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Dysregulation of cholesterol homeostasis is an early signal of ß-cell proteotoxicity characteristic of type 2 diabetes.
Gurlo, Tatyana; Liu, Ruoshui; Wang, Zhongying; Hoang, Jonathan; Ryazantsev, Sergey; Daval, Marie; Butler, Alexandra E; Yang, Xia; Blencowe, Montgomery; Butler, Peter C.
Afiliación
  • Gurlo T; Larry L. Hillblom Islet Research Center, David Geffen School of Medicine, University of California, Los Angeles, Los Angeles, California, United States.
  • Liu R; Department of Integrative Biology and Physiology, University of California, Los Angeles, Los Angeles, California, United States.
  • Wang Z; Larry L. Hillblom Islet Research Center, David Geffen School of Medicine, University of California, Los Angeles, Los Angeles, California, United States.
  • Hoang J; Larry L. Hillblom Islet Research Center, David Geffen School of Medicine, University of California, Los Angeles, Los Angeles, California, United States.
  • Ryazantsev S; Electron Imaging Center, California Nano Systems Institute, University of California, Los Angeles, Los Angeles, California, United States.
  • Daval M; Larry L. Hillblom Islet Research Center, David Geffen School of Medicine, University of California, Los Angeles, Los Angeles, California, United States.
  • Butler AE; Larry L. Hillblom Islet Research Center, David Geffen School of Medicine, University of California, Los Angeles, Los Angeles, California, United States.
  • Yang X; Department of Integrative Biology and Physiology, University of California, Los Angeles, Los Angeles, California, United States.
  • Blencowe M; Molecular, Cellular, and Integrative Physiology Interdepartmental Program, University of California, Los Angeles, Los Angeles, California, United States.
  • Butler PC; Department of Integrative Biology and Physiology, University of California, Los Angeles, Los Angeles, California, United States.
Physiol Genomics ; 56(9): 621-633, 2024 Sep 01.
Article en En | MEDLINE | ID: mdl-38949617
ABSTRACT
Type 2 diabetes (T2D) is a common metabolic disease due to insufficient insulin secretion by pancreatic ß-cells in the context of insulin resistance. Islet molecular pathology reveals a role for protein misfolding in ß-cell dysfunction and loss with islet amyloid derived from islet amyloid polypeptide (IAPP), a protein coexpressed and cosecreted with insulin. The most toxic form of misfolded IAPP is intracellular membrane disruptive toxic oligomers present in ß-cells in T2D and in ß-cells of mice transgenic for human IAPP (hIAPP). Prior work revealed a high degree of overlap of transcriptional changes in islets from T2D and prediabetic 9- to 10-wk-old mice transgenic for hIAPP with most changes being pro-survival adaptations and therefore of limited therapeutic guidance. Here, we investigated islets from hIAPP transgenic mice at an earlier age (6 wk) to screen for potential mediators of hIAPP toxicity that precede predominance of pro-survival signaling. We identified early suppression of cholesterol synthesis and trafficking along with aberrant intra-ß-cell cholesterol and lipid deposits and impaired cholesterol trafficking to cell membranes. These findings align with comparable lipid deposits present in ß-cells in T2D and increased vulnerability to develop T2D in individuals taking medications that suppress cholesterol synthesis.NEW & NOTEWORTHY ß-Cell failure in type 2 diabetes (T2D) is characterized by ß-cell misfolded protein stress due to the formation of toxic oligomers of islet amyloid polypeptide (IAPP). Most transcriptional changes in islets in T2D are pro-survival adaptations consistent with the slow progression of ß-cell loss. In the present study, investigation of the islet transcriptional signatures in a mouse model of T2D expressing human IAPP revealed decreased cholesterol synthesis and trafficking as a plausible early mediator of IAPP toxicity.
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Texto completo: 1 Colección: 01-internacional Base de datos: MEDLINE Asunto principal: Ratones Transgénicos / Colesterol / Diabetes Mellitus Tipo 2 / Células Secretoras de Insulina / Polipéptido Amiloide de los Islotes Pancreáticos / Homeostasis Límite: Animals / Humans / Male Idioma: En Revista: Physiol Genomics Asunto de la revista: BIOLOGIA MOLECULAR Año: 2024 Tipo del documento: Article País de afiliación: Estados Unidos Pais de publicación: Estados Unidos
Texto completo
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Texto completo: 1 Colección: 01-internacional Base de datos: MEDLINE Asunto principal: Ratones Transgénicos / Colesterol / Diabetes Mellitus Tipo 2 / Células Secretoras de Insulina / Polipéptido Amiloide de los Islotes Pancreáticos / Homeostasis Límite: Animals / Humans / Male Idioma: En Revista: Physiol Genomics Asunto de la revista: BIOLOGIA MOLECULAR Año: 2024 Tipo del documento: Article País de afiliación: Estados Unidos Pais de publicación: Estados Unidos