Rubicon in pancreatic beta cells plays a limited role in maintaining glucose homeostasis following increased insulin resistance

Endocrine journal

article

Shuhei Aoyama¹  Yuya Nishida¹  Yoshio Fujitani³  Ayako Fukunaka³  Takeshi Miyatsuka¹  Luka Suzuki¹  Miwa Himuro¹  Tamotsu Yoshimori⁵  Hirotaka Watada¹ 

[1] Department of Metabolism and Endocrinology, Juntendo University Graduate School of Medicine;Center for Therapeutic Innovations in Diabetes;Laboratory of Developmental Biology and Metabolism, Institute for Molecular and Cellular Regulation, Gunma University;Center for Identification of Diabetic Therapeutic Targets;Department of Intracellular Membrane Dynamics, Graduate School of Frontier Biosciences, Osaka University

关键词: Autophagy;    PI3K;    Rubicon;    Pancreatic beta cells;    Insulin resistance;   

DOI  :  10.1507/endocrj.EJ20-0326

学科分类：内分泌与代谢学

来源: Japan Endocrine Society

【 摘 要 】

Autophagy has been reported to play a crucial role in the maintenance of intracellular homeostasis, including in pancreatic beta cells. Rubicon, which interacts with the phosphoinositide 3-kinase (PI3K) complex, through autophagy-related 14 (ATG14), is among the few autophagy regulators that have been reported to inhibit autophagic flux to date and the deletion of Rubicon has been shown to increase autophagic flux. Based on previous results showing a causal relationship between autophagic dysfunction and pancreatic beta-cell impairment, we hypothesized that the deletion of Rubicon in pancreatic beta cells would improve cell integrity and confer protective effects. To test this hypothesis, we first confirmed that Rubicon knockdown (KD) promoted autophagic flux in βTC3 pancreatic beta-cell line. Next, we generated pancreatic beta-cell-specific Rubicon knockout (βKO) mice, by administering tamoxifen to Rubicon flox/flox :MIP-Cre-ERT mice, which showed normal glucose tolerance and insulin secretion under a normal chow diet, despite successful gene recombination. We also attempted to increase insulin resistance by feeding the mice with a high-fat diet for an additional 2 months to find little differences among the parameters evaluated for glucose metabolism. Finally, severe insulin resistance was induced with insulin receptor antagonist treatment, which resulted in comparable glucose homeostasis measurements between Rubicon βKO and control mice. In summary, these results suggest that in pancreatic beta cells, Rubicon plays a limited role in the maintenance of systemic glucose homeostasis.

【 授权许可】

Unknown