Autophagy Differentially Regulates Insulin Production and Insulin Sensitivity
| Autor: | Weiran Zhang, Nan Wang, Medha Priyadarshini, Jose Cordoba-Chacon, Brian T. Layden, Kenta Kuramoto, Congcong He, Soh Yamamoto, Xiaolei Situ |
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| Rok vydání: | 2018 |
| Předmět: |
0301 basic medicine
Autophagosome biology Chemistry Insulin medicine.medical_treatment Autophagy BECN1 medicine.disease General Biochemistry Genetics and Molecular Biology Cell biology Impaired glucose tolerance 03 medical and health sciences Insulin receptor 030104 developmental biology 0302 clinical medicine lcsh:Biology (General) Unfolded protein response biology.protein medicine Secretion lcsh:QH301-705.5 030217 neurology & neurosurgery |
| Zdroj: | Cell Reports, Vol 23, Iss 11, Pp 3286-3299 (2018) |
| ISSN: | 2211-1247 |
| Popis: | Summary: 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. Keywords: autophagosome, autophagy, β cell, Becn1, glucose tolerance, insulin granule, insulin-responsive tissue, insulin sensitivity, type 2 diabetes, vesicophagy |
| Databáze: | OpenAIRE |
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