論文 - 詳細
| RRC ID | 34822 |
|---|---|
| 著者 | Norlin S, Parekh VS, Naredi P, Edlund H. |
| タイトル | Asna1/TRC40 Controls β-Cell Function and Endoplasmic Reticulum Homeostasis by Ensuring Retrograde Transport. |
| ジャーナル | Diabetes |
| Abstract |
Type 2 diabetes (T2D) is characterized by insulin resistance and β-cell failure. Insulin resistance per se, however, does not provoke overt diabetes as long as compensatory β-cell function is maintained. The increased demand for insulin stresses the β-cell endoplasmic reticulum (ER) and secretory pathway, and ER stress is associated with β-cell failure in T2D. The tail recognition complex (TRC) pathway, including Asna1/TRC40, is implicated in the maintenance of endomembrane trafficking and ER homeostasis. To gain insight into the role of Asna1/TRC40 in maintaining endomembrane homeostasis and β-cell function, we inactivated Asna1 in β-cells of mice. We show that Asna1(β-/-) mice develop hypoinsulinemia, impaired insulin secretion, and glucose intolerance that rapidly progresses to overt diabetes. Loss of Asna1 function leads to perturbed plasma membrane-to-trans Golgi network and Golgi-to-ER retrograde transport as well as to ER stress in β-cells. Of note, pharmacological inhibition of retrograde transport in isolated islets and insulinoma cells mimicked the phenotype of Asna1(β-/-) β-cells and resulted in reduced insulin content and ER stress. These data support a model where Asna1 ensures retrograde transport and, hence, ER and insulin homeostasis in β-cells. |
| 巻・号 | 65(1) |
| ページ | 110-9 |
| 公開日 | 2016-1-1 |
| DOI | 10.2337/db15-0699 |
| PII | db15-0699 |
| PMID | 26438609 |
| MeSH | Animals Arsenite Transporting ATPases / genetics* Arsenite Transporting ATPases / metabolism Benzamides / pharmacology Blood Glucose / metabolism* Blotting, Western Cell Line, Tumor Cell Membrane / drug effects Cell Membrane / metabolism Diabetes Mellitus, Type 2 / genetics* Diabetes Mellitus, Type 2 / metabolism Endoplasmic Reticulum / drug effects Endoplasmic Reticulum / metabolism* Endoplasmic Reticulum Stress Endosomes / drug effects Endosomes / metabolism* Glucose Intolerance / genetics Glucose Intolerance / metabolism Golgi Apparatus / drug effects Golgi Apparatus / metabolism Homeostasis / genetics In Vitro Techniques Insulin / blood Insulin / metabolism* Insulin Secretion Insulin-Secreting Cells / metabolism* Intracellular Membranes / drug effects Intracellular Membranes / metabolism* Islets of Langerhans / metabolism Mice Mice, Knockout Qa-SNARE Proteins / metabolism Real-Time Polymerase Chain Reaction Thiophenes / pharmacology |
| IF | 7.72 |
| 引用数 | 12 |
| WOS 分野 | ENDOCRINOLOGY & METABOLISM |
| リソース情報 | |
| 実験動物マウス | RBRC01099 |