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Asna1/TRC40 Control...
Asna1/TRC40 Controls beta-Cell Function and Endoplasmic Reticulum Homeostasis by Ensuring Retrograde Transport
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- Norlin, Stefan (author)
- Umeå universitet,Umeå centrum för molekylär medicin (UCMM)
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- Parekh, Vishal S. (author)
- Umeå universitet,Umeå centrum för molekylär medicin (UCMM)
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Naredi, Peter (author)
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- Edlund, Helena (author)
- Umeå universitet,Umeå centrum för molekylär medicin (UCMM)
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(creator_code:org_t)
- 2015-10-05
- 2016
- English.
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In: Diabetes. - : American Diabetes Association. - 0012-1797 .- 1939-327X. ; 65:1, s. 110-119
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https://diabetes.dia...
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https://urn.kb.se/re...
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https://doi.org/10.2...
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Abstract
Subject headings
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- 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 Asnal 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 Asnal 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 Asnal ensures retrograde transport and, hence, ER and insulin homeostasis in beta-cells.
Subject headings
- MEDICIN OCH HÄLSOVETENSKAP -- Klinisk medicin -- Endokrinologi och diabetes (hsv//swe)
- MEDICAL AND HEALTH SCIENCES -- Clinical Medicine -- Endocrinology and Diabetes (hsv//eng)
- MEDICIN OCH HÄLSOVETENSKAP -- Medicinska och farmaceutiska grundvetenskaper -- Cell- och molekylärbiologi (hsv//swe)
- MEDICAL AND HEALTH SCIENCES -- Basic Medicine -- Cell and Molecular Biology (hsv//eng)
Publication and Content Type
- ref (subject category)
- art (subject category)
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