First Author | Norlin S | Year | 2016 |
Journal | Diabetes | Volume | 65 |
Issue | 1 | Pages | 110-9 |
PubMed ID | 26438609 | Mgi Jnum | J:246324 |
Mgi Id | MGI:5923670 | Doi | 10.2337/db15-0699 |
Citation | Norlin S, et al. (2016) Asna1/TRC40 Controls beta-Cell Function and Endoplasmic Reticulum Homeostasis by Ensuring Retrograde Transport. Diabetes 65(1):110-9 |
abstractText | Type 2 diabetes (T2D) is characterized by insulin resistance and beta-cell failure. Insulin resistance per se, however, does not provoke overt diabetes as long as compensatory beta-cell function is maintained. The increased demand for insulin stresses the beta-cell endoplasmic reticulum (ER) and secretory pathway, and ER stress is associated with beta-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 beta-cell function, we inactivated Asna1 in beta-cells of mice. We show that Asna1(beta-/-) 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 beta-cells. Of note, pharmacological inhibition of retrograde transport in isolated islets and insulinoma cells mimicked the phenotype of Asna1(beta-/-) beta-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 beta-cells. |