Genetic and nutritional control of pancreatic beta cell identity.

胰腺β细胞特性的遗传和营养控制。

• 批准号: MR/R022259/1
• 负责人: Guy Rutter
• 金额: $ 263.8万
• 依托单位: Imperial College London
• 依托单位国家: 英国
• 项目类别: Research Grant
• 财政年份: 2018
• 资助国家: 英国
• 起止时间: 2018 至 无数据
• 项目状态: 未结题
• 来源: https://gtr.ukri.org/projects?ref=MR%2FR022259%2F1
• 关键词: Genetic; nutritional; control; pancreatic; beta

Diabetes mellitus affects more than 20 m Europeans and 400 m individuals worldwide. The complications of the disease, including blindness, kidney failure, cardiovascular disease and cancer, drastically reduce quality of life, and consume almost 10 % of health care costs in most westernised nations. These figures are expected to increase further in coming years. The most common form, Type 2 diabetes (T2D), has both genetic and environmental causes, and is particularly prevalent in those affected by over-nutrition and obesity. Therapeutic approaches towards T2D have relied in the past on enhancing the actions of insulin, responsible for lowering blood glucose levels, and on stimulating insulin secretion. However, none of the existing therapies reverse the progressive loss of normal beta cell identity and function and hence the gradual worsening of disease symptoms. "Genome wide association studies" (GWAS) for T2D have now identified numerous genetic variants whose inheritance is associated with an increased risk of diabetes. The identification of these genes, most of which influence insulin production, provides both improved powers of prediction and, just as excitingly, potential new molecular targets for drug treatment. More than 100 hundred genetic loci have now been identified which collectively harbour almost 500 genes. Our work seeks firstly to determine which of the genes in selected loci are responsible for increased disease risk. This involves both genetic studies in man, and functional analyses based on studying the impact of deleting a particular gene from the disease relevant tissue - usually the pancreatic beta cell. We have shown that a changes in the expression of a gene termed STARD10, which is able to bind fat molecules (lipids) within the cell and carry them between discrete intracellular locations, is responsible for the increased diabetes risk observed in carriers with a specific set of genetic variants on chromosome 11. At present, however, we have very little idea how this gene affects the cell's metabolism to impair the release of insulin. Understanding this question is important since it may provide new ways in which to improve the production of the hormone in those individuals (more than 80 % of the population) who are at increased risk of diabetes thanks to carrying the risk variant of this gene.We will therefore perform cellular analyses using human islets, human-derived beta and beta-like cells, the latter produced in the test tube from embryonic stem cells, to determine the impact of deleting STARD10, and to understand how the variants associated with disease risk alter the expression of this gene.The second Aim of our studies is to understand how two gene products, LKB1 and AMPK, are able to regulate pancreatic beta cell function. We know that deleting either gene in the mouse beta cell leads to a change in cellular identity, leading to the up-regulation of other genes which are not normally expressed in the islet but present at high levels in nerve and liver cells. AMPK, which is itself regulated by LKB1, is of particular interest since this enzyme is controlled by nutrients including glucose. We will determine whether changes in the activity of either enzyme affect gene expression by prompting changes in the structure (opening or closing) of nuclear DNA. We will also determine the impact of small molecule AMPK activators, which hold therapeutic promise in diabetes, on beta cell function.Our final Aim is to determine whether the role of STARD10 in controlling beta cell function may be altered in the absence of LKB1, a phenomenon we have recently described for another GWAS gene, TCF7L2, or by changes in nutritional status. We will use novel and powerful technologies including genome editing, directed differentiation of human embryonic stem cells, mouse genetics, photopharmacology and imaging of the islet after engraftment within the mouse eye, to answer our questions.

糖尿病影响着2000多万欧洲人和全世界4亿人。这种疾病的并发症，包括失明，肾衰竭，心血管疾病和癌症，大大降低了生活质量，并消耗了大多数西方国家近10%的医疗保健费用。预计这些数字在今后几年将进一步增加。最常见的形式是2型糖尿病（T2 D），有遗传和环境原因，在营养过剩和肥胖的人群中特别普遍。T2 D的治疗方法过去依赖于增强胰岛素的作用，负责降低血糖水平，以及刺激胰岛素分泌。然而，现有的疗法都不能逆转正常β细胞身份和功能的逐渐丧失，从而逆转疾病症状的逐渐恶化。T2 D的“全基因组关联研究”（GWAS）现已确定了许多遗传变异，其遗传与糖尿病风险增加相关。这些基因中的大多数影响胰岛素的产生，这些基因的鉴定不仅提供了更好的预测能力，而且同样令人兴奋的是，还提供了潜在的药物治疗新分子靶点。现在已经确定了10000多个遗传位点，它们总共包含近500个基因。我们的工作首先试图确定选定的基因座中的哪些基因是导致疾病风险增加的原因。这涉及人类的遗传学研究，以及基于研究从疾病相关组织（通常是胰腺β细胞）中删除特定基因的影响的功能分析。我们已经证明，一种名为STARD 10的基因表达的变化，能够结合细胞内的脂肪分子（脂质）并将其携带到离散的细胞内位置，是导致在11号染色体上具有一组特定遗传变异的携带者中观察到的糖尿病风险增加的原因。然而，目前，我们对这种基因如何影响细胞的新陈代谢以损害胰岛素的释放知之甚少。理解这个问题是很重要的，因为它可能提供新的方法来提高这些人的激素生产（超过80%的人口）由于携带该基因的风险变体而增加了糖尿病的风险。因此，我们将使用人类胰岛、人类衍生的β和β样细胞进行细胞分析，后者在试管中由胚胎干细胞产生，我们研究的第二个目的是了解两种基因产物LKB 1和AMPK是如何调节胰腺β细胞功能的。我们知道，删除小鼠β细胞中的任何一个基因都会导致细胞特性的改变，从而导致其他基因的上调，这些基因通常不在胰岛中表达，但在神经和肝细胞中以高水平存在。AMPK本身受LKB 1调节，特别令人感兴趣，因为这种酶受包括葡萄糖在内的营养素控制。我们将确定两种酶活性的变化是否通过促进核DNA结构（打开或关闭）的变化来影响基因表达。我们还将确定小分子AMPK激活剂对β细胞功能的影响，这种激活剂在糖尿病中具有治疗前景，我们的最终目的是确定在缺乏LKB 1的情况下，STARD 10在控制β细胞功能中的作用是否会改变，这是我们最近描述的另一种GWAS基因TCF 7 L2的现象，或者是营养状况的变化。我们将使用新的和强大的技术，包括基因组编辑，人类胚胎干细胞的定向分化，小鼠遗传学，药理学和小鼠眼内移植后胰岛的成像，来回答我们的问题。

项目成果

320-OR: Bariatric Surgery Improves Ca2+ Dynamics across Pancreatic Islets In Vivo

320-OR：减肥手术可改善体内胰岛的 Ca2 动力学

• DOI: 10.2337/db20-320-or
• 发表时间: 2020
• 期刊: Diabetes
• 影响因子: 7.7
• 作者: AKALESTOU E

Vertical sleeve gastrectomy normalizes circulating glucocorticoid levels and lowers glucocorticoid action tissue-selectively in mice.

• DOI: 10.3389/fendo.2022.1020576
• 发表时间: 2022
• 期刊: FRONTIERS IN ENDOCRINOLOGY
• 影响因子: 5.2
• 作者: Akalestou, Elina;Lopez-Noriega, Livia;Christakis, Ioannis;Hu, Ming;Miras, Alexander D.;Leclerc, Isabelle;Rutter, Guy A.
• 通讯作者: Rutter, Guy A.