Investigating the role of immature beta cells in insulin release from the intact islet

研究未成熟β细胞在完整胰岛释放胰岛素中的作用

• 批准号: MR/S025618/1
• 负责人: David Hodson
• 金额: $ 68.99万
• 依托单位: University of Birmingham
• 依托单位国家: 英国
• 项目类别: Research Grant
• 财政年份: 2019
• 资助国家: 英国
• 起止时间: 2019 至 无数据
• 项目状态: 已结题
• 来源: https://gtr.ukri.org/projects?ref=MR%2FS025618%2F1
• 关键词: Investigating; role; immature; beta; cells

Type 2 diabetes mellitus (T2DM) occurs when pancreatic beta-cells are unable to release enough insulin to combat resistance to the hormone. The resulting increase in blood glucose levels drives a range of severe complications including cardiovascular disease, renal and liver failure, retinal degeneration and cancer. As such T2DM is considered an immediate healthcare crisis, affecting 1 in 10 adults in the UK and consuming 9% of the NHS annual budget. Despite intensive research efforts, T2DM incidence continues to rise and NHS spend is projected to double by 2035. To have any hope of halting this trend, we urgently need to open up new research avenues to identify mechanisms and therapeutic targets. Research from us and others over the past few years has shown that not all beta-cells are equal. Much like society, beta-cells possess different ages, abilities and capacities. When the proportions between these different beta-cells become imbalanced, for example during obesity, ageing or diabetes, then insulin release declines. In particular, predominance of younger or immature beta-cells is associated with generation of more beta-cells, but at the expense of insulin release. Despite this, practically nothing is known about the immature beta-cells that are normally resident in the healthy adult pancreas. Our most recent studies have shown that, contrary to expectation, immature beta-cells might in fact play a central role in regulating insulin release. We now aim to: 1) investigate how loss of immature cells influences behaviour of the other, more mature beta-cells;2) control the maturity status of individual beta-cells using light to directly explore their contribution to insulin release; 3) develop a mouse model where immature beta-cells can be made to be more mature using drugs in the food; 4) determine whether loss of immature beta-cells predisposes to T2DM. It is anticipated that these studies will provide an updated blueprint for insulin release, with relevance for T2DM treatment as well as the generation of islets from stem cells for transplantation.

2型糖尿病（T2 DM）发生在胰腺β细胞无法释放足够的胰岛素以对抗对激素的抵抗时。由此导致的血糖水平升高会导致一系列严重的并发症，包括心血管疾病、肾和肝功能衰竭、视网膜变性和癌症。因此，T2 DM被认为是一场迫在眉睫的医疗保健危机，影响英国十分之一的成年人，并消耗NHS年度预算的9%。尽管进行了大量的研究工作，但T2 DM的发病率仍在继续上升，预计到2035年，NHS的支出将翻一番。为了有希望阻止这一趋势，我们迫切需要开辟新的研究途径，以确定机制和治疗靶点。我们和其他人在过去几年的研究表明，并非所有的β细胞都是平等的。就像社会一样，β细胞拥有不同的年龄，能力和能力。当这些不同的β细胞之间的比例变得不平衡时，例如在肥胖，衰老或糖尿病期间，胰岛素释放就会下降。特别是，年轻或不成熟的β细胞的优势与更多β细胞的产生有关，但以胰岛素释放为代价。尽管如此，实际上对健康成人胰腺中通常存在的未成熟β细胞一无所知。我们最近的研究表明，与预期相反，未成熟的β细胞实际上可能在调节胰岛素释放方面发挥核心作用。我们现在的目标是：1）研究未成熟细胞的损失如何影响其他更成熟的β细胞的行为;2）使用光控制单个β细胞的成熟状态，以直接探索它们对胰岛素释放的贡献; 3）开发小鼠模型，其中可以使用食物中的药物使未成熟β细胞更加成熟; 4）确定未成熟β细胞的损失是否易患2型糖尿病。预计这些研究将为胰岛素释放提供更新的蓝图，与T2 DM治疗以及从干细胞生成用于移植的胰岛相关。

项目成果

Hypothalamic and brainstem glucose-dependent insulinotropic polypeptide receptor neurons employ distinct mechanisms to affect feeding.

• DOI: 10.1172/jci.insight.164921
• 发表时间: 2023-05-22
• 期刊: JCI INSIGHT
• 影响因子: 8
• 作者: Adriaenssens, Alice;Broichhagen, Johannes;de Bray, Anne;Ast, Julia;Hasib, Annie;Jones, Ben;Tomas, Alejandra;Burgos, Natalie Figueredo;Woodward, Orla;Lewis, Jo;O'Flaherty, Elisabeth;El, Kimberley;Cui, Canqi;Harada, Norio;Inagaki, Nobuya;Campbell, Jonathan;Brierley, Daniel;Hodson, David J.;Samms, Ricardo;Gribble, Fiona;Reimann, Frank
• 通讯作者: Reimann, Frank

The Effect of Ex Vivo Human Serum from Liver Disease Patients on Cellular Protein Synthesis and Growth.

• DOI: 10.3390/cells11071098
• 发表时间: 2022-03-24
• 期刊: Cells
• 影响因子: 6
• 作者: Allen SL;Seabright AP;Quinlan JI;Dhaliwal A;Williams FR;Fine NHF;Hodson DJ;Armstrong MJ;Elsharkaway AM;Greig CA;Lai YC;Lord JM;Lavery GG;Breen L
• 通讯作者: Breen L

Reagents and models for detecting endogenous GLP1R and GIPR.

• DOI: 10.1016/j.ebiom.2021.103739
• 发表时间: 2021-12
• 期刊: EBioMedicine
• 影响因子: 11.1
• 作者: Ast J;Broichhagen J;Hodson DJ
• 通讯作者: Hodson DJ

Revealing the tissue-level complexity of endogenous glucagon-like peptide-1 receptor expression and signaling.

• DOI: 10.1038/s41467-022-35716-1
• 发表时间: 2023-01-18
• 期刊: NATURE COMMUNICATIONS
• 影响因子: 16.6
• 作者: Ast, Julia;Nasteska, Daniela;Fine, Nicholas H. F.;Nieves, Daniel J.;Koszegi, Zsombor;Lanoiselee, Yann;Cuozzo, Federica;Viloria, Katrina;Bacon, Andrea;Luu, Nguyet T.;Newsome, Philip N.;Calebiro, Davide;Owen, Dylan M.;Broichhagen, Johannes;Hodson, David J.
• 通讯作者: Hodson, David J.

Expanded LUXendin Color Palette for GLP1R Detection and Visualization In Vitro and In Vivo.

• DOI: 10.1021/jacsau.2c00130
• 发表时间: 2022-04-25
• 期刊: JACS AU
• 影响因子: 8
• 作者: Ast, Julia;Novak, Alissa N;Podewin, Tom;Fine, Nicholas H F;Jones, Ben;Tomas, Alejandra;Birke, Ramona;RoSSmann, Kilian;Mathes, Bettina;Eichhorst, Jenny;Lehmann, Martin;Linnemann, Amelia K;Hodson, David J;Broichhagen, Johannes
• 通讯作者: Broichhagen, Johannes