| 1. |
- Norlin, Stefan, et al.
(author)
-
Asna1/TRC40 controls beta cell function and ER homeostasis by ensuring retrograde transport.
- 2016
-
In: Diabetes. - : American Diabetes Association. - 1939-327X .- 0012-1797. ; 65:1, s. 110-119
-
Journal article (peer-reviewed)abstract
- Type 2 diabetes (T2D) is characterized by insulin resistance and β-cell failure. Insulin resistance per se does, however, 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 maintenance of endomembrane trafficking and ER homeostasis. To gain insight into the role for Asna1/TRC40 in maintenance of endomembrane homeostasis and β-cell function we inactivated Asna1 in β-cells of mice. Here, 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-TGN as well as Golgi-to-ER retrograde transport, and ER stress in β-cells. Intriguingly, 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. Together, our data support a model where Asna1 ensures retrograde transport and hence ER and insulin homeostasis in β-cells.
|
|
