Autophagy Differentially Regulates Insulin Production and Insulin Sensitivity

Soh Yamamoto, Kenta Kuramoto, Nan Wang, Xiaolei Situ, Medha Priyadarshini, Weiran Zhang, Jose Cordoba-Chacon, Brian T Layden, Congcong He*

*Corresponding author for this work

Research output: Contribution to journalArticle

23 Scopus citations

Abstract

Autophagy, a stress-induced lysosomal degradative pathway, has been assumed to exert similar metabolic effects in different organs. Here, we establish a model where autophagy plays different roles in insulin-producing β cells versus insulin-responsive cells, utilizing knockin (Becn1F121A) mice manifesting constitutively active autophagy. With a high-fat-diet challenge, the autophagy-hyperactive mice unexpectedly show impaired glucose tolerance, but improved insulin sensitivity, compared to mice with normal autophagy. Autophagy hyperactivation enhances insulin signaling, via suppressing ER stress in insulin-responsive cells, but decreases insulin secretion by selectively sequestrating and degrading insulin granule vesicles in β cells, a process we term “vesicophagy.” The reduction in insulin storage, insulin secretion, and glucose tolerance is reversed by transient treatment of autophagy inhibitors. Thus, β cells and insulin-responsive tissues require different autophagy levels for optimal function. To improve insulin sensitivity without hampering secretion, acute or intermittent, rather than chronic, activation of autophagy should be considered in diabetic therapy development. Yamamoto et al. report that, in response to a high-fat-diet challenge, Becn1-mediated autophagy hyperactivation increases insulin sensitivity by reducing ER stress but decreases insulin secretion and storage via autophagic degradation of insulin granules. The results reveal differing roles of autophagy on metabolic regulation in insulin-responsive cells versus insulin-secreting β cells.

Original languageEnglish (US)
Pages (from-to)3286-3299
Number of pages14
JournalCell reports
Volume23
Issue number11
DOIs
StatePublished - Jun 12 2018

Keywords

  • Becn1
  • autophagosome
  • autophagy
  • glucose tolerance
  • insulin granule
  • insulin sensitivity
  • insulin-responsive tissue
  • type 2 diabetes
  • vesicophagy
  • β cell

ASJC Scopus subject areas

  • Biochemistry, Genetics and Molecular Biology(all)

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  • Cite this

    Yamamoto, S., Kuramoto, K., Wang, N., Situ, X., Priyadarshini, M., Zhang, W., Cordoba-Chacon, J., Layden, B. T., & He, C. (2018). Autophagy Differentially Regulates Insulin Production and Insulin Sensitivity. Cell reports, 23(11), 3286-3299. https://doi.org/10.1016/j.celrep.2018.05.032