Courtade Jaques A, Wang Evan Y, Yen Paul, Dai Derek L, Soukhatcheva Galina, Orban Paul C, Verchere C Bruce
Research Institute, BC Children's Hospital, 950 West 28th Avenue, Vancouver, BC, V5Z 4H4, Canada.
Department of Pathology and Laboratory Medicine, University of British Columbia, Vancouver, BC, Canada.
Diabetologia. 2017 Mar;60(3):453-463. doi: 10.1007/s00125-016-4174-2. Epub 2016 Dec 20.
AIMS/HYPOTHESIS: A contributor to beta cell failure in type 2 diabetes and islet transplants is amyloid formation by aggregation of the beta cell peptide, islet amyloid polypeptide (IAPP). Similar to the proinsulin processing pathway that generates insulin, IAPP is derived from a prohormone precursor, proIAPP, which requires cleavage by prohormone convertase (PC) 1/3 and PC2 in rodent pancreatic beta cells. We hypothesised that loss of PC2 would promote beta cell death and dysfunction in a rodent model of human beta cell proIAPP overexpression.
We generated an islet transplant model wherein immune-deficient mouse models of diabetes received islets expressing amyloidogenic human proIAPP and lacking PC2, leading to restoration of normoglycaemia accompanied by increased secretion of human proIAPP. Blood glucose levels were analysed for up to 16 weeks in transplant recipients and grafts were assessed for islet amyloid and beta cell number and death.
Hyperglycaemia (blood glucose >16.9 mmol/l) returned in 94% of recipients of islets expressing human proIAPP and lacking PC2, whereas recipients of islets that express human proIAPP and normal PC2 levels remained normoglycaemic for at least 16 weeks. Islet graft failure was accompanied by a ∼20% reduction in insulin-positive cells, yet the degree of amyloid deposition and beta cell apoptosis was similar to those of controls expressing human proIAPP with functional PC2 levels.
CONCLUSIONS/INTERPRETATION: PC2 deficiency in transplanted mouse islets expressing human proIAPP promotes beta cell loss and graft failure. Our data suggest that impaired NH-terminal processing and increased secretion of human proIAPP promote beta cell failure.
目的/假设：2型糖尿病和胰岛移植中β细胞功能衰竭的一个原因是β细胞肽胰岛淀粉样多肽（IAPP）聚集形成淀粉样蛋白。与产生胰岛素的胰岛素原加工途径类似，IAPP来源于一种激素原前体——前IAPP，在啮齿动物胰腺β细胞中，它需要激素原转化酶（PC）1/3和PC2进行切割。我们假设PC2缺失会在人β细胞前IAPP过表达的啮齿动物模型中促进β细胞死亡和功能障碍。
我们建立了一个胰岛移植模型，其中糖尿病免疫缺陷小鼠模型接受表达淀粉样蛋白生成性人前IAPP且缺乏PC2的胰岛，导致血糖恢复正常，同时人前IAPP分泌增加。对移植受体的血糖水平进行长达16周的分析，并对移植物的胰岛淀粉样蛋白、β细胞数量和死亡情况进行评估。
94%接受表达人前IAPP且缺乏PC2的胰岛的受体出现高血糖（血糖>16.9 mmol/L），而接受表达人前IAPP且PC2水平正常的胰岛的受体至少16周内保持血糖正常。胰岛移植失败伴随着胰岛素阳性细胞减少约20%，然而淀粉样蛋白沉积程度和β细胞凋亡与表达具有功能性PC2水平的人前IAPP的对照组相似。
结论/解读：在表达人前IAPP的移植小鼠胰岛中，PC2缺乏会促进β细胞丢失和移植失败。我们的数据表明，人前IAPP的N端加工受损和分泌增加会促进β细胞功能衰竭。
