷 葡萄糖耐受性受损（前糖尿病）和T2D。尽管研究强调了两个内部的存在 内分泌和外分泌胰腺之间通信的胰轴（岛 - acinar轴和 腺泡 - 单轴），对外分泌胰腺的任何直接影响对β细胞的任何直接影响很少 功能。我们最近设计了一种手术小鼠模型，其中胰腺导管输注1％乙酸 （ACA）导致了外分泌胰腺的完整消融，但重要的是，胰岛完全保留。这 模型使我们能够在胰腺中研究β细胞功能，而胰岛则保留其天然神经 和脉管系统，但在没有外分泌胰腺的情况下。我们还建立了一种使用的遗传模型 白喉毒素受体通过弹性启动子选择性地在腺泡细胞中选择性表达以快速消融 腺泡细胞使用白喉毒素。我们在老鼠中以及现在在非人类隐私处的初步数据，显示 在 外分泌胰腺消融。在遗传模型中观察类似的表型，两种仅腺泡消融 外科模型中的全球外分泌（ACINI和管道）消融支持我们的假设是 明确确定为β细胞的细胞。 该建议旨在通过该模型中了解该模型的葡萄糖稳态生理学的改善 执行高血糖夹。它还旨在通过检查这项研究的潜在翻译性 外分泌胰腺损失在肥胖引起的高血糖的小鼠模型中的影响并鉴定 损失外分泌组织后改善胰岛素分泌的根本原因。另外，重要的是 这项研究的目的是尝试识别对β细胞功能有不良影响的腺泡分泌因子。 该项目的成功完成将为这项研究的最终目标提供基础 T2D的治疗靶点，可以物理增加胰岛素分泌，尤其是第一阶段 引起低血糖。