Increased insulin demand promotes while pioglitazone prevents pancreatic beta cell apoptosis in Wfs1 knockout mice
Increased insulin demand promotes while pioglitazone prevents pancreatic beta cell apoptosis in Wfs1 knockout mice
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DOI：
10.1007/s00125-009-1270-6
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发表时间：
2009-04-01
期刊：
影响因子：
8.2
通讯作者：
Tanizawa, Y.
中科院分区：
文献类型：
--
作者：
Akiyama, M.;Hatanaka, M.;Tanizawa, Y.
WFS 1基因编码一种内质网（ER）膜包埋蛋白，称为Wolfram综合征1蛋白，其纯合突变导致人类选择性β细胞丢失。这种蛋白质的功能和这种基因突变导致β细胞死亡的机制仍然没有完全了解。我们假设肥胖/胰岛素抵抗导致的胰岛素需求增加导致胰腺β细胞的ER应激，从而促进β细胞死亡。我们研究了通过引入agglutinin致死性黄色突变（A（y）/a），在具有轻度肥胖和胰岛素抵抗的C57 BL/6 J背景下饲养Wfs 1（-/-）小鼠的效果。我们还用吡格列酮治疗了小鼠。在C57 BL/6 J背景下繁殖的Wfs 1（-/-）小鼠很少在24周龄时发生明显的糖尿病，仅显示轻度的β细胞损失。然而，Wfs 1（-/-）A（y）/a小鼠早在8周时就出现了选择性β细胞丢失和严重的胰岛素缺乏型糖尿病。这种β细胞损失是由于细胞凋亡。在Wfs 1（+/+）A（y）/a胰岛中，ER分子伴侣免疫球蛋白结合蛋白（BiP）/78 kDa葡萄糖调节蛋白（GRP 78）和真核翻译起始因子2 α亚基（eIF 2 α）的磷酸化水平明显升高。在Wfs 1（-/-）A（y）/a鼠胰岛中，两者的水平进一步增加。电子显微镜显示Wfs 1（-/-）A（y）/a鼠β细胞中ER显著扩张。有趣的是，吡格列酮治疗保护β细胞免于凋亡，几乎完全阻止了糖尿病的发展。Wfs 1缺陷的β细胞对ER应激敏感。增加的胰岛素需求促进体内此类细胞的凋亡。吡格列酮显著地抑制了这一过程并预防糖尿病。由于常见的WFS 1基因变异最近已被证明会导致2型糖尿病的风险，我们的研究结果可能与2型糖尿病中β细胞的逐渐但进行性损失有关。
The WFS1 gene encodes an endoplasmic reticulum (ER) membrane-embedded protein called Wolfram syndrome 1 protein, homozygous mutations of which cause selective beta cell loss in humans. The function(s) of this protein and the mechanism by which the mutations of this gene cause beta cell death are still not fully understood. We hypothesised that increased insulin demand as a result of obesity/insulin resistance causes ER stress in pancreatic beta cells, thereby promoting beta cell death.We studied the effect of breeding Wfs1 (-/-) mice on a C57BL/6J background with mild obesity and insulin resistance, by introducing the agouti lethal yellow mutation (A (y) /a). We also treated the mice with pioglitazone.Wfs1 (-/-) mice bred on a C57BL/6J background rarely develop overt diabetes by 24 weeks of age, showing only mild beta cell loss. However, Wfs1 (-/-) A (y) /a mice developed selective beta cell loss and severe insulin-deficient diabetes as early as 8 weeks. This beta cell loss was due to apoptosis. In Wfs1 (+/+) A (y) /a islets, levels of ER chaperone immunoglobulin-binding protein (BiP)/78 kDa glucose-regulated protein (GRP78) and phosphorylation of eukaryotic translation initiation factor 2, subunit alpha (eIF2 alpha) apparently increased. Levels of both were further increased in Wfs1 (-/-) A (y) /a murine islets. Electron micrography revealed markedly dilated ERs in Wfs1 (-/-) A (y) /a murine beta cells. Interestingly, pioglitazone treatment protected beta cells from apoptosis and almost completely prevented diabetes development.Wfs1-deficient beta cells are susceptible to ER stress. Increased insulin demand prompts apoptosis in such cells in vivo. Pioglitazone, remarkably, suppresses this process and prevents diabetes. As common WFS1 gene variants have recently been shown to confer a risk of type 2 diabetes, our findings may be relevant to the gradual but progressive loss of beta cells in type 2 diabetes.