GRP94 Is an Essential Regulator of Pancreatic β-Cell Development, Mass, and Function in Male Mice
GRP94 Is an Essential Regulator of Pancreatic β-Cell Development, Mass, and Function in Male Mice
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DOI：
10.1210/en.2017-00685
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发表时间：
2018-02-01
期刊：
影响因子：
4.8
通讯作者：
Wang, Hongjun
中科院分区：
文献类型：
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作者：
Kim, Do-Sung;Song, Lili;Wang, Hongjun
胰腺β细胞群缺陷导致1型和2型糖尿病。我们研究了葡萄糖调节蛋白（GRP）94（一种在胰腺腺泡和胰岛中大量表达的内质网蛋白）在β细胞发育、存活和功能中的作用。我们使用了条件性敲除（KO）小鼠，其中GRP 94基因，Hsp 90 b1，在胰腺和十二指肠同源框1（Pdx 1）表达细胞中特异性缺失。这些Hsp 90 b1（flox/flox）; Pdx 1（Cre）KO小鼠在胚胎第16.5天至E18.5天表现出胰腺发育不全，并且在出生后4周具有显著减少的β细胞质量。进一步的机制研究表明，在Pdx 1（+）内分泌祖细胞和分化的β细胞中，GRP 94的缺失降低了β细胞增殖，增加了细胞凋亡。尽管Hsp 90 b1（flox/flox）; Pdx 1（Cre）KO小鼠在8周龄时保持血糖正常，但它们表现出葡萄糖耐量受损。总之，这些发现表明GRP 94是胰腺β细胞发育、质量和功能的重要调节因子。
Deficiencies in pancreatic beta-cell mass contribute to both type 1 and type 2 diabetes. We investigated the role of the glucose-regulated protein (GRP) 94, an endoplasmic reticulum protein abundantly expressed in the pancreatic acini and islets, in beta-cell development, survival, and function. We used a conditional knockout (KO) mouse in which the GRP94 gene, Hsp90b1, was specifically deleted in pancreatic and duodenal homeobox 1 (Pdx1)-expressing cells. These Hsp90b1 (flox/flox); Pdx1(Cre) KO mice exhibited pancreatic hypoplasia at embryonic day (E) 16.5 to E18.5 and had significantly reduced beta-cell mass at 4 weeks after birth. Further mechanistic studies showed that deletion of GRP94 reduced beta-cell proliferation with increased cell apoptosis in both Pdx1(+) endocrine progenitor cells and differentiated beta cells. Although Hsp90b1 (flox/flox); Pdx1(Cre) KO mice remained euglycemic at 8 weeks of age, they exhibited impaired glucose tolerance. In aggregate, these findings indicate that GRP94 is an essential regulator of pancreatic beta-cell development, mass, and function.