PARACRINE FEEDBACK BY PANCREATIC DELTA CELLS TO CONTROL GLUCAGON AND INSULIN RELEASE AND MANAGE DIABETES

胰腺 Delta 细胞的旁分泌反馈控制胰高血糖素和胰岛素释放并控制糖尿病

• 批准号: 10186732
• 负责人: Mark O. Huising
• 金额: $ 39.25万
• 依托单位: UNIVERSITY OF CALIFORNIA AT DAVIS
• 依托单位国家: 美国
• 财政年份: 2017
• 资助国家: 美国
• 起止时间: 2017-07-01 至 2023-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10186732
• 关键词: Address; Adult; Affect; Alpha Cell; American; Attenuated; Beta Cell; Blood Glucose; Calcium; D Cells; Data; Diabetes Mellitus; Disease; Epidemic; Equilibrium; Feedback; Functional disorder; G-Protein-Coupled Receptors; Genetic; Glucagon; Glucose; Goals; Health; Human; Hyperglycemia; Insulin; Insulin deficiency; Insulin-Dependent Diabetes Mellitus; Intervention; Islets of Langerhans; Laboratories; Learning; Liver; Measures; Mediating; Mission; Modeling; Mus; National Institute of Diabetes and Digestive and Kidney Diseases; Non-Insulin-Dependent Diabetes Mellitus; Pancreatic delta Cell; Pathway interactions; Patients; Perfusion; Pharmacology; Physiological; Plasma; Positioning Attribute; Prediabetes syndrome; Public Health; Quality of life; Research; Rest; Role; Secondary to; Somatostatin; Source; Streptozocin; System; Testing; Therapeutic Intervention; base; blood glucose regulation; calcium indicator; cell type; diabetes management; diabetic; experimental study; improved; in vivo; inducible gene expression; innovation; insulin secretion; islet; new technology; new therapeutic target; novel; novel strategies; paracrine; peptide hormone; prospective; response; restoration; selective expression; standard care; targeted treatment

Half of US adults have diabetes or pre-diabetes, illustrating a critical need for novel diabetes treatments. There is a fundamental gap in the understanding of how paracrine feedback in the islet controls insulin and glucagon. The long-term goal is to elucidate the key players in (patho)physiological crosstalk within pancreatic islets in order to identify novel therapeutic targets. The overall objective in this application is to understand delta cell-mediated feedback control. The peptide hormone urocortin3 (Ucn3) promotes somatostatin (Sst) secretion from delta cells in order to attenuate insulin and glucagon. This feedback determines the set-point for plasma glucose, but is perturbed in diabetes and contributes to its pathophysiology. The central hypothesis is that the pancreatic delta cell is a local control hub that determines the homeostatic set point for glucose and can be targeted to rebalance glucagon and insulin in diabetes. This hypothesis was formulated on the basis of preliminary data produced in the applicants' laboratory. The rationale for the proposed research is to understand how Ucn3 and Sst control insulin and glucagon, thus identifying delta cell-dependent feedback as a novel target for diabetes treatment. This hypothesis will be tested in 3 specific aims. Aim 1 tests the hypothesis that delta cells secrete most of their Sst under control of GPCR activation by Ucn3, which assures delayed, beta cell-dependent Sst secretion. Insulin and Sst release will be measured in parallel by islet perfusion, and the mechanistic similarities and differences of delta and beta cell activation will be investigated following the selective expression of the GCaMP6 calcium indicator in both cell types. Aim 2 tests the hypothesis that beta cell-derived Ucn3 promotes Sst release to inhibit alpha cells under high glucose, while Ucn3 from human alpha cells reflects a separate feedback loop to attenuate glucagon at low glucose. This hypothesis is supported by the applicants' preliminary observations that Ucn3 promotes Sst secretion and inhibits alpha cell activity and glucagon release. Glucagon secretion and calcium responses of alpha cells within intact islets will be measured following genetic and pharmacological inhibition of Ucn3. We will also test the effect of `humanizing' feedback control in mice by the inducible expression of Ucn3 in mouse alpha cells. Aim 3 tests the hypothesis that loss of Ucn3-dependent negative feedback aggravates diabetes by allowing inappropriate glucagon release. We will measure alpha and beta cell responses in islets of diabetes models using GCaMP6 in the presence and absence of Ucn3, and the restoration of delta cell feedback using chemicogenetics in vivo secondary to STZ-induced diabetes. The research is conceptually and technically innovative, in the applicants' opinion, as it evaluates the important physiological role of delta cells within intact islets in attenuating alpha and beta cell activity. It attains this by applying new technologies to overcome the hurdles that have previously precluded such studies. This is significant because delta cell control over glucagon and insulin secretion has broad translational importance and could uncover novel strategies to curb the diabetes epidemic in the US.

我们一半的成年人患有糖尿病或糖尿病前，这说明了对新型糖尿病治疗的迫切需求。理解胰岛中的旁分泌反馈如何控制胰岛素和胰高血糖素的基本差距。长期目标是阐明胰岛中（Patho）生理串扰的主要参与者，以识别新型的治疗靶标。该应用程序的总体目的是了解三角细胞介导的反馈控制。肽激素尿素素3（UCN3）促进三角细胞的生长抑素（SST）分泌，以减轻胰岛素和胰高血糖素。这种反馈决定了血浆葡萄糖的设定点，但在糖尿病中受到干扰，并有助于其病理生理学。中心假设是胰腺三角细胞是一个局部控制枢纽，它决定了葡萄糖的稳态设定点，并且可以针对糖尿病中的重新平衡胰高血糖素和胰岛素。该假设是根据申请人实验室中产生的初步数据提出的。拟议的研究的基本原理是了解UCN3和SST控制胰岛素和胰高血糖素如何确定Delta细胞依赖性反馈是糖尿病治疗的新靶标。该假设将以3个特定目的进行检验。 AIM 1检验了以下假设：三角细胞通过UCN3控制其SST的大部分SST，这确保了延迟的β细胞依赖性SST分泌。胰岛素和SST释放将通过胰岛灌注并行测量，并在两种细胞类型中的GCAMP6钙指标的选择性表达后，将研究三角洲和β细胞激活的机械相似性和差异。 AIM 2检验了以下假设：β细胞衍生的UCN3促进SST释放以抑制高葡萄糖下的α细胞，而人α细胞的UCN3反映了一个单独的反馈回路，以减轻低葡萄糖处的胰高血糖素。该假设得到了申请人的初步观察，即UCN3促进了SST分泌并抑制α细胞活性和胰高血糖素的释放。在UCN3的遗传和药理抑制后，将测量完整胰岛内α细胞的胰高血糖素分泌和钙反应。我们还将通过小鼠α细胞中UCN3的诱导表达来测试小鼠中“人性化”反馈控制的效果。 AIM 3检验了以下假设：UCN3依赖性负反馈的丧失通过允许不适当的胰高血糖素释放加剧糖尿病。我们将使用GCAMP6在UCN3的存在下使用GCAMP6在糖尿病模型的胰岛中测量α和β细胞反应，并使用继发于STZ诱导的糖尿病的体内化学遗传学在体内恢复三角细胞的反馈。在申请人的意见中，这项研究在概念和技术上是创新的，因为它评估了完整胰岛在减弱α和β细胞活性中的重要生理作用。它通过应用新技术来克服以前排除此类研究的障碍来实现这一目标。这很重要，因为三角细胞对胰高血糖素和胰岛素分泌的控制具有广泛的翻译重要性，并且可以揭示抑制美国糖尿病流行的新型策略。