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Details

Autor(en) / Beteiligte
Titel
Chop / Ddit3 depletion in β cells alleviates ER stress and corrects hepatic steatosis in mice
Ist Teil von
  • Science translational medicine, 2021-07, Vol.13 (604)
Ort / Verlag
United States
Erscheinungsjahr
2021
Quelle
MEDLINE
Beschreibungen/Notizen
  • Type 2 diabetes (T2D) is a metabolic disorder characterized by hyperglycemia, hyperinsulinemia, and insulin resistance (IR). During the early phase of T2D, insulin synthesis and secretion by pancreatic β cells is enhanced, which can lead to proinsulin misfolding that aggravates endoplasmic reticulum (ER) protein homeostasis in β cells. Moreover, increased circulating insulin may contribute to fatty liver disease. Medical interventions aimed at alleviating ER stress in β cells while maintaining optimal insulin secretion are therefore an attractive therapeutic strategy for T2D. Previously, we demonstrated that germline gene deletion preserved β cells in high-fat diet (HFD)-fed mice and in leptin receptor-deficient mice. In the current study, we further investigated whether targeting specifically in murine β cells conferred therapeutic benefits. First, we showed that deletion in β cells alleviated β cell ER stress and delayed glucose-stimulated insulin secretion (GSIS) in HFD-fed mice. Second, β cell-specific deletion prevented liver steatosis and hepatomegaly in aged HFD-fed mice without affecting basal glucose homeostasis. Third, we provide mechanistic evidence that depletion reduces ER Ca buffering capacity and modulates glucose-induced islet Ca oscillations, leading to transcriptional changes of ER chaperone profile ("ER remodeling"). Last, we demonstrated that a GLP1-conjugated antisense oligonucleotide strategy recapitulated the reduction in liver triglycerides and pancreatic insulin content. In summary, our results demonstrate that depletion in β cells provides a therapeutic strategy to alleviate dysregulated insulin secretion and consequent fatty liver disease in T2D.
Sprache
Englisch
Identifikatoren
ISSN: 1946-6234
eISSN: 1946-6242
DOI: 10.1126/scitranslmed.aba9796
Titel-ID: cdi_pubmed_primary_34321322

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