Autophagy Differentially Regulates Insulin Production and Insulin Sensitivity

Abstract

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.

A high glucose diet induces autophagy in a HLH-30/TFEB-dependent manner and impairs the normal lifespan of C. elegans

“…In fact, it has been shown that genetic hyperactivation of autophagy exacerbates glucose intolerance in mice fed a high fat diet; however, this change can be reversed by transient inhibition of autophagy. Therefore, autophagy is considered a double-edged sword that can promote either cell survival or death [ 5 ].…”

Tinospora cordifolia preserves pancreatic beta cells and enhances glucose uptake in adipocytes to regulate glucose metabolism in diabetic rats

“…In addition, Sharma et al (Sharma et al, ) recently reported the autophagy promoting effect of clerodane furano diterpene glycoside from T. cordifolia . Autophagy regulates body weight via differentially regulating insulin production and insulin sensitivity (Yamamoto et al, ). TCSE may contain furano diterpene glycosides, which could regulate insulin secretion in pancreatic beta cells and insulin sensitivity in adipocytes via modulating autophagy machinery.…”

Beclin-1-mediated activation of autophagy improves proximal and distal urea cycle disorders

“…To investigate Becn1 functions in vivo, a knock-in mouse model carrying a Becn1 mutation (Becn1 F121A ) resulting in constitutively active autophagy has been recently generated (Rocchi et al, 2017). In these mice Phe121 is mutated into alanine resulting in disruption of the BECN1-BCL2 binding and constitutive activation of BECN1 and autophagy in multiple tissues, including liver (Fernandez et al, 2018;Rocchi et al, 2017;Yamamoto et al, 2018).…”