Eric Liu

Pancreatic islet β-cell dysfunction is a signature feature of Type 2 diabetes pathogenesis. Consequently, knowledge of signals that regulate β-cell function is of immense clinical relevance. Transforming growth factor (TGF)-β signaling plays a critical role in pancreatic development although the role of this pathway in the adult pancreas is obscure. Here, we define an important role of the TGF-β pathway in regulation of insulin gene transcription and β-cell function. We identify insulin as a TGF-β target gene and show that the TGF-β signaling effector Smad3 occupies the insulin gene promoter and represses insulin gene transcription. In contrast, Smad3 small interfering RNAs relieve insulin transcriptional repression and enhance insulin levels. Transduction of adenoviral Smad3 into primary human and non-human primate islets suppresses insulin content, whereas, dominant-negative Smad3 enhances insulin levels. Consistent with this, Smad3-deficient mice exhibit moderate hyperinsulinemia and mild hypoglycemia. Moreover, Smad3 deficiency results in improved glucose tolerance and enhanced glucose-stimulated insulin secretion in vivo. In ex vivo perifusion assays, Smad3-deficient islets exhibit improved glucose-stimulated insulin release. Interestingly, Smad3-deficient islets harbor an activated insulin-receptor signaling pathway and TGF-β signaling regulates expression of genes involved in β-cell function. Together, these studies emphasize TGF-β/Smad3 signaling as an important regulator of insulin gene transcription and β-cell function and suggest that components of the TGF-β signaling pathway may be dysregulated in diabetes. Pancreatic islet β-cell dysfunction is a signature feature of Type 2 diabetes pathogenesis. Consequently, knowledge of signals that regulate β-cell function is of immense clinical relevance. Transforming growth factor (TGF)-β signaling plays a critical role in pancreatic development although the role of this pathway in the adult pancreas is obscure. Here, we define an important role of the TGF-β pathway in regulation of insulin gene transcription and β-cell function. We identify insulin as a TGF-β target gene and show that the TGF-β signaling effector Smad3 occupies the insulin gene promoter and represses insulin gene transcription. In contrast, Smad3 small interfering RNAs relieve insulin transcriptional repression and enhance insulin levels. Transduction of adenoviral Smad3 into primary human and non-human primate islets suppresses insulin content, whereas, dominant-negative Smad3 enhances insulin levels. Consistent with this, Smad3-deficient mice exhibit moderate hyperinsulinemia and mild hypoglycemia. Moreover, Smad3 deficiency results in improved glucose tolerance and enhanced glucose-stimulated insulin secretion in vivo. In ex vivo perifusion assays, Smad3-deficient islets exhibit improved glucose-stimulated insulin release. Interestingly, Smad3-deficient islets harbor an activated insulin-receptor signaling pathway and TGF-β signaling regulates expression of genes involved in β-cell function. Together, these studies emphasize TGF-β/Smad3 signaling as an important regulator of insulin gene transcription and β-cell function and suggest that components of the TGF-β signaling pathway may be dysregulated in diabetes. Incidence of the “metabolic syndrome,” a complex condition linked to insulin resistance, type 2 diabetes and obesity, is increasing worldwide (1Kahn S.E. Hull R.L. Utzschneider K.M. Nature. 2006; 444: 840-846Crossref PubMed Scopus (3541) Google Scholar). The pancreatic islet β-cell, due to its unique function of insulin synthesis and glucose-stimulated insulin secretion, is a prime target of affliction in diabetes (2Weir G.C. Bonner-Weir S. Diabetes. 2004; 53: S16-S21Crossref PubMed Scopus (816) Google Scholar). In addition, a majority of Type 2 diabetes patients develop insulin resistance in target organs of insulin action: liver, muscle, and adipose tissue (3Herman M.A. Kahn B.B. J. Clin. Investig. 2006; 116: 1767-1775Crossref PubMed Scopus (270) Google Scholar). Improved mechanistic understanding of normal β-cell function and insulin action is needed to enable early diagnosis of β-cell dysfunction and insulin resistance and to facilitate development of new rational therapeutics for diabetes. The transforming growth factor-β (TGF-β) 3The abbreviations used are: TGF-β, transforming growth factor-β; BMP, bone morphogenetic protein; CA-ALK, constitutively active activin-like kinase; Ad, adenoviral; GSIS, glucose-stimulated insulin secretion; GSIR, glucose-stimulated insulin release; FBS, fetal bovine serum; siRNA, small interfering RNA; ChIP, chromatin immunoprecipitation; GAPDH, glyceraldehyde-3-phosphate dehydrogenase; GFP, green fluorescent protein; SBE, Smad-binding element; ERK, extracellular signal-regulated kinase. superfamily, which includes the TGF-β isoforms, activins, and the bone morphogenetic proteins (BMPs), regulates gene expression in diverse cell types and is involved in a myriad of cellular processes including cell proliferation, differentiation, and apoptosis (4Attisano L. Wrana J.L. Science. 2002; 296: 1646-1647Crossref PubMed Scopus (1138) Google Scholar, 5Feng X.H. Derynck R. Annu. Rev. Cell Dev. Biol. 2005; 21: 659-693Crossref PubMed Scopus (1544) Google Scholar, 6Massague J. Blain S.W. Lo R.S. Cell. 2000; 103: 295-309Abstract Full Text Full Text PDF PubMed Scopus (2092) Google Scholar). Activated TGF-β family isoforms signal via dual Type II and Type I transmembrane serine/threonine kinase receptors and effector Smad transcription factors (4Attisano L. Wrana J.L. Science. 2002; 296: 1646-1647Crossref PubMed Scopus (1138) Google Scholar, 5Feng X.H. Derynck R. Annu. Rev. Cell Dev. Biol. 2005; 21: 659-693Crossref PubMed Scopus (1544) Google Scholar, 6Massague J. Blain S.W. Lo R.S. Cell. 2000; 103: 295-309Abstract Full Text Full Text PDF PubMed Scopus (2092) Google Scholar). Ligand binding and receptor activation leads to phosphorylation and activation of Smads, which translocate to the nucleus and regulate transcription of target genes. Development of the endocrine and exocrine pancreas is controlled by factors that include members of the TGF-β superfamily (7Kim S.K. Hebrok M. Genes Dev. 2001; 15: 111-127Crossref PubMed Scopus (346) Google Scholar, 8Kim S.K. MacDonald R.J. Curr. Opin. Genet. Dev. 2002; 12: 540-547Crossref PubMed Scopus (204) Google Scholar). In addition, TGF-β signaling has been implicated in pancreatic diseases (9Rane S.G. Lee J.H. Lin H.M. Cytokine Growth Factor Rev. 2006; 17: 107-119Crossref PubMed Scopus (79) Google Scholar). BMP signaling plays an instructive role during early pancreatic development (7Kim S.K. Hebrok M. Genes Dev. 2001; 15: 111-127Crossref PubMed Scopus (346) Google Scholar, 8Kim S.K. MacDonald R.J. Curr. Opin. Genet. Dev. 2002; 12: 540-547Crossref PubMed Scopus (204) Google Scholar, 9Rane S.G. Lee J.H. Lin H.M. Cytokine Growth Factor Rev. 2006; 17: 107-119Crossref PubMed Scopus (79) Google Scholar) and regulates mature β-cell function (10Gannon M. Cell Metab. 2007; 5: 157-159Abstract Full Text Full Text PDF PubMed Scopus (12) Google Scholar, 11Goulley J. Dahl U. Baeza N. Mishina Y. Edlund H. Cell Metab. 2007; 5: 207-219Abstract Full Text Full Text PDF PubMed Scopus (109) Google Scholar), whereas activin signaling regulates islet morphogenesis and β-cell mass (12Yamaoka T. Idehara C. Yano M. Matsushita T. Yamada T. Ii S. Moritani M. Hata J. Sugino H. Noji S. Itakura M. J. Clin. Investig. 1998; 102: 294-301Crossref PubMed Scopus (135) Google Scholar, 13Zhang Y.Q. Cleary M.M. Si Y. Liu G. Eto Y. Kritzik M. Dabernat S. Kayali A.G. Sarvetnick N. Diabetes. 2004; 53: 2024-2033Crossref PubMed Scopus (52) Google Scholar). TGF-β isoforms are expressed in the epithelium and mesenchyme of embryonic pancreas and in adult pancreas (14Yamanaka Y. Friess H. Buchler M. Beger H.G. Gold L.I. Korc M. Diabetes. 1993; 42: 746-756Crossref PubMed Scopus (0) Google Scholar). Islet cells demonstrate diffuse cytoplasmic immunostaining for TGF-β isoforms with most of the positive islet cells co-expressing insulin. TGF-β receptors (TβRI and TβRII) are present in the pancreatic epithelium and mesenchyme during early stages of development and postnatally in pancreatic islets and ducts. Furthermore, Smad proteins are expressed in the pancreas, which elucidates that components needed for activation of the canonical TGF-β signaling exist within the pancreas. Disruption of TGF-β signaling at the receptor level using mice expressing the dominant-negative TGF-β type II receptor (DNTβRII) resulted in increased proliferation of pancreatic acinar cells and severely perturbed acinar differentiation (15Bottinger E.P. Jakubczak J.L. Roberts I.S. Mumy M. Hemmati P. Bagnall K. Merlino G. Wakefield L.M. EMBO J. 1997; 16: 2621-2633Crossref PubMed Scopus (217) Google Scholar). Additionally, DNTβRII mice exhibit increased endocrine precursors and proliferating endocrine cells, with an abnormal accumulation of endocrine cells around the developing ducts of mid-late stage embryonic pancreas (16Tulachan S.S. Tei E. Hembree M. Crisera C. Prasadan K. Koizumi M. Shah S. Guo P. Bottinger E. Gittes Dev. Biol. 2007; PubMed Scopus Google Scholar). mice expressing in exhibit abnormal small islet cell of normal adult islets although the islet cell mass is L. S. M. T. C. H. Sarvetnick N. J. Google Scholar). these studies the of TGF-β signaling in β-cell its role in β-cell growth and function. In this we the role of TGF-β signaling in β-cell function and its in insulin and glucose-stimulated insulin Cell pancreatic β-cell C. in with FBS, and and cells in with in with FBS, which of of is in which is to the TGF-β cells with and with with glucose which of Islet primate and human pancreatic islets and as M. J. 2005; 53: PubMed Scopus Google Scholar, Lee J. J.L. K. R. PubMed Scopus Google Scholar) with and islets using and with type in and The pancreatic for at by by at for and with The islets using a a for TGF-β of mice as and islets in a with of the with and islets in of islets with and for and gene by the human insulin promoter to by M. and G. into the and of the by of the of of the and is (15Bottinger E.P. Jakubczak J.L. Roberts I.S. Mumy M. Hemmati P. Bagnall K. Merlino G. Wakefield L.M. EMBO J. 1997; 16: 2621-2633Crossref PubMed Scopus (217) Google Scholar, S. S. P. S. EMBO J. 1998; 17: PubMed Scopus Google Scholar, C. J. Genes Dev. 1997; PubMed Scopus Google Scholar, J. Biol. 2002; Full Text Full Text PDF PubMed Scopus Google Scholar, S. P. J. Biol. 1998; Full Text Full Text PDF PubMed Scopus Google Scholar, J.L. L. R. J. Nature. PubMed Scopus Google Scholar, J. Biol. 2002; Full Text Full Text PDF PubMed Scopus Google Scholar, E. 2007; PubMed Scopus (79) Google Scholar). of the TGF-β receptor kinase and in with of of Smad expression using cells with with glucose and with for using the enhanced and to by the to at with of of condition as siRNA, of with is for cells, with with Smad3 expression used in that using a proteins and chromatin with for at and in binding via with and at for The with at and complex and by using the and the transcriptional of insulin II promoter to a in and the transcriptional of II insulin promoter to an in and Smad3 The of the the of Smad3 cells with Smad3 with of using in and and with Smad3 in of cells for in and with and for 2 the by insulin cells primary islets with at and the insulin level to Pancreatic insulin by the pancreas in and at islets with and in with as and into and by and used to the and as Transduction by at a of of islets with in with with and The expression of and by of non-human primate human of adenoviral of with is for and as R.J. L. R. H. Roberts C. EMBO J. PubMed Google Scholar). a with to and in a in which a to and by the and tolerance and mice of and at the for glucose glucose-stimulated insulin secretion, mice for and with glucose of at the in and insulin using an and and in at and with and for with and insulin used by the used as to develop a and of the of the β-cell using The of the β-cell mass by the β-cell in the pancreatic by the of these The in and Islet islets and mice a and in a perifusion The of bovine and with and for in glucose and for the at to a of a glucose glucose of the at the of the islets for insulin secretion by as with H. H. C. J. J. Biol. Full Text PDF PubMed Google Scholar) and results are as of for islets in and a of as S. Liu J.L. Y. J. Diabetes. 2001; PubMed Scopus Google Scholar). of a and to with the primary by with by and used as used and Cell Smad3 and cells with and for using the to the of to using the transcription gene expression by using with and in The results are as in gene expression to in this are as S.E. The the in glucose tolerance by of with the at TGF-β/Smad3 the of TGF-β insulin gene transcription we a human insulin islets to TGF-β as by a activation of the TGF-β and Smad-binding Interestingly, TGF-β in primary islets and exhibit a TGF-β due to expression expression TGF-β to cells as by enhanced In contrast, and Interestingly, resulted in a of of cells with small of the kinase insulin promoter repression by Interestingly, the of in the of by the small kinase that may a insulin promoter the role of TGF-β in repression of we a constitutively active kinase kinase that the for activation of by expression enhanced in contrast, the insulin promoter Together, these studies that TGF-β signaling represses insulin promoter Smad proteins are the of TGF-β signaling X.H. Derynck R. Annu. Rev. Cell Dev. Biol. 2005; 21: 659-693Crossref PubMed Scopus (1544) Google Scholar). TGF-β the activated receptors and and We the role of and Smad3 in repression of the insulin Interestingly, the insulin promoter Smad3 and constitutively active Smad3 a of Smad3 activated in cells constitutively active to the that is to activation S. S. P. S. EMBO J. 1998; 17: PubMed Scopus Google Scholar, S. P. J. Biol. 1998; Full Text Full Text PDF PubMed Scopus Google Scholar). and constitutively active Smad3 constitutively activated which be by activated to The and of Smad3 facilitate its and are critical for the binding and the of Smad3 to with transcription factors (4Attisano L. Wrana J.L. Science. 2002; 296: 1646-1647Crossref PubMed Scopus (1138) Google Scholar, 5Feng X.H. Derynck R. Annu. Rev. Cell Dev. Biol. 2005; 21: 659-693Crossref PubMed Scopus (1544) Google Scholar). we activation of by Smad3 with in the In contrast, by by Smad3 with within the and that these are for these results the of Smad3 in insulin gene TGF-β signaling is via of Smad transcription factors to of the TGF-β target in complex with (4Attisano L. Wrana J.L. Science. 2002; 296: 1646-1647Crossref PubMed Scopus (1138) Google Scholar, 5Feng X.H. Derynck R. Annu. Rev. Cell Dev. Biol. 2005; 21: 659-693Crossref PubMed Scopus (1544) Google Scholar, J. Rev. Cell Biol. 2000; PubMed Scopus Google Scholar). Smad transcription factors that the In addition, to the TGF-β target gene Smad K. H. J. Biol. Full Text Full Text PDF PubMed Scopus Google Scholar). Furthermore, the is as as K. H. J. Biol. Full Text Full Text PDF PubMed Scopus Google Scholar). Interestingly, of the of the insulin the transcription Smad and Smad in to that facilitate with of insulin transcription K. Diabetes. 2006; PubMed Scopus Google Scholar, K. H. M. Cell Dev. Biol. 2000; PubMed Scopus Google Scholar). at to to to and to the of the human insulin promoter to which the Smad3 binding resulted in a repression of by Smad3 and results of an important role for Smad3 in regulation of insulin gene we Smad3 transcription factors are present in the to the insulin promoter in Smad3 promoter we chromatin using and that of the insulin in we Smad3 to the insulin promoter in and In using an we binding of the transcription factor which is of promoter of a and a the insulin of Smad3 and which active TGF-β signaling Y. Cell. Biol. 2004; PubMed Scopus Google Scholar, J. Y. J. Biol. Full Text Full Text PDF PubMed Scopus Google Scholar, T. S. M. E. K. J. K. P. EMBO J. 1997; 16: PubMed Scopus Google Scholar), resulted in of whereas, Smad3 binding these results identify insulin as a target of gene repression of Smad3 in and results that TGF-β signaling enhance insulin levels. We this by small interfering Smad3 of and cells with resulted in a in Smad3 level In of cells with In contrast, repression of of cells resulted in a in and insulin and the that exist the and human insulin K. Diabetes. 2006; PubMed Scopus Google Scholar), we regulation of insulin and secretion by Smad3 is in of Smad3 into non-human primate islet and into islets human with islets with to in and and In contrast, of Smad3 resulted in these suggest that enhanced signaling suppresses the insulin level and its secretion, whereas, signaling that Smad3-deficient and that Smad3 is in the within the nucleus of of the pancreatic islets Smad3 β-cell function in we mice with an in the Smad3 mice are and to although exhibit a growth and mild deficiency R.J. L. R. H. Roberts C. EMBO J. PubMed Google Scholar, L. Y. Cell. Biol. PubMed Google Scholar). Pancreatic to the Furthermore, the pancreatic islet β-cell and insulin in mice to that in mice and and β-cell we insulin and glucose in and in mice and Interestingly, we that the mice increased insulin and and glucose and whereas, glucose of glucose of with that in Furthermore, pancreatic insulin increased in mice to mice Together, these results a role for Smad3 insulin and glucose in glucose tolerance and glucose-stimulated insulin secretion in with mice exhibit increased pancreatic insulin and with and and and mice exhibit enhanced glucose with 2 of and of glucose for enhanced insulin signaling in islets and of and of and by using of as a with mice exhibit increased insulin secretion at an glucose of in in mice is within glucose ex vivo islet perifusion islets type and mice to for in glucose and for the glucose by with a of to of the a glucose at and results a are as of We the of Smad3 in glucose by glucose glucose a in and a to normal in mice and mice a in with glucose at and and mice glucose mice as by the the Interestingly, an glucose of a increased glucose-stimulated insulin secretion in vivo in mice with mice in in the mice within of glucose Furthermore, ex vivo glucose-stimulated insulin enhanced in with glucose increased to The insulin signaling pathway is a regulator of normal β-cell function T. Kahn Annu. Rev. PubMed Scopus Google Scholar), and we the of this pathway in phosphorylation of insulin signaling pathway and in islets with that in islets that Smad3 deficiency glucose tolerance and enhances by the insulin signaling TGF-β/Smad3 of Genes in the role of TGF-β/Smad3 signaling in β-cell we the expression level of genes involved in insulin glucose glucose insulin and We the expression of these genes in islets and to that in The expression of and 2 and that of the and in islets with that in islets of the glucose and that of the in glucose in islets with that in islets we that genes involved in glucose insulin and as and are in islets with that in islets results that of TGF-β/Smad3 signaling enhances expression of genes involved in β-cell function. that TGF-β/Smad3 signals be to expression of these genes and we this We cells that the constitutively active expression to increased phosphorylation of Smad3 of TGF-β which of the of activated signaling β-cell function. We the of cell growth and by the gene expression of genes and In addition, we the expression of and genes that β-cell growth and proliferation S. J. Clin. Investig. 2004; PubMed Scopus (0) Google Scholar, S.G. P. G. E.P. M. Genet. PubMed Scopus Google Scholar, S.G. E.P. 2000; 5: PubMed Google Scholar). in we expression of GAPDH, and in cells, with cells, of of In contrast, expression of genes involved in insulin glucose glucose insulin and the role of TGF-β in expression of genes that β-cell we the of TGF-β in primary islets mice with TGF-β by TGF-β resulted in of the majority of genes that regulate β-cell function as and In contrast, expression of genes and and genes and TGF-β the used in this these results that TGF-β/Smad3 signaling regulates genes involved in β-cell whereas, of Smad3 signaling TGF-β/Smad3 signals these genes. The TGF-β superfamily, of TGF-β, activins, and regulates the of diverse cell types X.H. Derynck R. Annu. Rev. Cell Dev. Biol. 2005; 21: 659-693Crossref PubMed Scopus (1544) Google Scholar, 6Massague J. Blain S.W. Lo R.S. Cell. 2000; 103: 295-309Abstract Full Text Full Text PDF PubMed Scopus (2092) Google Scholar, J. Rev. Cell Biol. 2000; PubMed Scopus Google Scholar). is that TGF-β signaling plays a critical role in early pancreatic development and pancreatic diseases (7Kim S.K. Hebrok M. Genes Dev. 2001; 15: 111-127Crossref PubMed Scopus (346) Google Scholar, 8Kim S.K. MacDonald R.J. Curr. Opin. Genet. Dev. 2002; 12: 540-547Crossref PubMed Scopus (204) Google Scholar, 9Rane S.G. Lee J.H. Lin H.M. Cytokine Growth Factor Rev. 2006; 17: 107-119Crossref PubMed Scopus (79) Google Scholar), the role of this pathway in adult pancreatic function has been obscure. Here, we that TGF-β via the transcription factor regulates insulin gene transcription and adult β-cell function. TGF-β/Smad3 represses the insulin promoter and suppresses insulin level and In contrast, of signaling results in insulin and insulin insulin ex vivo in Smad3-deficient primary islets and in vivo in β-cell function in islets by activated insulin receptor signaling and increased gene expression of factors that β-cell function. In contrast, TGF-β signals expression of genes that insulin glucose glucose insulin and these identify TGF-β/Smad3 signaling as an important regulator of insulin gene transcription and β-cell function. regulation of insulin secretion, as in to at the level of H. S. S. Liu J. T. S.G. H. Diabetes. 2002; PubMed Google Scholar), whereas, the of insulin the regulation of insulin at the transcriptional and K. Diabetes. 2006; PubMed Scopus Google Scholar, K. H. M. Cell Dev. Biol. 2000; PubMed Scopus Google Scholar). In to the knowledge of transcriptional activation of the insulin is the transcriptional repression that regulate insulin gene we the human insulin we repression of the and insulin Lin and S. G. Furthermore, of the Smad binding within the of the human insulin promoter the are in and transcriptional is by to be within the the transcription which and transcription factors K. Diabetes. 2006; PubMed Scopus Google Scholar, K. H. M. Cell Dev. Biol. 2000; PubMed Scopus Google Scholar). The transcription factor is a primary regulator of insulin expression with and regulation H.M. J. E. K. J. 2005; PubMed Scopus Google Scholar). and regulate the insulin promoter H. K. PubMed Scopus Google Scholar, M. J. J. Biol. 1997; Full Text Full Text PDF PubMed Scopus Google Scholar) and an to to as the within the glucose to the human insulin promoter K. Diabetes. 2006; PubMed Scopus Google Scholar, K. H. M. Cell Dev. Biol. 2000; PubMed Scopus Google Scholar). Interestingly, the as a transcriptional in primary islet cells and as a transcriptional in and in K. Diabetes. 2006; PubMed Scopus Google Scholar). The as as the and binding are in to the that we identify is needed to the these in insulin gene transcription. of the human insulin promoter that the Smad binding to repression by Smad3 this an important role for Smad3 in insulin promoter is that binding of and the of the insulin that insulin are in with the insulin in cells with activated signaling the that TGF-β/Smad3 signals regulate insulin gene We the of insulin gene transcription its synthesis and TGF-β/Smad3 the of insulin transcription the of insulin Interestingly, we that has a of which is by a small is that TGF-β by the of TGF-β majority of which is in in the fetal bovine may the TGF-β signaling pathway is Furthermore, we that Smad3 the insulin promoter in a we that in to the TGF-β of insulin promoter repression that Smad3 occupies the insulin promoter insulin as a TGF-β target is that a Smad3 occupies the insulin promoter in cells with an is that in cells Smad3 to the insulin promoter by a TGF-β activation of Smads, phosphorylation of Smad3 by has been R. Nature. PubMed Scopus Google Scholar). although of TGF-β signaling in β-cell may be to Smad3 and to the insulin in in Smad3 is within the the and in the with its to the and cytoplasmic Cell. 2002; Full Text Full Text PDF PubMed Scopus Google Scholar). is that this of Smad3 in Interestingly, of Smad3 and which an activated TGF-β signaling the insulin whereas Smad3 binding is The that results in of binding Smad3 is and are needed to this We that an and may the insulin promoter in cells that a the of gene In contrast, active TGF-β in the of a Smad3 may the insulin an and of gene transcription target gene been K. Y. Eto K. M.A. PubMed Scopus Google Scholar, R.S. Biol. 2006; 5: PubMed Scopus Google Scholar). We that of Smad3 signaling leads to ex vivo and in vivo is that the of TGF-β/Smad3 insulin gene transcription may be of its role in of expression of genes involved in insulin glucose glucose insulin and are in islets in cells a constitutively active pathway Interestingly, we an activated insulin receptor signaling pathway in islets which is with the enhanced β-cell function in the Smad3 signaling results in enhanced phosphorylation of insulin signaling pathway and increased expression of genes that regulate β-cell function in the are is that the mild hyperinsulinemia in the mice may activation of the insulin signaling is that TGF-β/Smad3 signaling with the insulin signaling pathway in the studies using Smad3 mice are these TGF-β to a the of and of glucose N. N. J. E. Clin. Full Text PDF PubMed Scopus (12) Google Scholar, C. J. PubMed Google Scholar). at glucose TGF-β insulin whereas at a glucose the of TGF-β N. N. J. E. Clin. Full Text PDF PubMed Scopus (12) Google Scholar, C. J. PubMed Google Scholar). studies are needed to the of the dual and β-cell function and to this is by Interestingly, dual and of TGF-β in are to primary and Wakefield L.M. U. S. PubMed Scopus Google Scholar). of the role of and in β-cell function the important role of TGF-β superfamily signaling in this cell type J. Dahl U. Baeza N. Mishina Y. Edlund H. Cell Metab. 2007; 5: 207-219Abstract Full Text Full Text PDF PubMed Scopus (109) Google Scholar, MacDonald R.J. S.K. Biol. 2006; PubMed Scopus (109) Google Scholar, P. R. E. U. S. PubMed Scopus Google Scholar). signaling plays a role in insulin secretion by genes involved in glucose secretion, and insulin J. Dahl U. Baeza N. Mishina Y. Edlund H. Cell Metab. 2007; 5: 207-219Abstract Full Text Full Text PDF PubMed Scopus (109) Google Scholar). of regulation of genes with β-cell function are with an important role of the TGF-β superfamily signaling in pancreas β-cell function. The that TGF-β/Smad3 signals insulin transcription and insulin level and insulin secretion, whereas of Smad3 leads to improved β-cell function suggest that abnormal TGF-β signaling may of We that TGF-β/Smad3 may regulate β-cell function in of increased insulin including insulin resistance, obesity, and during β-cell Furthermore, results that TGF-β/Smad3 signaling enhance insulin and insulin secretion suggest that of TGF-β/Smad3 signaling be for β-cell differentiation and β-cell during diabetes. We C. and and and members of the for and and for and critical of the with

Avoidable hospital readmissions not only contribute to the high costs of healthcare in the US, but also have an impact on the quality of care for patients. Large scale adoption of Electronic Health Records (EHR) has created the opportunity to proactively identify patients with high risk of hospital readmission, and apply effective interventions to mitigate that risk. To that end, in the past, numerous machine-learning models have been employed to predict the risk of 30-day hospital readmission. However, the need for an accurate and real-time predictive model, suitable for hospital setting applications still exists. Here, using data from more than 300,000 hospital stays in California from Sutter Health's EHR system, we built and tested an artificial neural network (NN) model based on Google's TensorFlow library. Through comparison with other traditional and non-traditional models, we demonstrated that neural networks are great candidates to capture the complexity and interdependency of various data fields in EHRs. LACE, the current industry standard, showed a precision (PPV) of 0.20 in identifying high-risk patients in our database. In contrast, our NN model yielded a PPV of 0.24, which is a 20% improvement over LACE. Additionally, we discussed the predictive power of Social Determinants of Health (SDoH) data, and presented a simple cost analysis to assist hospitalists in implementing helpful and cost-effective post-discharge interventions.