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Deletion of ABCB10 in beta-cells protects from high-fat diet induced insulin resistance

OBJECTIVE: The contribution of beta-cell dysfunction to type 2 diabetes (T2D) is not restricted to insulinopenia in the late stages of the disease. Elevated fasting insulinemia in normoglycemic humans is a major factor predicting the onset of insulin resistance and T2D, demonstrating an early altera...

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Autores principales: Shum, Michael, Segawa, Mayuko, Gharakhanian, Raffi, Viñuela, Ana, Wortham, Matthew, Baghdasarian, Siyouneh, Wolf, Dane M., Sereda, Samuel B., Nocito, Laura, Stiles, Linsey, Zhou, Zhiqiang, Gutierrez, Vincent, Sander, Maike, Shirihai, Orian S., Liesa, Marc
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Elsevier 2021
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8689243/
https://www.ncbi.nlm.nih.gov/pubmed/34823065
http://dx.doi.org/10.1016/j.molmet.2021.101403
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author Shum, Michael
Segawa, Mayuko
Gharakhanian, Raffi
Viñuela, Ana
Wortham, Matthew
Baghdasarian, Siyouneh
Wolf, Dane M.
Sereda, Samuel B.
Nocito, Laura
Stiles, Linsey
Zhou, Zhiqiang
Gutierrez, Vincent
Sander, Maike
Shirihai, Orian S.
Liesa, Marc
author_facet Shum, Michael
Segawa, Mayuko
Gharakhanian, Raffi
Viñuela, Ana
Wortham, Matthew
Baghdasarian, Siyouneh
Wolf, Dane M.
Sereda, Samuel B.
Nocito, Laura
Stiles, Linsey
Zhou, Zhiqiang
Gutierrez, Vincent
Sander, Maike
Shirihai, Orian S.
Liesa, Marc
author_sort Shum, Michael
collection PubMed
description OBJECTIVE: The contribution of beta-cell dysfunction to type 2 diabetes (T2D) is not restricted to insulinopenia in the late stages of the disease. Elevated fasting insulinemia in normoglycemic humans is a major factor predicting the onset of insulin resistance and T2D, demonstrating an early alteration of beta-cell function in T2D. Moreover, an early and chronic increase in fasting insulinemia contributes to insulin resistance in high-fat diet (HFD)-fed mice. However, whether there are genetic factors that promote beta-cell-initiated insulin resistance remains undefined. Human variants of the mitochondrial transporter ABCB10, which regulates redox by increasing bilirubin synthesis, have been associated with an elevated risk of T2D. The effects of T2D ABCB10 variants on ABCB10 expression and the actions of ABCB10 in beta-cells are unknown. METHODS: The expression of beta-cell ABCB10 was analyzed in published transcriptome datasets from human beta-cells carrying the T2D-risk ABCB10 variant. Insulin sensitivity, beta-cell proliferation, and secretory function were measured in beta-cell-specific ABCB10 KO mice (Ins1(Cre)-Abcb10(flox/flox)). The short-term role of beta-cell ABCB10 activity on glucose-stimulated insulin secretion (GSIS) was determined in isolated islets. RESULTS: Carrying the T2Drisk allele G of ABCB10 rs348330 variant was associated with increased ABCB10 expression in human beta-cells. Constitutive deletion of Abcb10 in beta-cells protected mice from hyperinsulinemia and insulin resistance by limiting HFD-induced beta-cell expansion. An early limitation in GSIS and H(2)O(2)-mediated signaling caused by elevated ABCB10 activity can initiate an over-compensatory expansion of beta-cell mass in response to HFD. Accordingly, increasing ABCB10 expression was sufficient to limit GSIS capacity. In health, ABCB10 protein was decreased during islet maturation, with maturation restricting beta-cell proliferation and elevating GSIS. Finally, ex-vivo and short-term deletion of ABCB10 in islets isolated from HFD-fed mice increased H(2)O(2) and GSIS, which was reversed by bilirubin treatments. CONCLUSIONS: Beta-cell ABCB10 is required for HFD to induce insulin resistance in mice by amplifying beta-cell mass expansion to maladaptive levels that cause fasting hyperinsulinemia.
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spelling pubmed-86892432021-12-30 Deletion of ABCB10 in beta-cells protects from high-fat diet induced insulin resistance Shum, Michael Segawa, Mayuko Gharakhanian, Raffi Viñuela, Ana Wortham, Matthew Baghdasarian, Siyouneh Wolf, Dane M. Sereda, Samuel B. Nocito, Laura Stiles, Linsey Zhou, Zhiqiang Gutierrez, Vincent Sander, Maike Shirihai, Orian S. Liesa, Marc Mol Metab Original Article OBJECTIVE: The contribution of beta-cell dysfunction to type 2 diabetes (T2D) is not restricted to insulinopenia in the late stages of the disease. Elevated fasting insulinemia in normoglycemic humans is a major factor predicting the onset of insulin resistance and T2D, demonstrating an early alteration of beta-cell function in T2D. Moreover, an early and chronic increase in fasting insulinemia contributes to insulin resistance in high-fat diet (HFD)-fed mice. However, whether there are genetic factors that promote beta-cell-initiated insulin resistance remains undefined. Human variants of the mitochondrial transporter ABCB10, which regulates redox by increasing bilirubin synthesis, have been associated with an elevated risk of T2D. The effects of T2D ABCB10 variants on ABCB10 expression and the actions of ABCB10 in beta-cells are unknown. METHODS: The expression of beta-cell ABCB10 was analyzed in published transcriptome datasets from human beta-cells carrying the T2D-risk ABCB10 variant. Insulin sensitivity, beta-cell proliferation, and secretory function were measured in beta-cell-specific ABCB10 KO mice (Ins1(Cre)-Abcb10(flox/flox)). The short-term role of beta-cell ABCB10 activity on glucose-stimulated insulin secretion (GSIS) was determined in isolated islets. RESULTS: Carrying the T2Drisk allele G of ABCB10 rs348330 variant was associated with increased ABCB10 expression in human beta-cells. Constitutive deletion of Abcb10 in beta-cells protected mice from hyperinsulinemia and insulin resistance by limiting HFD-induced beta-cell expansion. An early limitation in GSIS and H(2)O(2)-mediated signaling caused by elevated ABCB10 activity can initiate an over-compensatory expansion of beta-cell mass in response to HFD. Accordingly, increasing ABCB10 expression was sufficient to limit GSIS capacity. In health, ABCB10 protein was decreased during islet maturation, with maturation restricting beta-cell proliferation and elevating GSIS. Finally, ex-vivo and short-term deletion of ABCB10 in islets isolated from HFD-fed mice increased H(2)O(2) and GSIS, which was reversed by bilirubin treatments. CONCLUSIONS: Beta-cell ABCB10 is required for HFD to induce insulin resistance in mice by amplifying beta-cell mass expansion to maladaptive levels that cause fasting hyperinsulinemia. Elsevier 2021-11-23 /pmc/articles/PMC8689243/ /pubmed/34823065 http://dx.doi.org/10.1016/j.molmet.2021.101403 Text en © 2021 The Author(s) https://creativecommons.org/licenses/by/4.0/This is an open access article under the CC BY license (http://creativecommons.org/licenses/by/4.0/).
spellingShingle Original Article
Shum, Michael
Segawa, Mayuko
Gharakhanian, Raffi
Viñuela, Ana
Wortham, Matthew
Baghdasarian, Siyouneh
Wolf, Dane M.
Sereda, Samuel B.
Nocito, Laura
Stiles, Linsey
Zhou, Zhiqiang
Gutierrez, Vincent
Sander, Maike
Shirihai, Orian S.
Liesa, Marc
Deletion of ABCB10 in beta-cells protects from high-fat diet induced insulin resistance
title Deletion of ABCB10 in beta-cells protects from high-fat diet induced insulin resistance
title_full Deletion of ABCB10 in beta-cells protects from high-fat diet induced insulin resistance
title_fullStr Deletion of ABCB10 in beta-cells protects from high-fat diet induced insulin resistance
title_full_unstemmed Deletion of ABCB10 in beta-cells protects from high-fat diet induced insulin resistance
title_short Deletion of ABCB10 in beta-cells protects from high-fat diet induced insulin resistance
title_sort deletion of abcb10 in beta-cells protects from high-fat diet induced insulin resistance
topic Original Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8689243/
https://www.ncbi.nlm.nih.gov/pubmed/34823065
http://dx.doi.org/10.1016/j.molmet.2021.101403
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