Abstract
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 Forkhead box protein 1 (FoxO1) acetylation and nuclear retention was followed by progressive FoxO1 loss in β cells that 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 that 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.
Highlights
The mechanisms underlying the effects of exocrine dysfunction on the development of diabetes remain largely unknown
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
In Ptf1a-Cre mice, in which SMAD7 was deleted in the majority of the pancreatic cells [21, 25, 26],  cells were isolated by laser capture microdissection (LCM) after insulin staining, and the purity of the  cells was assured by analyzing gene transcripts
Summary
Pancreas-specific (SMAD7Ptf1a) 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 SMAD7Ptf1a (supplemental Fig. 1, A and B). In Ptf1a-Cre mice, in which SMAD7 was deleted in the majority of the pancreatic cells [21, 25, 26],  cells were isolated by laser capture microdissection (LCM) after insulin staining, and the purity of the  cells was assured by analyzing gene transcripts (supplemental Fig. 2, A and B). Pancreatic SMAD7 Knockout Accelerates  Cell Dysfunction with Age—SMAD7Ptf1a mice developed late-onset, gradual loss of body weight (Fig. 1A) with age-dependent progressive glucose intolerance (detectable as early as 20 weeks of age), fol-
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