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: 10675473
• 负责人: Mohamed Saleh
• 金额: $ 16.32万
• 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/10675473
• 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; 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; 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) 是美国和全世界的一个主要健康问题，导致高发病率和死亡率。 据 CDC 称，2017 年，约 3250 万人患有 T2D，估计美国有 8800 万成年人 患有糖尿病前期。糖尿病是第七大死因，并已成为第一大生物医学疾病 美国的财政负担，估计 2017 年国民经济损失达 3270 亿美元。目前， T2D 没有根治方法。 研究表明，葡萄糖以双相模式诱导胰岛素分泌：初始第一相、 它发展迅速，但只持续几分钟，然后是最低点，然后是持续的第二阶段。损失 第一相胰岛素分泌减少和第二相分泌减少是 T2D 的特征。很好 已知第一相胰岛素分泌的减少是最早发现的有害缺陷 糖耐量受损（糖尿病前期）和 T2D。尽管研究强调存在两种内部 内分泌胰腺和外分泌胰腺之间的胰腺轴（岛叶轴和腺泡轴） 腺泡-岛叶轴），但很少有人关注胰腺外分泌对 β 细胞的直接影响 功能。我们最近设计了一种手术小鼠模型，其中胰管输注 1% 乙酸 (AcA) 导致外分泌胰腺完全消融，但重要的是完全保留了胰岛。这 该模型使我们能够在胰腺中原位研究 β 细胞功能，同时胰岛保留其天然神经支配 和脉管系统，但没有外分泌胰腺。我们还建立了一个遗传模型，使用 白喉毒素受体通过弹性蛋白酶启动子在腺泡细胞中选择性表达，从而快速消融 腺泡细胞使用白喉毒素。我们在小鼠和现在的非人类灵长类动物中的初步数据显示 葡萄糖耐量和第一相胰岛素分泌显着改善至超正常水平 胰腺外分泌消融。在遗传模型中观察到仅腺泡消融的相似表型 手术模型中的整体外分泌（腺泡和导管）消融支持了我们的假设，即腺泡 对 β 细胞特别有害的细胞。 该提案旨在通过以下方式了解该模型中葡萄糖稳态生理学的改进 进行高血糖钳夹。它还旨在通过检查来测试这项研究的潜在可翻译性 外分泌胰腺损失对肥胖引起的高血糖小鼠模型的影响并确定 外分泌组织丧失后胰岛素分泌改善的根本原因。另外，一个重要的 本研究的目的是试图找出对 β 细胞功能有不利影响的腺泡分泌因子。 该项目的成功完成将为本研究的最终目标提供基础 T2D 的治疗靶点可以在生理上增加胰岛素分泌，特别是第一阶段，而无需 引起低血糖。