Liver-islet and intra-islet cross talk in alpha cell hyperplasia and beta cell regeneration

α细胞增生和β细胞再生中的肝胰岛和胰岛内串扰

• 批准号: 10540191
• 负责人: WILLIAM L HOLLAND
• 金额: $ 45.48万
• 依托单位: UNIVERSITY OF UTAH
• 依托单位国家: 美国
• 财政年份: 2017
• 资助国家: 美国
• 起止时间: 2017-09-15 至 2026-05-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10540191
• 关键词: Ablation; Aftercare; Alpha Cell; Amino Acids; Animal Model; Apoptosis; Apoptotic; Area; B-Lymphocytes; Beta Cell; Blood Glucose; CHES1 gene; Carbohydrates; Cell Survival; Cells; Communication; Data; Diabetic mouse; Dissection; Ductal Epithelial Cell; FGF2 gene; Fasting; Fatty acid glycerol esters; Fc Receptor; Fibroblast Growth Factor Receptors; Functional Regeneration; Genetic; Genetic Transcription; Glucagon; Glucagon Receptor; Gluconeogenesis; Glucose; Hepatic; Hormones; Human; Hyperplasia; Impairment; Inbred NOD Mice; Insulin; Insulin-Dependent Diabetes Mellitus; Islets of Langerhans; Link; Liver; Mediating; Mediator of activation protein; Metabolic Diseases; Modeling; Monoclonal Antibodies; Mus; Natural regeneration; Non-Insulin-Dependent Diabetes Mellitus; Panic; Persons; Pharmaceutical Preparations; Phosphorylation; Plasma; Prevention; Production; Proteins; Publishing; Recombinant Fibroblast Growth Factor; Rodent; Role; Signal Transduction; Skeletal Muscle; Source; Structure of alpha Cell of islet; Tetracyclines; Tissues; Transcription Repressor; Transgenic Mice; Up-Regulation; Work; amino acid metabolism; antagonist; blood glucose regulation; cell regeneration; diabetic; euglycemia; functional restoration; glucose production; improved; in vivo; in vivo regeneration; incretin hormone; insulin secretion; islet; mouse model; non-diabetic; novel; overexpression; pancreatic juice; precursor cell; prevent; promoter; regenerative; uptake

ABSTRACT While evaluating the potential for glucagon receptor antagonists (GRAs) to maintain glucose homeostasis in T1D rodents, we noted that GRAs promote β−cell survival and regeneration. Remarkably, GRA-treated mice maintained normal blood glucose, even after the treatment was withdrawn. Our recently published data suggest that: 1) ablation or antagonism of the glucagon receptor (GcgR) blunts apoptosis and stimulates regeneration of functional β-cell mass in mice; 2) much of this new insulin+ mass derives from the conversion of α−cell precursors into insulin-producing cells; and 3) GRAs restore sustainable euglycemia and insulin production in diabetic NOD mice and in mice grafted with human islets. Our preliminary results suggest that the β-cytotrophic effects of GRAs occur through both islet autonomous effects and through a well described liver- α-cell axis4-7 which triggers α-cell hyperplasia through AA-dependent mechanisms (Figure 1). We have identified Foxn3, a glucagon-responsive transcriptional repressor and novel mediator of glycemia8-11, as the previously-undefined integrator by which glucagon alters amino acid metabolism. In parallel, we have identified the GRA-driven upregulation of fibroblast growth factor 2 (FGF2), a target of the proliferative transcriptional co-factor Yes-associated protein 1 (YAP1) that is expressed in Sox9+ ductal cells, as a key contributor to GRA-mediated revival of a regenerative niche within the islet. We hypothesize that impaired glucagon action promotes hepatic Foxn3-mediated α-cell hyperplasia via changes in amino acid metabolism and an FGF2-mediated regenerative niche within the islet to allow α-cell to β-cell conversion in T1D. We will evaluate our hypothesis using a cadre of novel, validated, and uniquely-suited mouse models which facilitate our genetic dissection of the mechanisms linking the loss of glucagon signaling to altered hepatic utilization of amino acids, α-cell hyperplasia, and the restoration of functional β-cell mass via two aims. 1) Using PANIC- ATTAC diabetic mice, cultured murine islets, and cultured human islets, we will examine the islet-autonomous effects of glucagon receptor antagonism or ablation on β-cell survival and β-cell regeneration. 2) We will examine α-cell hyperplasia, β-cell survival and the regeneration of functional β−cell mass after liver-specific deletion or overexpression of Foxn3.

摘要 在评估胰高血糖素受体拮抗剂（GRA）维持葡萄糖稳态的潜力时， T1 D啮齿动物，我们注意到GRA促进β细胞存活和再生。值得注意的是， 维持正常的血糖，即使在治疗停止后。我们最近公布的数据 提示：1）胰高血糖素受体（GcgR）的消融或拮抗作用减弱了细胞凋亡，并刺激了 小鼠中功能性β细胞团的再生; 2）这种新的胰岛素+团的大部分来源于转化 α-细胞前体转化为胰岛素产生细胞; 3）GRA恢复可持续的内皮细胞和胰岛素 在糖尿病NOD小鼠和移植人类胰岛的小鼠中产生。我们的初步结果表明， GRA的β-细胞营养作用通过胰岛自主作用和充分描述的肝- α-细胞轴4 -7通过AA依赖性机制触发α-细胞增生（图1）。我们有 Foxn 3是一种胰高血糖素反应性转录抑制因子，也是一种新的血糖调节因子8 -11， 以前未定义的整合剂，胰高血糖素通过该整合剂改变氨基酸代谢。同时，我们有 确定了GRA驱动的成纤维细胞生长因子2（FGF 2）的上调，FGF 2是细胞增殖的靶点。 转录辅因子Yes相关蛋白1（YAP 1），在Sox 9+导管细胞中表达，作为一个关键的 有助于GRA介导的胰岛内再生小生境的恢复。我们假设 胰高血糖素通过改变氨基酸代谢促进肝脏Foxn 3介导的α细胞增生 以及胰岛内FGF 2介导的再生小生境，以允许T1 D中的α细胞向β细胞转化。我们将 使用一系列新颖的、经过验证的、合适的小鼠模型来评估我们的假设， 我们对胰高血糖素信号丢失与肝脏对胰高血糖素的利用改变之间的机制进行了遗传解剖， 氨基酸、α细胞增生和功能性β细胞群的恢复。1)使用PANIC- ATTAC糖尿病小鼠、培养的鼠胰岛和培养的人胰岛，我们将检查胰岛自主性 胰高血糖素受体拮抗或消融对β细胞存活和β细胞再生的影响。2)我们将 检查α细胞增生，β细胞存活和功能性β细胞团的再生， Foxn 3的缺失或过表达。