Benefits and harms of activating ATF6 in beta cells

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ABSTRACT Pancreatic beta cell insulin production is the critical lynchpin that determines diabetes resistance or susceptibility. ER stress is one cause of beta cell dysfunction and failure, not only in T2D but also in T1D and some forms of monogenic diabetes. Many published reports show that the ATF6 pathway, one of three principal ER stress response pathways, plays important roles in cellular adaptation to stress. In particular, ATF6 is known to drive beneficial effects including increased ER capacity, cell survival in the face of stress, and more recently evidence from our group and several others implicate ATF6 in beta cell compensatory proliferation in response to insulin demand. For these reasons, activation of ATF6 has been proposed as a potential beta cell therapeutic approach that might improve beta cell mass and insulin production capacity. We have developed two novel, exciting tools that allow us to activate ATF6 in beta cells with temporal precision, either ex vivo or in vivo in live mice. Initial experiments, however, show that when we indiscriminately activate ATF6 for an extended period of time we observe a mix of beneficial and harmful effects, in some ways reminiscent of glucotoxic beta cell failure. Specifically, we do observe evidence of increased beta cell proliferation and survival, but activating ATF6 in vivo continuously for a 14-day period leads to frank glucose intolerance due to beta cell dysfunction. Remarkably, if we allow ATF6 to turn off, beta cell function gradually returns to normal. Molecular and morphological preliminary data suggest that in vivo chronic continuous ATF6 activation mimics, in many ways, chronic beta cell stress in T2D, with similarities to mouse and human observations. As such, this model represents a tremendous opportunity to study the proximate causes of beta cell failure after chronic activation of one ER stress response pathway (ATF6), as well as a unique and exciting chance to understand the in vivo recovery process if that stress pathway activation is able to shut off. In this project we will explore the causes of beta cell failure after ATF6 activation, with in-depth molecular, morphological and tissue homeostasis experiments. We will determine the cellular and molecular bases for beta cell recovery when ATF6 is allowed to turn off. Finally, we turn our attention to the molecular mechanisms driving benefits and harms of ATF6 activation and seek to identify conditions in which beneficial responses can be separated from harmful responses, to see whether it may be possible in the future to harness ATF6 for safe therapeutic potential in diabetes treatment or prevention. If successful, this project will lead to important new insight into beta cell stress-induced diabetes, the in vivo recovery process after ATF6-induced beta cell dysfunction, the molecular mechanisms by which ATF6 drives benefits and harms, and whether it may be possible to separate benefit from harm for future therapeutic benefit.