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Publication
Autophagy Differentially Regulates Insulin Production and Insulin Sensitivity.
Authors Yamamoto S, Kuramoto K, Wang N, Situ X, Priyadarshini M, Zhang W, Cordoba-Chacon
J, Layden BT, He C
Submitted By Submitted Externally on 7/31/2018
Status Published
Journal Cell reports
Year 2018
Date Published 6/1/2018
Volume : Pages 23 : 3286 - 3299
PubMed Reference 29898399
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 ß 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 ß 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, ß 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.




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