Beta Cell Adaptation to Stress in Baboon Pancreas After Partial Pancreatectomy

描述（由申请人提供）：胰岛淀粉样胰腺多肽（IAPP）在胰岛中的沉积是人2型糖尿病胰腺的特征性特征，但代表了很久以前开始的过程的最后阶段。最近的证据表明，淀粉样蛋白生成肽的细胞毒性不是由光学显微镜可见的沉积物引起的，而是由细胞内原纤维聚集体和充当非选择性离子通道的可溶性低聚物引起的。毒性IAPP原纤维和寡聚体与阿尔茨海默病（AD）相关的淀粉样蛋白（A）原纤维和寡聚体具有共同的结构，表明2型糖尿病（T2 DM）和AD的发病机制相似。此外，胰腺细胞表达高水平的AD相关肽，T2 DM通常与AD相关。非人灵长类动物（NHP）是研究淀粉样蛋白生成肽在胰岛细胞失代偿中作用的理想模型，因为NHP与人类非常相似地自发发生胰岛淀粉样变性和T2 DM。我们的具体目标是：（1）学习;- 胰岛素敏感（IS）和胰岛素抵抗（IR）狒狒的细胞功能、形态和超微结构;（2）检查胰岛素分泌需求急性增加的影响（通过部分胰腺切除术，PPx实现）对细胞功能，形态和超微结构的影响（特别强调IAPP和A？）在正常葡萄糖耐受（NGT）IS和IR狒狒中的作用;（3）检查旨在预防PPx诱导的细胞失代偿的不同治疗干预的效果;（4）检验异常A？代谢和谷氨酸转运体（GLT-1）活性可能诱导PPx诱导的细胞失代偿的假设。 - 细胞死亡;（5）研究IAPP和A？在狒狒胰腺中（PPx前后）体内和体外在？细胞系和分离的狒狒胰岛中诱导细胞毒性的分子机制。重点将放在淀粉样蛋白生成、内质网（ER）应激、胰岛素信号传导（胰岛素受体底物-2，IRS-2）和降解（胰岛素降解酶，IDE）、谷氨酸转运（GLT- 1）和代谢（？氨基丁酸（GABA）;（6）研究负责Exenglutamine对体内和体外细胞扩增/新生和存活的有益作用的分子机制，特别强调IAPP-和 A？诱导的细胞毒性和ER应激、胰岛素信号传导和降解以及谷氨酸转运和代谢。了解狒狒淀粉样蛋白沉积和细胞死亡的分子机制可以为新的治疗方法提供理论基础。公共卫生相关性：我们的项目旨在：1）阐明在肥胖和2型糖尿病的新型非人灵长类动物模型狒狒中适应胰岛素产生胰腺细胞代谢需求增加的生理和分子机制，以及旨在保护胰岛素产生细胞的新疗法的效果，2）阐明胰岛素中异常蛋白质沉积和细胞死亡的细胞和分子机制-在狒狒胰岛和β细胞系中产生胰腺，以及旨在预防这种现象的新疗法的效果。鉴于这种非人灵长类动物与人类的遗传相似性极高，并且有可能剖析胰岛素产生细胞死亡的新分子机制以及一些药物可以预防的机制，这些研究将使我们能够发现新的治疗方法，以防止受2型糖尿病影响的患者的胰岛素产生胰腺细胞的损失。

DESCRIPTION (provided by applicant): Deposition of islet amyloid pancreatic polypeptide (IAPP) in the islets of Langerhans is the characteristic feature of human type 2 diabetic pancreas but represents the final stage of a process started long before. Recent evidence suggests that ¿-cell toxicity of amyloidogenic peptides results, not in the deposits visible by light microscopy, but rather from intracellular fibril aggregates and soluble oligomers that act as non-selective ion channels. Toxic IAPP fibrils and oligomers share a common structure with Alzheimer Disease (AD)-related ¿-amyloid (A¿) fibrils and oligomers, suggesting a similar pathogenesis of type 2 diabetes mellitus (T2DM) and AD. Moreover, pancreatic ¿-cells express high levels of AD-related peptides, and T2DM is frequently associated with AD. Non human primates (NHPs) represent ideal models to study the role of amyloidogenic peptides in ¿-cell decompensation, because NHPs spontaneously develop islet amyloidosis and T2DM very similarly to humans. Our specific aims are: (1) to study ¿-cell function, morphology, and ultrastructure in insulin sensitive (IS) and insulin resistant (IR) baboons; (2) to examine the effects of an acute increase in insulin secretory demand (achieved by partial pancreatectomy, PPx) on ¿-cell function, morphology and ultrastructure (with particular emphasis on IAPP and A¿) in normal glucose tolerant (NGT) IS and IR baboons; (3) to examine the effects of different therapeutic interventions aimed at preventing PPx-induced ¿-cell decompensation; (4) to test the hypothesis that abnormal A¿ metabolism and glutamate transporter (GLT-1) activity may induce ¿-cell death; (5) to study the molecular mechanisms responsible for IAPP- and A¿-induced cytotoxicity in vivo in the baboon pancreas (prior and after PPx) and in vitro in ¿-cells lines and isolated baboon islets. Particular emphasis will be placed in amyloidogenesis, and endoplasmic reticulum (ER) stress, insulin signaling (insulin receptor substrate-2, IRS-2) and degradation (insulin degrading enzyme, IDE), and glutamate transport (GLT- 1) and metabolism (production of ?-aminobutyric acid, GABA); (6) to study the molecular mechanisms responsible for the beneficial effect of Exenatide on ¿-cell expansion/neogenesis and survival in vivo and in vitro with particular emphasis on IAPP- and A¿-induced cytotoxicity and ER stress, insulin signaling and degradation, and glutamate transport and metabolism. Understanding the molecular mechanisms of amyloid deposition and ¿-cell death in the baboon could provide the rationale for the novel therapeutic approaches. PUBLIC HEALTH RELEVANCE: Our project is aimed at: 1) Clarifying the physiological and molecular mechanisms of adaptation to increased metabolic demand of insulin-producing pancreatic cell in a novel non-human primate model of obesity and type 2 diabetes, the baboon, and the effect of new therapies aimed at the protection of insulin producing cells, 2) clarifying the cellular and molecular mechanisms underlying abnormal protein deposition and cell death in insulin-producing pancreatic in baboon islets of Langerhans and beta cell lines and the effect of new therapies aimed at preventing this phenomenon. Given the extremely high genetic similarity of this non human primate to humans and the possibility to dissect novel molecular mechanisms of insulin producing cell death as well as the mechanisms by which some drugs could prevent it, these studies will allow us to discover new treatments to prevent the loss of insulin-producing pancreatic cells in patients affected by type 2 diabetes mellitus.