The mechanisms underlying the effects of exocrine dysfunction on the development of diabetes remain largely unknown. Here, we show that pancreatic depletion of SMAD7 resulted in age-dependent increases in β-cell dysfunction, with accelerated glucose intolerance, followed by overt diabetes. The accelerated β-cell dysfunction and loss of proliferation capacity, two features of β-cell aging, appeared to be non-cell-autonomous, secondary to the adjacent exocrine failure as a bystander effect. Increased FoxO1 acetylation and nuclear retention was followed by progressive FoxO1 loss in β-cells, which marked the onset of diabetes. Moreover, forced FoxO1 expression in β-cells prevented β-cell dysfunction and loss in this model. Thus, we present a model of accelerated β-cell aging, which may be useful for studying the mechanisms underlying β-cell failure in diabetes. Moreover, we provide evidence highlighting a critical role of FoxO1 in maintaining β-cell identity in the context of SMAD7 failure.
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