Details

Autor(en) / Beteiligte

• Yong, Jing
• Parekh, Vishal S
• Reilly, Shannon M
• Nayak, Jonamani
• Chen, Zhouji
• Lebeaupin, Cynthia
• Jang, Insook
• Zhang, Jiangwei
• Prakash, Thazha P
• Sun, Hong
• Murray, Sue
• Guo, Shuling
• Ayala, Julio E
• Satin, Leslie S
• Saltiel, Alan R
• Kaufman, Randal J

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.