Edited by Jeffrey E. PessinThe 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  cell dysfunction with accelerated glucose intolerance, followed by overt diabetes. The accelerated  cell dysfunction and loss of proliferation capacity, two features of  cell aging, appeared to be non-cell-autonomous, secondary to the adjacent exocrine failure as a "bystander effect." Increased Forkhead box protein 1 (FoxO1) acetylation and nuclear retention was followed by progressive FoxO1 loss in  cells that marked the onset of diabetes. Moreover, forced FoxO1 expression in  cells prevented  cell dysfunction and loss in this model. Thus, we present a model of accelerated  cell aging that may be useful for studying the mechanisms underlying  cell failure in diabetes. Moreover, we provide evidence highlighting a critical role of FoxO1 in maintaining  cell identity in the context of SMAD7 failure. Cell dysfunction and failure are hallmarks of type 2 diabetes (1-4). Oxidative stress, endoplasmic reticulum stress, hypoxic stress, and cytokine toxicity can all lead to  cell apoptosis, autophagy, and replication defects, resulting in global  cell failure (3, 4). Thus,  cell replacement may be an ideal strategy for treating diabetes (5). Although  cell neogenesis from non- cell sources has been extensively studied, most evidence suggests that postnatal  cell expansion predominantly results from  cell replication (6 -11). However, normally, the  cell replication ratio is fairly low in young adult mice and then gets progressively lower with increasing age (4, 12-16). Meanwhile, recent studies strongly suggest that protection of the differentiated phenotype of existing  cells is critical for the maintenance of a functional  cell mass and for the prevention of type 2 diabetes (2,(17)(18)(19), in which the transcription factor Forkhead box protein 1 (FoxO1) 3 appears to play a key protective role against  cell senescence and failure.TGF superfamily signaling pathways are essential for pancreas development (20), postnatal  cell homeostasis, and proper function (21-23). Binding of TGF superfamily ligands to a type II receptor catalyzes the phosphorylation of a type I receptor to trigger downstream signaling cascades. SMAD7 is a general inhibitor of all TGF superfamily pathways, and we have shown recently that SMAD7 plays a critical role during pancreas development and  cell replication (20,(22)(23)(24). Here we studied  cell function in a model of pancreatic SMAD7 depletion (SMAD7 Ptf1a ).
ResultsPancreas-specific (SMAD7 Ptf1a ) SMAD7 Knockout Mice-To characterize the role of SMAD7 in  cell development and postnatal  cell mass homeostasis, we deleted pancreatic SMAD7 by crossing SMAD7fx/fx mice with Ptf1a-Cre mice to generate Ptf1a-Cre; SMAD7fx/fx mice, simplified as SMAD7 Ptf1a (supplemental Fig. 1, A and B). In Ptf1a-Cre mice, in which SMAD7 was deleted in the major...