Title: Understanding the molecular mechanisms of hyperinsulinaemic hypoglycaemia and developing novel therapies

高胰岛素性低血糖（HH）是一种复杂的医学病症，胰腺的β细胞分泌过多的激素胰岛素。这是一种非常重要的控制血糖（葡萄糖）水平的激素。血液中过多的胰岛素会导致严重的低血糖（低血糖）。由于血糖是大脑必不可少的燃料，任何导致低血糖的事情都会导致永久性的脑损伤。HH通常在新生儿期出现症状性低血糖（易怒、喂养不良、癫痫发作、昏迷和猝死）。然而，有一些类型的HH可以在以后出现（在婴儿期或儿童期）。HH患者的血糖水平通常很难控制，这些患者几乎总是需要静脉注射高浓度葡萄糖来维持正常的血糖水平（正常血糖）。大奥蒙德街儿童医院NHS信托是HH患者的国家和国际转诊中心。主要研究者是大奥蒙德街儿童医院HH服务的临床领导，该服务由英国国民保健服务体系委托。某些形式的HH是遗传的，具有遗传基础（先天性HH）。到目前为止，已经描述了导致先天性HH的10种不同遗传途径（基因）的异常。所有这些基因的异常约占对药物治疗无反应的患者的90%，但只有约20%的患者对药物治疗有反应。因此，有大量的患者有医学反应形式的先天性HH，其遗传基础仍不清楚。作为MRC资助的研究项目的一部分，在过去的3年里，我们收集了来自英国和世界各地的先天性HH患者的DNA样本（1800）。每个患者都进行了系统的表型和基因分型，并收集了所有的生化数据。我们已经确定了一组独特的患者，他们的CHI没有已知的遗传原因。在这组患者中，我们获得了大量的初步数据。因此，该患者队列为我们提供了一个独特的平台来进行拟议的研究。了解这些患者的HH机制不仅将为胰腺β细胞生理学提供新的见解，而且还将为糖尿病等更常见的疾病提供见解。在一些先天性HH患者中，低血糖非常严重，目前唯一可用的治疗方法是进行大手术切除几乎整个胰腺（接近全胰腺切除术）。然而，一旦胰腺被切除，孩子们就会患上另一种终生严重的疾病——糖尿病。因此，迫切需要开发新的医学疗法，以避免近全胰切除术。我们最近在极少数对常规药物治疗无反应的严重先天性HH患者(4)中尝试了一种新的口服药物。有趣的是，所有这些患者的血糖水平在这种新疗法的作用下都有所改善，而且他们没有接受胰腺切除术。这些非常早期的观察结果表明，这种药物可能有助于我们治疗其他患有CHI的儿童。我们现在想了解这种药物对先天性HH儿童的药理学作用。在这项研究中，我们将使用分子遗传学（如外显子组和基因组测序）的最新尖端技术，试图了解所有迄今为止尚未发现遗传原因的HH患者的病因。利用形态蛋白质组学方法，我们将致力于为患有弥漫性和局灶性先天性HH的儿童开发新的治疗方案。

Hyperinsulinaemic hypoglycaemia (HH) is a complex medical condition where the beta-cells of the pancreas make too much of the hormone, insulin. This is a very important hormone which controls the blood sugar (glucose) level. Too much insulin in the blood can cause severe low blood glucose levels (hypoglycaemia). Since blood glucose is an essential fuel for the brain, anything that leads to hypoglycaemia will lead to permanent brain damage. HH usually presents in the newborn period with symptomatic (irritability, poor feeding, seizures, coma and sudden death) hypoglycaemia. However there are some types of HH which can present later (in infancy or childhood period). In HH the blood glucose level is often very difficult to control and these patients virtually always require concentrated intravenous dextrose infusions to maintain normal blood glucose levels (normoglycaemia). Great Ormond Street Children's Hospital NHS Trust is a national and international referral center for patients with HH. The Principle Investigator is the clinical lead for the HH service at Great Ormond Street Children's Hospital and the service is commissioned by NHS England. Certain forms of HH are inherited and have a genetic basis (congenital HH). So far abnormalities in 10 different genetic pathways (genes) have been described which lead to congenital HH. Abnormalities in all these genes account for about 90% of patients who are unresponsive to medical therapy but only about 20% of patients who are medically response. Thus there are a large number of patients with medically responsive forms of congenital HH where the genetic basis is still not known. As part of a MRC funded research project, over the last 3 years we have collected DNA samples (1800) on patients with congenital HH from all over the UK and the world. Each of these patients has been systemically phenotyped and genotyped and all the biochemical data collected. We have identified a unique group pf patients with no known genetic cause of their CHI. In this group of patients we have generated a substantial amount of preliminary data. This patient cohort thus therefore provides us a with unique platform to undertake the proposed research. Understanding the mechanisms of HH in these patients will not only provide novel insights into pancreatic beta-cell physiology but an insight into the more common conditions such as diabetes mellitus. In some patients with congenital HH the hypoglycaemia is so severe that the only treatment available at the moment is to undertake a major operation to remove nearly the whole pancreas (near total pancreatectomy). However once the pancreas is removed children develop another lifelong and serious condition called diabetes mellitus. Hence there is an urgent need to develop new medical therapies so that we can avoid a near total pancreatectomy. We have recently tried a new oral medication in a very small number of patients (4) with severe Congenital HH who were unresponsive to conventional medical therapies. Interestingly blood sugar levels improved in all these patients in response to this new treatment and they have not undergone a pancreatectomy. These very early observations suggest that this medication might help us in treating other children with CHI. We now want to understand the pharmacology of this medication in children with congenital HH. In this research study we will use the latest cutting edge techniques in molecular genetics (like exome and genome sequencing) to try and understand the cause of the HH in all those patients where we have not found a genetic cause so far. Using a morphoproteomics approach we will aim to develop new treatment options for children with diffuse and focal fros of congenital HH.