Reduced insulin exocytosis in human pancreatic β-cells with gene variants linked to type 2 diabetes.
Reduced insulin exocytosis in human pancreatic β-cells with gene variants linked to type 2 diabetes.
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DOI：
10.2337/db11-1516
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发表时间：
2012-07
期刊：
影响因子：
7.7
通讯作者：
Eliasson L
中科院分区：
文献类型：
--
作者：
Rosengren AH;Braun M;Mahdi T;Andersson SA;Travers ME;Shigeto M;Zhang E;Almgren P;Ladenvall C;Axelsson AS;Edlund A;Pedersen MG;Jonsson A;Ramracheya R;Tang Y;Walker JN;Barrett A;Johnson PR;Lyssenko V;McCarthy MI;Groop L;Salehi A;Gloyn AL;Renström E;Rorsman P;Eliasson L
2型糖尿病（T2D）的大多数遗传风险变异影响胰岛素分泌，但它们影响胰岛功能的机制在很大程度上仍然未知。我们对人类胰岛进行功能表征，以确定糖尿病和非糖尿病供体的分泌、生物物理和超微结构特征与遗传风险谱的关系。t2dm供者的胰岛胰岛素分泌受损，消瘦的供者比肥胖的糖尿病供者更明显。我们评估了14种疾病易感性变异对葡萄糖感知、胞吐和结构测量的影响。TCF7L2和ADRA2A附近的变异体与葡萄糖诱导的胰岛素分泌减少有关，而ADRA2A、KCNJ11、KCNQ1和TCF7L2附近的易感性变异体与去极化诱发的胰岛素胞外分泌减少有关。KCNQ1、ADRA2A、KCNJ11、HHEX/IDE和SLC2A2变体影响颗粒对接。我们将我们的结果结合起来，为β细胞功能障碍创建了一种新的遗传风险评分，包括异常颗粒对接，胞吐Ca2+敏感性降低和胰岛素释放减少。随着时间的推移，高风险评分的个体对静脉注射葡萄糖的反应受损，胰岛素分泌恶化。我们的研究结果强调了T2D中β细胞胞吐缺陷的重要性，并证明了细胞表型表征在阐明复杂遗传疾病中的潜力。
The majority of genetic risk variants for type 2 diabetes (T2D) affect insulin secretion, but the mechanisms through which they influence pancreatic islet function remain largely unknown. We functionally characterized human islets to determine secretory, biophysical, and ultrastructural features in relation to genetic risk profiles in diabetic and nondiabetic donors. Islets from donors with T2D exhibited impaired insulin secretion, which was more pronounced in lean than obese diabetic donors. We assessed the impact of 14 disease susceptibility variants on measures of glucose sensing, exocytosis, and structure. Variants near TCF7L2 and ADRA2A were associated with reduced glucose-induced insulin secretion, whereas susceptibility variants near ADRA2A, KCNJ11, KCNQ1, and TCF7L2 were associated with reduced depolarization-evoked insulin exocytosis. KCNQ1, ADRA2A, KCNJ11, HHEX/IDE, and SLC2A2 variants affected granule docking. We combined our results to create a novel genetic risk score for β-cell dysfunction that includes aberrant granule docking, decreased Ca2+ sensitivity of exocytosis, and reduced insulin release. Individuals with a high risk score displayed an impaired response to intravenous glucose and deteriorating insulin secretion over time. Our results underscore the importance of defects in β-cell exocytosis in T2D and demonstrate the potential of cellular phenotypic characterization in the elucidation of complex genetic disorders.
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影响因子：
7.7
作者：
Deng, SP;Vatamaniuk, M;Markmann, JF
通讯作者：
Markmann, JF
影响因子：
8.8
作者：
Goto, M.;Holgersson, J.;Korsgren, O.
通讯作者：
Korsgren, O.
影响因子：
8.2
作者：
Boesgaard, T. W.;Zilinskaite, J.;Hansen, T.
通讯作者：
Hansen, T.
影响因子：
7.7
作者：
Hamming KS;Soliman D;Matemisz LC;Niazi O;Lang Y;Gloyn AL;Light PE
通讯作者：
Light PE
影响因子：
7.7
作者：
Butler, AE;Janson, J;Butler, PC
通讯作者：
Butler, PC