A Smad Signaling Network Regulates Islet Cell Proliferation

El-Gohary, Yousef; Tulachan, Sidhartha; Wiersch, John; Guo, Ping; Welsh, Carey; Prasadan, Krishna; Paredes, Jose; Shiota, Chiyo; Xiao, Xianmin; Wada, Yoko; Diaz, Marilyn; Gittes, George K.

doi:10.2337/db13-0432

Cited by 67 publications

(119 citation statements)

References 49 publications

Supporting

Mentioning

114

Contrasting

Order By: Relevance

“…Adult β cells lacking NeuroD1 reexpress NPY, coincident with altered metabolic and insulin secretion profiles that resemble immature β cells (15). NPY also marks a highly proliferative insulin -cell-type derived from β cells that contributes to compensatory β cell expansion upon partial pancreatectomy (34). Impairment of β cell maturity contributes to β cell dysfunction in diabetes (17,18,35).…”

Section: Discussionmentioning

confidence: 99%

Neuropeptide Y expression marks partially differentiated β cells in mice and humans

Rodnoi¹,

Rajkumar²,

Moin³

et al. 2017

JCI Insight

View full text Add to dashboard Cite

Section: Discussionmentioning

confidence: 99%

Neuropeptide Y expression marks partially differentiated β cells in mice and humans

Rodnoi¹,

Rajkumar²,

Moin³

et al. 2017

JCI Insight

View full text Add to dashboard Cite

“…TGF␤ superfamily signaling pathways are essential for pancreas development (20), postnatal ␤ cell homeostasis, and proper function (21)(22)(23). Binding of TGF␤ superfamily ligands to a type II receptor catalyzes the phosphorylation of a type I receptor to trigger downstream signaling cascades.…”

mentioning

confidence: 99%

Forkhead Box Protein 1 (FoxO1) Inhibits Accelerated β Cell Aging in Pancreas-specific SMAD7 Mutant Mice

Xiao¹,

Chen

Guo

et al. 2017

Journal of Biological Chemistry

Self Cite

View full text Add to dashboard Cite

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...

show abstract

“…Smad7 in particular was found to mediate b-cell proliferation after a loss of b-cells by first inducing dedifferentiation. 11 Further, another member of the TGFb superfamily, Nodal, has recently been identified in human islets and found to promote b-cell proliferation while maintaining differentiation status and cell viability. 12 This finding is an important contribution to the field through the rare use of human islets which further strengthens the clinical relevance and importance of studying the role of this superfamily in b-cell homeostasis.…”

mentioning

confidence: 99%

Effects of activin A on survival, function and gene expression of pancreatic islets from non-diabetic and diabetic human donors

Brown

Ungerleider

Bonomi

et al. 2014

Islets

View full text Add to dashboard Cite

A Smad Signaling Network Regulates Islet Cell Proliferation

Cited by 67 publications

References 49 publications

Neuropeptide Y expression marks partially differentiated β cells in mice and humans

Neuropeptide Y expression marks partially differentiated β cells in mice and humans

Forkhead Box Protein 1 (FoxO1) Inhibits Accelerated β Cell Aging in Pancreas-specific SMAD7 Mutant Mice

Effects of activin A on survival, function and gene expression of pancreatic islets from non-diabetic and diabetic human donors

Contact Info

Product

Resources

About