Asna1/TRC40 controls beta cell function and ER homeostasis by ensuring retrograde transport.

Norlin, Stefan (author)

Parekh, Vishal S (author)

Naredi, Peter, 1955 (author): Gothenburg University,Göteborgs universitet,Institutionen för kliniska vetenskaper, Avdelningen för kirurgi,Institute of Clinical Sciences, Department of Surgery

Edlund, Helena (author)

(creator_code:org_t)

2015-10-05
2016
English.
In: Diabetes. - : American Diabetes Association. - 1939-327X .- 0012-1797. ; 65:1, s. 110-119

Related links:: https://diabetes.dia...; show more...; https://gup.ub.gu.se...; https://doi.org/10.2...; show less...

Abstract Subject headings

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.

By the author/editor: Norlin, Stefan; Parekh, Vishal S; Naredi, Peter, 1 ...; Edlund, Helena

About the subject

MEDICAL AND HEALTH SCIENCES: MEDICAL AND HEAL ...; and Clinical Medicin ...; and Surgery

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