Beta Cell Adaptation to Stress in Baboon Pancreas After Partial Pancreatectomy

狒狒胰腺部分切除术后β细胞对应激的适应

• 批准号: 7655613
• 负责人: Franco Battista Ennio Folli
• 金额: $ 45.47万
• 依托单位: UNIVERSITY OF TEXAS HLTH SCIENCE CENTER
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-06-10 至 2011-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7655613
• 关键词: Acute; Affect; Alzheimer' s Disease; Aminobutyric Acids; Amyloid; Amyloid deposition; Amyloidosis; Animals; Apoptosis; Beta Cell; Cell Death; Cell Line; Cell Size; Cell physiology; Cells; Characteristics; Complementary DNA; Deposition; Diabetes Mellitus; Exposure to; Genetic; Glucose; Glutamate Transporter; Glutamates; Human; Hypertrophy; In Vitro; Insulin; Insulin Resistance; Insulinase; Ion Channel; Islets of Langerhans; Mediating; Metabolic; Metabolism; Modeling; Molecular; Morphology; Non-Insulin-Dependent Diabetes Mellitus; Obesity; Pancreas; Pancreatectomy; Pancreatic Polypeptide; Papio; Pathogenesis; Patients; Peptides; Pharmaceutical Preparations; Physiological; Placebos; Process; Production; Proteins; Rattus; Relative (related person); Residual state; Role; Staging; Stress; Structure; Testing; Therapeutic Intervention; Toxic effect; Visible Radiation; Work; amyloidogenesis; cytotoxicity; diabetic; endoplasmic reticulum stress; exenatide; extracellular; gamma-Aminobutyric Acid; glucose tolerance; human IRS2 protein; in vivo; insulin secretion; insulin sensitivity; insulin signaling; islet; light microscopy; nonhuman primate; novel; novel therapeutic intervention; prevent; protective effect; public health relevance; response

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.

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类2型糖尿病胰腺的特征，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，淀粉样肽的细胞毒性不是由光学显微镜可见的沉积物产生的，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产生的。有毒的 IAPP 原纤维和寡聚物与阿尔茨海默病 (AD) 相关的 ¿-淀粉样蛋白 (A¿) 原纤维和寡聚物具有共同的结构，表明 2 型糖尿病 (T2DM) 和 AD 具有相似的发病机制。此外，胰腺β细胞表达高水平的AD相关肽，并且T2DM通常与AD相关。非人灵长类动物 (NHP) 是研究淀粉样肽在 细胞失代偿中的作用的理想模型，因为 NHP 会自发地产生胰岛淀粉样变性和 T2DM，与人类非常相似。我们的具体目标是：（1）研究胰岛素敏感（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的急剧增加（通过部分胰腺切除术，PPx 实现）对正常耐糖（NGT）IS 和 IR 狒狒中 ¿ 细胞功能、形态和超微结构（特别强调 IAPP 和 A¿）的影响； (3) 检查旨在预防 PPx 诱导的 ¿ 细胞失代偿的不同治疗干预措施的效果； (4) 检验异常 A¿ 代谢和谷氨酸转运蛋白 (GLT-1) 活性可能诱发的假设 ¿-细胞死亡； (5) 研究狒狒胰腺体内（PPx 之前和之后）IAPP 和 A¿ 诱导的细胞毒性以及体外 ¿ 细胞系和分离的狒狒胰岛细胞毒性的分子机制。将特别强调淀粉样蛋白生成、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），以及谷氨酸转运（GLT-1）和代谢（γ-氨基丁酸，GABA的产生）； (6) 研究艾塞那肽在体内和体外对 ¿ 细胞扩增/新生和存活产生有益影响的分子机制，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。公共健康相关性：我们的项目旨在：1) 阐明在肥胖和 2 型糖尿病的新型非人类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) 阐明潜在的细胞和分子机制 朗格汉斯狒狒胰岛和β细胞系中产生胰岛素的胰腺中异常蛋白质沉积和细胞死亡，以及旨在预防这种现象的新疗法的效果。鉴于这种非人类灵长类动物与人类具有极高的遗传相似性，并且有可能剖析胰岛素产生细胞死亡的新分子机制以及某些药物可以预防这种死亡的机制，这些研究将使我们能够发现新的治疗方法，以防止 2 型糖尿病患者产生胰岛素的胰腺细胞损失。