The role of impaired glucagon secretion in life-threatening hypoglycaemia of type 1 diabetes: mechanism and therapeutic potential

胰岛在调节血糖方面起着核心作用。它们通过分泌两种激素胰岛素（降血糖）和胰高血糖素（升血糖）来达到这一目的。1型糖尿病（T1D）是由自身免疫攻击杀死分泌胰岛素的β细胞引起的，但其他胰岛细胞（包括产生胰高血糖素的α细胞）仍然存在。我们对T1D对α细胞的急性和长期影响的理解是粗略的，但很明显，释放缺陷加剧了胰岛素缺乏的影响，使T1D更难治疗。在1型糖尿病（T1D）中，内源性胰岛素产生的损失必须通过胰岛素注射来治疗。然而，胰岛素的剂量必须小心，以使血糖低于正常范围（低血糖）不会发生。正常情况下，血糖下降会触发胰高血糖素释放的强烈刺激，但这种机制（“反调节”）在许多T1D患者中是错误的。这会增加严重低血糖的风险，并可能导致昏迷和死亡。据估计，十分之一的T1D患者死于低血糖。在胰岛素治疗的2型糖尿病（T2D）患者中，低血糖也是一个问题。事实上，由于90%的糖尿病患者患有T2D（全球约4亿人），低血糖影响的T2D患者数量远远超过T1D患者。一旦发生低血糖，再次发生低血糖发作的风险显著增加。潜在的机制尚不清楚。我们的初步数据表明，反调节性胰高血糖素分泌的丧失是由释放胰高血糖素的α细胞的“葡萄糖失明”引起的。我们现在将确定这种缺陷在T1D的发病和发展过程中是如何以及何时发生的，以及是否可以通过药物来纠正，其中一些药物已经用于治疗T2D患者。我们的实验室开创了胰岛α细胞的表征：首先使用小鼠胰岛，随后在人类胰岛（来自牛津临床胰岛分离和移植中心）。然而，从患有T1D的供体获得人类胰岛的机会非常有限（它们不用于移植），对于一些试点研究，我们也将使用一种成熟且广泛使用的人类T1D模型（NOD小鼠）。目前还没有对NOD小鼠胰高血糖素分泌功能的研究。我们的初步研究表明，它们忠实地概括了临床上在T1D患者中所见的胰高血糖素分泌缺陷。该项目的最终目标是预防（或降低）低血糖的风险。这将使更积极的胰岛素治疗达到更好的血糖控制，从而减少继发性并发症（心脏和肾衰竭，失明等）。

The pancreatic islets play a central role in the regulation of blood glucose. They do so, by secreting the two hormones insulin (glucose-lowering) and glucagon (glucose-increasing). Type-1 diabetes (T1D) is caused by an autoimmune attack killing the insulin-secreting beta-cells but the other islet cells (including the glucagon-producing alpha-cells) remain. Our understanding of the acute and longterm impact of T1D on the alpha-cells is sketchy but it is clear that defects in the release exacerbate the impact of the insulin deficiency and make T1D more difficult to treat. In type-1 diabetes (T1D), the loss of endogenous insulin production must be treated with insulin injections. However, insulin must be carefully dosed so that a fall in blood glucose below the normal range (hypoglycaemia) does not occur. Normally, a fall in blood glucose triggers strong stimulation of glucagon release but this mechanism ('counter-regulation') is faulty in many people with T1D. This increases the risk of severe hypoglycaemia and may result in coma and death. It has been estimated that one in ten T1D patients die of hypoglycaemia. Hypoglycaemia is also a problem in insulin-treated patients with type 2 diabetes (T2D). In fact, because 90% of all diabetic patients have T2D (>400 million worldwide), hypoglycaemia affect a far greater number of patients with T2D than with T1D. Once hypoglycaemia has occurred, the risk of experiencing another hypoglycaemic episode is dramatically increased. The underlying mechanisms are not known.Our preliminary data suggest that the loss of counter-regulatory glucagon secretion is caused by a 'glucose blindness' of the glucagon-releasing alpha-cells. We will now determine how and when this defect develops during the onset and progression of T1D and whether it can be corrected by medicines, some of which are already used to treat patients with T2D. Our laboratory pioneered the characterisation of the islet alpha-cells: first using mouse islets and subsequently in human islets (from the Oxford Clinical Islet Isolation and Transplantation Centre). However, access to human pancreatic islets from donors with T1D is very limited (they are not used for transplantation) and for some of pilot studies we will also use a well-established and widely used model of human T1D (the NOD mouse). There have been no functional studies of glucagon secretion in NOD mice. Our preliminary studies suggest that they faithfully recapitulate the glucagon secretion defects seen clinically in patients with T1D.The ultimate goal of this project is to prevent (or reduce the risk of) hypoglycaemia. This would enable more aggressive insulin therapy to achieve better glucose control with resultant reduction of secondary complications (heart and kidney failure, blindness etc.).