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Molecular Mechanisms for Pancreatic Islet Disfunction in Development of Diabetes Mellitus-a study using WFS1 knockout mice

糖尿病发生过程中胰岛功能障碍的分子机制——WFS1基因敲除小鼠的研究

基本信息

批准号：
17590264
负责人：
ISHIHARA Hisamitsu
金额：
$ 2.24万
依托单位：
Tohoku University
依托单位国家：
日本
项目类别：
Grant-in-Aid for Scientific Research (C)
财政年份：
2005
资助国家：
日本
起止时间：
2005 至 2006
项目状态：
已结题

项目摘要

Establishment of WFS1-deficient insulinoma cell lines. To examine the influence of WFS1-deficiency specifically in a homogenous β-cell population, β-cell lines were established by crossing wfs1^<-/-> mice with IT6 mice expressing simian virus 40 large T antigen under the insulin promoter. We found impaired insulin secretion in response to high glucose, which was recovered by adenovirus-mediated expression of wild-type WFS 1 but not of mutant WFS1 proteins found in Wolfram-syndrome patients.Role of WFS1 protein in intracellular calcium homeostasis. We analyzed WFS1-knockdown and-overexpressing HEK293 cells, and found that WFS1 protein modulates [Ca^<2+>]_<er> by positively regulating the ER Ca^<2+> uptake, which is associated with changes in the [Ca^<2+>]_<cyt> response evoked by Ca^<2+> store depletion.Identification of the translational suppressor 4E-BP1 as a pro-survival factor in β-cells under ER stress. Expression profiling in WFS1-deficient islets revealed increased 4E-BPI expression. We found that expression of 4E-BP1 was also enhanced in islets under ER stress in mouse models of diabetes. 4E-BP1 induction was found to be mediated by the transcription factor ATF4. 4E-BP1-deficient MIN6 β-cells were more vulnerable to apoptosis triggered by ER stress, with greater induction of C/EBP homologue protein. Furthermore, Eif4ebp1 deletion exacerbated hyperglycemia, with accelerated (3-cell failure, in mouse diabetes models with ER stress. Thus, 4E-BP1 induction is a pro-survival signal for (3-cells under ER stress and a potential therapeutic target for diabetes.Increased glucagon secretion from WFS1-deficient islets. Pyruvate was previously shown to stimulate glucagon secretion. In this study, we found increased alpha cell numbers and enhanced pyruvate-stimulated glucagon secretion in WFS1-deficient islets.Multiple abnormalities are suggested to contribute development of diabetes in the mouse model of Wolfram syndrome.

wfs1缺失型胰岛素瘤细胞系的建立。为了研究wfs1缺乏对同质β细胞群的特异性影响，在胰岛素启动子作用下，将表达猴病毒40大T抗原的IT6小鼠与wfs1^<-/->小鼠杂交，建立了β细胞系。我们发现高糖患者胰岛素分泌受损，通过腺病毒介导的野生型WFS1蛋白的表达而不是wolfram综合征患者突变型WFS1蛋白的表达来恢复。WFS1蛋白在细胞内钙稳态中的作用。我们分析了WFS1敲低和过表达的HEK293细胞，发现WFS1蛋白通过正向调节er Ca^<2+>摄取来调节[Ca^<2+>]_<er>，这与Ca^<2+>储存耗尽引起的[Ca^<2+>]_<cyt>反应的变化有关。内质网应激下β细胞中翻译抑制因子4E-BP1作为促存活因子的鉴定。在缺乏wfs1的胰岛中，表达谱显示4E-BPI表达增加。我们发现，在内质网应激的小鼠糖尿病模型中，胰岛中4E-BP1的表达也增强了。发现4E-BP1的诱导是由转录因子ATF4介导的。4e - bp1缺失的MIN6 β-细胞更容易受到内质网应激引发的凋亡，C/EBP同源蛋白的诱导作用更强。此外，在内质网应激的小鼠糖尿病模型中，Eif4ebp1缺失加剧了高血糖，加速了3细胞衰竭。因此，4E-BP1诱导是内质网应激下（3-细胞）的促生存信号，是糖尿病的潜在治疗靶点。缺乏wfs1的胰岛胰高血糖素分泌增加。丙酮酸曾被证明能刺激胰高血糖素的分泌。在这项研究中，我们发现在wfs1缺陷的胰岛中，α细胞数量增加，丙酮酸刺激的胰高血糖素分泌增加。多种异常提示在Wolfram综合征小鼠模型中促进糖尿病的发展。

项目成果

期刊论文数量（23）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

WFSl protein modulates the free Ca2+ concentration in the endoplasmic reticulum

WFS1蛋白调节内质网中的游离Ca 2 浓度

DOI：
发表时间：
2006
期刊：
FEBS Lett. 580
影响因子：
0
作者：
Greimel;P.;Daisuke Takei
通讯作者：
Daisuke Takei

Bone marrow (BM) transplantation promotes p-cell regeneration after acute injury through BM cell mobilization.

骨髓 (BM) 移植通过 BM 细胞动员促进急性损伤后的 p 细胞再生。

DOI：
发表时间：
2007
期刊：
Endocrinoligy (in press)
影响因子：
0
作者：
Ding Y.;et al.;Nagata K;Yutaka Hasegawa
通讯作者：
Yutaka Hasegawa

Secondary sulfonylurea failure: Comparison of period until insulin treatment between diabetic patients treated with gliclazide and glibenclamide

DOI：
10.1016/j.diabres.2005.04.002
发表时间：
2005-12-01
期刊：
DIABETES RESEARCH AND CLINICAL PRACTICE
影响因子：
5.1
作者：
Satoh, J;Takahashi, K;Oka, Y
通讯作者：
Oka, Y

Cell type-specific activation of metabolism reveals that β-cell secretion suppresses glucagon release from α-cells in rat pancreatic islets

细胞类型特异性代谢激活揭示β细胞分泌抑制大鼠胰岛中α细胞释放胰高血糖素

DOI：
发表时间：
2006
期刊：
影响因子：
0
作者：
Rui Takahashi;H. Ishihara;Akira Tamura;Suguru Yamaguchi;Takahiro Yamada;Daisuke Takei;H. Katagiri;H. Endou;Y. Oka
通讯作者：
Y. Oka

Neuronal pathway from the liver modulates energy expenditure and systemic insulin sensitivity