首页> 外文期刊>Diabetes >hZnT8 (Slc30a8) Transgenic Mice That Overexpress the R325W Polymorph Have Reduced Islet Zn~(2+) and Proinsulin Levels, Increased Glucose Tolerance After a High-Fat Diet, and Altered Levels of Pancreatic Zinc Binding Proteins
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hZnT8 (Slc30a8) Transgenic Mice That Overexpress the R325W Polymorph Have Reduced Islet Zn~(2+) and Proinsulin Levels, Increased Glucose Tolerance After a High-Fat Diet, and Altered Levels of Pancreatic Zinc Binding Proteins

机译:过量表达R325W多态性的hZnT8(Slc30a8)转基因小鼠降低了胰岛Zn〜(2+)和胰岛素原水平,高脂饮食后增加了葡萄糖耐量,并且胰腺锌结合蛋白水平改变。

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摘要

Zinc (Zn~(2+)) is involved in both type 1 diabetes (T1DM) and type 2 diabetes (T2DM). The wild-type (WT) form of the β-cell-specific Zn~(2+) transporter, ZNT8, is linked to T2DM susceptibility. ZnT8 null mice have a mild phe-notype with a slight decrease in glucose tolerance, whereas patients with the ZnT8 R325W polymorphism (rs13266634) have decreased proinsulin staining and susceptibility to T2DM. We measured Zn~(2+), insulin, and proinsulin stainings and performed intraperftoneal glucose tolerance testing in transgenic mice overexpressing hZnT8 WT or hZnT8 R325W fed a normal or high-fat diet. The hZnT8 R325W transgenic line had lower pancreatic [Zn~(2+)]_i and proinsulin and higher insulin and glucose tolerance compared with control littermates after 10 weeks of a high-fat diet in male mice. The converse was true for the hZnT8 WT transgenic line, and dietary Zn~(2+) supplementation also induced glucose intolerance. Finally, pancreatic zinc binding proteins were identified by Zn~(2+)-affinity chromatography and proteomics. Increasing pancreatic Zn~(2+) (hZnT8WT) induced nucleoside di-phosphate kinase B, and Zn~(2+) reduction (hZnT8RW) induced carboxypeptidase A1. These data suggest that pancreatic Zn~(2+) and proinsulin levels covary but are inversely variant with insulin or glucose tolerance in the HFD model of T2DM suggesting novel therapeutic targets.
机译:锌(Zn〜(2+))参与1型糖尿病(T1DM)和2型糖尿病(T2DM)。 β细胞特异性Zn〜(2+)转运蛋白ZNT8的野生型(WT)与T2DM易感性有关。 ZnT8无效的小鼠具有轻度的表型,其糖耐量略有降低,而具有ZnT8 R325W多态性(rs13266634)的患者的胰岛素原染色和对T2DM的敏感性降低。我们测量了Zn〜(2+),胰岛素和胰岛素原的染色,并在过表达正常或高脂饮食的hZnT8 WT或hZnT8 R325W过表达的转基因小鼠中进行了腹膜内葡萄糖耐量测试。高脂饮食10周后,与对照组同窝仔猪相比,hZnT8 R325W转基因品系具有较低的胰腺[Zn〜(2 +)] _ i和胰岛素原,并且具有较高的胰岛素和葡萄糖耐受性。相反,对于hZnT8 WT转基因品系,则是正确的,而饮食中的Zn〜(2+)补充也会引起葡萄糖耐受不良。最后,通过Zn〜(2 +)-亲和层析和蛋白质组学鉴定了胰腺锌结合蛋白。胰腺Zn〜(2+)(hZnT8WT)诱导的核苷二磷酸激酶B的增加,而Zn〜(2+)还原(hZnT8RW)诱导的羧肽酶A1的诱导。这些数据表明胰腺锌〜(2+)和胰岛素原水平共存,但在T2DM的HFD模型中与胰岛素或葡萄糖耐量相反,提示新的治疗靶点。

著录项

  • 来源
    《Diabetes》 |2017年第2期|551-559|共9页
  • 作者单位

    Department of Ophthalmology and the Neuroscience Center of Excellence, Louisiana State University Health Sciences Center, New Orleans, LA;

    Department of Ophthalmology and the Neuroscience Center of Excellence, Louisiana State University Health Sciences Center, New Orleans, LA;

    Department of Ophthalmology and the Neuroscience Center of Excellence, Louisiana State University Health Sciences Center, New Orleans, LA ,Department of Neurology, Stony Brook University Hospital, Stony Brook, NY;

  • 收录信息 美国《科学引文索引》(SCI);美国《化学文摘》(CA);
  • 原文格式 PDF
  • 正文语种 eng
  • 中图分类
  • 关键词

  • 入库时间 2022-08-18 03:46:06

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