Paracrine feedback by pancreatic delta cells to control glucagon and insulin release and manage diabetes

胰腺δ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: 10660399
• 负责人: Mark O. Huising
• 金额: $ 47.97万
• 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 2028-03-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10660399
• 关键词: Address; Adult; Agonist; Alpha Cell; American; Ants; Attenuated; Behavior; Beta Cell; Biosensor; CDC42 gene; Calcium; Cell surface; Cells; Cilia; Cyclic AMP; Cytoskeleton; D Cells; Diabetes Mellitus; Disease; Dyes; Epidemic; Equilibrium; Exocytosis; Exocytosis Inhibition; F-Actin; Feedback; Fluorescence Resonance Energy Transfer; Gap Junctions; Genetic Transcription; Glucagon; Glucose; Goals; Guanosine Triphosphate Phosphohydrolases; Health; Hormones; Hyperglycemia; Hypoglycemia; Individual; Injections; Insulin; Insulin deficiency; Islet Cell; Islets of Langerhans; Learning; Literature; Liver; Measures; Mediating; Mission; National Institute of Diabetes and Digestive and Kidney Diseases; Nutrient; Pancreatic delta Cell; Pathway interactions; Patients; Persistent Hyperinsulinemia Hypoglycemia of Infancy; Physiological; Physiology; Positioning Attribute; Prediabetes syndrome; Public Health; Publishing; Quality of life; Research; Role; SSTR2 gene; SSTR3 gene; Somatostatin; Somatostatin Receptor; Source; Structure of beta Cell of islet; Testing; Therapeutic; Time; Tolbutamide; Translating; blood glucose regulation; cell behavior; diabetes management; experimental study; improved; innovation; insulin secretion; islet; new technology; new therapeutic target; novel; novel strategies; paracrine; prevent; response; restraint; standard care; type I and type II diabetes

Half of US adults have diabetes or pre-diabetes, illustrating a critical need for novel 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 (patho)physiological crosstalk within pancreatic islets in order to identify novel therapeutic targets. The overall objective in this application is to understand how endogenous SST inhibits Ca2+ and cAMP pathways in alpha and beta cells concurrently to balance inhibition of insulin and glucagon exocytosis. How a single inhibitory hormone can balance the inhibition of beta and alpha cells is a major and poorly understood aspect of islet physiology. The central hypothesis is that the pancreatic delta cell coordinates with beta cells to attenuate insulin and glucagon secretion by inhibiting Ca2+ and cAMP while concurrently remodeling the F-actin cytoskeleton to limit exocytosis. The rationale for the proposed research is that elucidating the mechanisms and circumstances of delta inhibition of alpha and beta cells would establish a better understanding of the physiological role of delta cells. This hypothesis will be tested in 3 specific aims. Aim 1 tests the hypothesis that beta and delta cells coordinate responses largely independently of gap junctions via the exchange of paracrine factors. Beta and delta cell calcium behavior will be quantified across hundreds of beta and delta cells in the same intact islets by GCaMP6. Dye injection experiments will determine if gap junctions can account for the coordinated delta and beta cell behavior. Aim 2 tests the hypothesis that endogenous delta cell feedback inhibition leads to robust intra-islet elevations of SST that coordinate alpha and beta cell behaviors via the combined inhibition of cAMP and Ca2+. Beta cells primarily respond to glucose with Ca2+. Insulin release is potentiated by cAMP. Ca2+ and cAMP will be quantified across hundreds of alpha and beta cells expressing biosensors for Ca2+ and cAMP in islets with or without SST. We will quantify local SST release via unique Sstr2 and Sstr3 (ant)agonists to determine the relative importance of cilia SSTR3 and cell-surface Sstr2. Aim 3 tests the hypothesis that activation of SSTR2 and SSTR3 on alpha and beta cells differentially inhibits exocytosis by remodeling the cortical F-actin network by activating RhoA GTPase. F-actin remodeling will be tested directly using FRET biosensors for RhoA expressed by stable MIN6 cells and primary islets in response to SST, by measuring dynamic remodeling of cortical F-actin via LifeAct, and by quantifying transcriptional changes to stimulation of primary alpha and beta cells with SSTR2 and SSTR3-selective agonists. 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 towards novel strategies to curb the diabetes epidemic in the US.

一半的美国成年人患有糖尿病或糖尿病前期，这表明迫切需要新的治疗方法。有一个 在理解胰岛旁分泌反馈如何控制胰岛素和胰高血糖素方面存在根本性的差距。的 长期目标是阐明胰岛内的（病理性）生理串扰，以鉴定新的 治疗目标本申请的总体目标是了解内源性SST如何抑制Ca 2 + 和cAMP途径，以平衡胰岛素和胰高血糖素胞吐作用的抑制。 单一的抑制激素如何平衡β细胞和α细胞的抑制是一个主要的， 了解胰岛生理学方面。核心假设是胰腺δ细胞与 通过抑制Ca 2+和cAMP同时抑制β细胞的胰岛素和胰高血糖素分泌， 重塑F-肌动蛋白细胞骨架以限制胞吐作用。拟议研究的理由是， 阐明α和β细胞的δ抑制的机制和情况将建立一个更好的 了解δ细胞的生理作用。这一假设将在3个具体目标中进行检验。Aim 1测试 假设β和δ细胞协调反应很大程度上独立于间隙连接，通过 旁分泌因子的交换。β和δ细胞钙行为将在数百个β细胞中进行量化。 和δ细胞在相同的完整胰岛中通过GCaMP 6。染料注射实验将确定缝隙连接是否 可以解释δ细胞和β细胞的协同行为目的2检验了内源性δ 细胞反馈抑制导致协调α和β细胞的SST的强烈胰岛内升高 通过cAMP和Ca ~（2+）的联合抑制来实现。β细胞主要以Ca 2+响应葡萄糖。 胰岛素释放由cAMP增强。将在数百个α和β细胞中定量Ca 2+和cAMP 在有或没有SST的胰岛中表达Ca 2+和cAMP的生物传感器。我们将通过以下方式量化当地SST释放： 独特的Sstr 2和Sstr 3（ant）激动剂，以确定纤毛Sstr 3和细胞表面Sstr 2的相对重要性。 目的3检验α细胞和β细胞上SSTR 2和SSTR 3的激活差异性抑制 通过激活RhoA GT3蛋白重塑皮质F-肌动蛋白网络，胞吐。F-肌动蛋白重塑将是 使用FRET生物传感器直接测试由稳定的MIN 6细胞和原代胰岛表达的RhoA， SST，通过LifeAct测量皮质F-肌动蛋白的动态重塑，并通过定量转录变化 涉及用SSTR 2和SSTR 3选择性激动剂刺激原代α和β细胞。这项研究是 在申请人看来，这在概念上和技术上都是创新的，因为它评估了重要的生理功能， 完整胰岛内的δ细胞在减弱α和β细胞活性中的作用。它通过应用新的 技术，以克服以前排除此类研究的障碍。这一点意义重大，因为 δ细胞对胰高血糖素和胰岛素分泌的控制对于新策略具有广泛的转化重要性 来遏制美国糖尿病的流行。

项目成果

Nine residues in HLA-DQ molecules determine with susceptibility and resistance to type 1 diabetes among young children in Sweden.

• DOI: 10.1038/s41598-021-86229-8
• 发表时间: 2021-04-23
• 期刊: Scientific reports
• 影响因子: 4.6
• 作者: Zhao LP;Papadopoulos GK;Moustakas AK;Bondinas GP;Carlsson A;Larsson HE;Ludvigsson J;Marcus C;Persson M;Samuelsson U;Wang R;Pyo CW;Geraghty DE;Lernmark Å
• 通讯作者: Lernmark Å

An Intraislet Paracrine Signaling Pathway That Enables Glucagon to Stimulate Pancreatic β-Cells.

胰高血糖素能够刺激胰腺β细胞的胰岛内旁分泌信号通路。

• DOI: 10.2337/dbi23-0023
• 发表时间: 2023
• 期刊: Diabetes
• 影响因子: 7.7
• 作者: Caicedo,Alejandro;Huising,MarkO;Wess,Jürgen
• 通讯作者: Wess,Jürgen

Coordination between ECM and cell-cell adhesion regulates the development of islet aggregation, architecture, and functional maturation.

• DOI: 10.7554/elife.90006
• 发表时间: 2023-08-23
• 期刊: eLife
• 影响因子: 7.7
• 作者: Tixi W;Maldonado M;Chang YT;Chiu A;Yeung W;Parveen N;Nelson MS;Hart R;Wang S;Hsu WJ;Fueger P;Kopp JL;Huising MO;Dhawan S;Shih HP
• 通讯作者: Shih HP

Paracrine regulation of insulin secretion.

• DOI: 10.1007/s00125-020-05213-5
• 发表时间: 2020-10
• 期刊: Diabetologia
• 影响因子: 8.2
• 作者: Huising MO

Evidence for a Neogenic Niche at the Periphery of Pancreatic Islets.

• DOI: 10.1002/bies.201800119
• 发表时间: 2018-11
• 期刊: BioEssays : news and reviews in molecular, cellular and developmental biology
• 作者: Huising MO;Lee S;van der Meulen T
• 通讯作者: van der Meulen T