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Published Only

Disruption of the Autophagy-Regulatory Becn1-Bcl2 Complex Impairs Insulin Storage and Secretion in Mice

  1. SOH YAMAMOTO,
  2. NAN WANG,
  3. WEIRAN ZHANG and
  4. CONGCONG HE
  1. Chicago, IL
Diabetes 2018 Jul; 67(Supplement 1): -. https://doi.org/10.2337/db18-2432-PUB
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Abstract

Autophagy, a stress-induced lysosomal degradation pathway, has thought to exert similar metabolic effects in different organs. Yet the function and tissue-specific requirement of autophagy in metabolic regulation remain enigmatic. Here we establish a new model in which autophagy plays different roles in insulin-producing β cells vs. insulin-responsive cells, utilizing a point mutant (Becn1F121A) mouse model manifesting constitutively active autophagy under non-autophagy-inducing conditions. In response to high-fat diet challenge, we found unexpectedly that the autophagy-hyperactive mice show impaired glucose tolerance, but improved insulin sensitivity, compared to mice with normal levels of autophagy. We further demonstrated that autophagy hyperactivation increases insulin sensitivity in insulin-responsive cells, but decreases insulin load and secretion by sequestrating and degrading secretory vesicles containing insulin granules in β cells, a process we characterized as vesicophagy. The reduction in insulin secretion was not due to islet degeneration; instead, the β cell mass was expanded in the mutant mice, suggesting higher β cell regeneration. The reduction in insulin storage, insulin secretion, and glucose tolerance in autophagy-hyperactive mice can be reversed by transient treatment of an autophagy-blocking ULK1 kinase inhibitor. Thus, we conclude that β cells and insulin-responsive tissues require different levels of autophagy for their optimal functions. Importantly, our findings suggest that acute or intermittent, rather than chronic, activation of autophagy should be considered in therapeutic development against type 2 diabetes, to improve insulin sensitivity without negatively affecting insulin secretion.

Disclosure S. Yamamoto: None. N. Wang: None. W. Zhang: None. C. He: None.

  • © 2018 by the American Diabetes Association.
http://www.diabetesjournals.org/content/license

Readers may use this article as long as the work is properly cited, the use is educational and not for profit, and the work is not altered. More information is available at http://www.diabetesjournals.org/content/license.

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Diabetes: 67 (Supplement 1)

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July 2018, 67(Supplement 1)
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Disruption of the Autophagy-Regulatory Becn1-Bcl2 Complex Impairs Insulin Storage and Secretion in Mice
SOH YAMAMOTO, NAN WANG, WEIRAN ZHANG, CONGCONG HE
Diabetes Jul 2018, 67 (Supplement 1) 2432-PUB; DOI: 10.2337/db18-2432-PUB

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Disruption of the Autophagy-Regulatory Becn1-Bcl2 Complex Impairs Insulin Storage and Secretion in Mice
SOH YAMAMOTO, NAN WANG, WEIRAN ZHANG, CONGCONG HE
Diabetes Jul 2018, 67 (Supplement 1) 2432-PUB; DOI: 10.2337/db18-2432-PUB
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