β-cell ABCA1 influences insulin secretion, glucose homeostasis and response to thiazolidinedione treatment
β-cell ABCA1 influences insulin secretion, glucose homeostasis and response to thiazolidinedione treatment
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DOI：
10.1038/nm1546
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发表时间：
2007-03-01
期刊：
影响因子：
82.9
通讯作者：
Hayden, Michael R.
中科院分区：
文献类型：
--
作者：
Brunham, Liam R.;Kruit, Janine K.;Hayden, Michael R.
2型糖尿病的特征是外周胰岛素抵抗和β细胞分泌胰岛素减少。这种疾病中β细胞功能障碍的原因尚不完全清楚，但可能包括这种细胞内有毒脂质的积聚。我们研究了ABCA1，一种细胞胆固醇转运体，在β细胞中胆固醇稳态和胰岛素分泌中的作用。在β细胞中ABCA1特异性失活的小鼠出现明显的糖耐量受损和胰岛素分泌缺陷，但胰岛素敏感性正常。从这些小鼠分离的胰岛在体外显示出胆固醇稳态改变和胰岛素分泌受损。我们发现，罗格列酮是过氧化物酶体增殖物激活受体-伽马的激活剂，它上调β细胞中的ABCA1，需要β细胞ABCA1来发挥其对糖耐量的有益作用。这些实验确立了ABCA1在β细胞胆固醇稳态和胰岛素分泌中的新作用，并表明胆固醇积累可能有助于2型糖尿病的β细胞功能障碍。
Type 2 diabetes is characterized by both peripheral insulin resistance and reduced insulin secretion by beta-cells. The reasons for beta-cell dysfunction in this disease are incompletely understood but may include the accumulation of toxic lipids within this cell type. We examined the role of Abca1, a cellular cholesterol transporter, in cholesterol homeostasis and insulin secretion in beta-cells. Mice with specific inactivation of Abca1 in beta-cells had markedly impaired glucose tolerance and defective insulin secretion but normal insulin sensitivity. Islets isolated from these mice showed altered cholesterol homeostasis and impaired insulin secretion in vitro. We found that rosiglitazone, an activator of the peroxisome proliferator-activated receptor-gamma, which upregulates Abca1 in beta-cells, requires beta-cell Abca1 for its beneficial effects on glucose tolerance. These experiments establish a new role for Abca1 in beta-cell cholesterol homeostasis and insulin secretion, and suggest that cholesterol accumulation may contribute to beta-cell dysfunction in type 2 diabetes.