[Research Articles] Chop/Ddit3 depletion in {beta} cells alleviates ER stress and corrects hepatic steatosis in mice
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 Chop gene deletion preserved β cells in high-fat diet (HFD)–fed mice and in leptin receptor–deficient db/db mice. In the current study, we further investigated whether targeting Chop/Ddit3 specifically in murine β cells conferred therapeutic benefits. First, we showed that Chop deletion in β cells alleviated β cell ER stress and delayed glucose-stimulated insulin secretion (GSIS) in HFD-fed mice. Second, β cell–specific Chop deletion prevented liver steatosis and hepatomegaly in aged HFD-fed mice without affecting basal glucose homeostasis. Third, we provide mechanistic evidence that Chop depletion reduces ER Ca2+ buffering capacity and modulates glucose-induced islet Ca2+ oscillations, leading to transcriptional changes of ER chaperone profile ("ER remodeling"). Last, we demonstrated that a GLP1-conjugate...
Source: Science Translational Medicine - Category: Biomedical Science Authors: Yong, J., Parekh, V. S., Reilly, S. M., Nayak, J., Chen, Z., Lebeaupin, C., Jang, I., Zhang, J., Prakash, T. P., Sun, H., Murray, S., Guo, S., Ayala, J. E., Satin, L. S., Saltiel, A. R., Kaufman, R. J. Tags: Research Articles Source Type: research
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