The role of impaired glucagon secretion in life-threatening hypoglycaemia of type 1 diabetes: mechanism and therapeutic potential
胰高血糖素分泌受损在 1 型糖尿病危及生命的低血糖中的作用:机制和治疗潜力
基本信息
- 批准号:MR/V011979/1
- 负责人:
- 金额:$ 129.98万
- 依托单位:
- 依托单位国家:英国
- 项目类别:Research Grant
- 财政年份:2021
- 资助国家:英国
- 起止时间:2021 至 无数据
- 项目状态:未结题
- 来源:
- 关键词:
项目摘要
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.).
胰岛在血糖调节中起着中心作用。它们通过分泌两种荷尔蒙胰岛素(降糖)和胰高血糖素(升糖)来做到这一点。1型糖尿病(T1D)是由自身免疫攻击导致的,杀死了分泌胰岛素的β细胞,但其他胰岛细胞(包括产生胰高血糖素的阿尔法细胞)仍然存在。我们对T1D对阿尔法细胞的急性和长期影响的了解还很粗略,但很明显,释放缺陷会加剧胰岛素缺乏的影响,并使T1D更难治疗。在1型糖尿病(T1D)中,内源性胰岛素产生的丧失必须通过胰岛素注射来治疗。然而,胰岛素的剂量必须谨慎,这样血糖才不会降到正常范围以下(低血糖)。正常情况下,血糖下降会强烈刺激胰高血糖素的释放,但这种机制(逆调节)在许多T1D患者中是有缺陷的。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,每十名T1D患者中就有一人死于低血糖。低血糖也是胰岛素治疗的2型糖尿病(T2D)患者的一个问题。事实上,由于90%的糖尿病患者患有T2D(全球有4亿人),低血糖对T2D患者的影响远远大于T1D患者。一旦发生低血糖,经历另一次低血糖发作的风险显著增加。其潜在机制尚不清楚。我们的初步数据表明,胰升糖素反调节分泌的丧失是由于释放胰升血糖素的阿尔法细胞的“葡萄糖失明”所致。我们现在将确定这种缺陷是如何以及何时在T1D的发生和发展过程中发展起来的,以及是否可以通过药物来纠正它,其中一些药物已经用于治疗T2D患者。我们的实验室率先对胰岛α细胞进行了表征:首先使用小鼠胰岛,随后在人类胰岛中(来自牛津临床胰岛分离和移植中心)。然而,从患有T1D的捐赠者那里获取人类胰岛的途径非常有限(它们不用于移植),在一些试点研究中,我们还将使用一个成熟且广泛使用的人类T1D模型(NOD小鼠)。目前还没有关于NOD小鼠分泌胰高血糖素的功能研究。我们的初步研究表明,它们忠实地概括了临床上在T1 D患者中看到的胰高血糖素分泌缺陷。该项目的最终目标是预防(或降低)低血糖风险。这将使更积极的胰岛素治疗能够实现更好的血糖控制,从而减少继发性并发症(心肾衰竭、失明等)。
项目成果
期刊论文数量(10)
专著数量(0)
科研奖励数量(0)
会议论文数量(0)
专利数量(0)
Heterogenous impairment of α cell function in type 2 diabetes is linked to cell maturation state.
- DOI:10.1016/j.cmet.2021.12.021
- 发表时间:2022-02-01
- 期刊:
- 影响因子:29
- 作者:Dai XQ;Camunas-Soler J;Briant LJB;Dos Santos T;Spigelman AF;Walker EM;Arrojo E Drigo R;Bautista A;Jones RC;Avrahami D;Lyon J;Nie A;Smith N;Zhang Y;Johnson J;Manning Fox JE;Michelakis ED;Light PE;Kaestner KH;Kim SK;Rorsman P;Stein RW;Quake SR;MacDonald PE
- 通讯作者:MacDonald PE
Reducing hyperglucagonaemia in type 2 diabetes using low-dose glibenclamide: Results of the LEGEND-A pilot study.
- DOI:10.1111/dom.14740
- 发表时间:2022-08
- 期刊:
- 影响因子:0
- 作者:
- 通讯作者:
GLP-1 metabolite GLP-1(9-36) is a systemic inhibitor of mouse and human pancreatic islet glucagon secretion
GLP-1 代谢物 GLP-1(9-36) 是小鼠和人胰岛胰高血糖素分泌的全身抑制剂
- DOI:10.1007/s00125-023-06060-w
- 发表时间:2023
- 期刊:
- 影响因子:8.2
- 作者:Gandasi N
- 通讯作者:Gandasi N
Arginine-vasopressin mediates counter-regulatory glucagon release and is diminished in type 1 diabetes.
- DOI:10.7554/elife.72919
- 发表时间:2021-11-17
- 期刊:
- 影响因子:7.7
- 作者:Kim A;Knudsen JG;Madara JC;Benrick A;Hill TG;Abdul Kadir L;Kellard JA;Mellander L;Miranda C;Lin H;James T;Suba K;Spigelman AF;Wu Y;MacDonald PE;Wernstedt Asterholm I;Magnussen T;Christensen M;Vilsbøll T;Salem V;Knop FK;Rorsman P;Lowell BB;Briant LJ
- 通讯作者:Briant LJ
Acetyl-CoA-carboxylase 1 (ACC1) plays a critical role in glucagon secretion.
- DOI:10.1038/s42003-022-03170-w
- 发表时间:2022-03-18
- 期刊:
- 影响因子:5.9
- 作者:Veprik A;Denwood G;Liu D;Bany Bakar R;Morfin V;McHugh K;Tebeka NN;Vetterli L;Yonova-Doing E;Gribble F;Reimann F;Hoehn KL;Hemsley PA;Ahnfelt-Rønne J;Rorsman P;Zhang Q;de Wet H;Cantley J
- 通讯作者:Cantley J
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Olof Rorsman其他文献
Role of the C‐terminus of SUR in the differential regulation of β‐cell and cardiac KATP channels by MgADP and metabolism
SUR C 末端在 MgADP 和代谢对 β 细胞和心脏 KATP 通道的差异调节中的作用
- DOI:
- 发表时间:
2018 - 期刊:
- 影响因子:0
- 作者:
Natascia Vedovato;Olof Rorsman;Konstantin Hennis;F. Ashcroft;P. Proks - 通讯作者:
P. Proks
Olof Rorsman的其他文献
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{{ truncateString('Olof Rorsman', 18)}}的其他基金
Characterization of human islet cells: functional and transcriptional studies
人类胰岛细胞的表征:功能和转录研究
- 批准号:
G0801995/1 - 财政年份:2009
- 资助金额:
$ 129.98万 - 项目类别:
Research Grant
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University of Minnesota Clinical Center for the Restoration of Impaired Awareness of Hypoglycemia in Type 1 Diabetes
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- 批准号:
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Characterizing the evolution of impaired hypoglycemia awareness in people with type 1 diabetes and the impact of automated insulin delivery and exercise on restoring hypoglycemia awareness
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Regulation of alpha-cell glucagon secretion by mitochondrial anaplerosis-cataplerosis
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Metabolic regulation of islet hormone secretion in diabetes
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