Loss of the Exocrine Pancreas Improves Glucose Tolerance and Insulin Secretion

摘要 2型糖尿病(T2D)是美国和世界范围内的一个主要健康问题，导致高发病率和死亡率。 根据美国疾病控制与预防中心的数据，2017年，约3250万人患有T2D，美国估计有8800万成年人 有糖尿病前驱症状。糖尿病是导致死亡的第七大原因，并已成为生物医学领域的头号杀手。 美国的财政负担，预计2017年全国经济成本为3270亿美元。目前，有 T2D无法根治。 研究表明，葡萄糖诱导胰岛素分泌有两个阶段：最初的第一阶段， 这一阶段发展迅速，但只持续了几分钟，随后是最低点，然后是持续的第二阶段。损失 第一时相胰岛素分泌减少和第二时相分泌减少是T2D的特征。这很好 已知第一时相胰岛素分泌减少是在 糖耐量受损(糖尿病前期)和T2D。尽管研究强调了两个内部存在的 胰腺内分泌和外分泌之间的交通轴(胰岛-腺泡轴和 腺泡-岛轴)，但很少有人注意到胰腺外分泌对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，在该模型中，胰腺导管内注入1%醋酸 (ACA)导致外分泌胰腺完全消融，但重要的是完全保留胰岛。这 模型使我们能够原位研究β细胞在胰腺中的功能，其中胰岛保留其固有的神经支配 和血管系统，但没有外分泌的胰腺。我们还建立了一个遗传模型，它使用 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以快速消融 使用白喉毒素的腺泡细胞。我们在老鼠身上的初步数据，以及现在在非人类灵长类动物身上的数据，显示出 糖耐量和第一时相胰岛素分泌显著改善至超过正常水平 胰腺外分泌切除。在遗传模型中观察到两种仅有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)消融支持我们的假设，即它是腺泡。 对β细胞特别有害的细胞。 这项建议旨在通过以下方式了解该模型中葡萄糖稳态的生理学改善 进行高血糖钳夹手术。它还旨在测试这项研究的潜在可译性 肥胖性高血糖小鼠胰腺外分泌减少的影响及鉴定 外分泌组织丧失后胰岛素分泌改善的根本原因。此外，还有一个重要的 本研究的目的是试图确定对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这项研究的最终目标提供基础，即产生 T2D的治疗靶点可以生理性地增加胰岛素的分泌，特别是第一阶段，而不是 导致低血糖。

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.