Reduction in Pancreatic Transcription Factor PDX-1 Impairs Glucose-stimulated Insulin Secretion

Briššová, Marcela; Shiota, Masakazu; Nicholson, Wendell E.; Gannon, Maureen; Knobel, Susan M.; Piston, David W.; Wright, Christopher V.E.; Powers, Alvin C.

doi:10.1074/jbc.m111272200

Cited by 359 publications

(348 citation statements)

References 63 publications

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“…Consistent with our findings, Glut2 was elevated in Smad3 knockout islets [38]. A strong reduction in Glut2 expression is an early indicator of beta cell stress and possibly dedifferentiation in many mouse models of glucose intolerance or diabetes [45], including mice with reduced Pdx1 [46]. It will be interesting in the future to examine the characteristics and plasticity of the population of adult pancreatic cells with low Glut2 expression.…”

Section: Discussionsupporting

confidence: 88%

Reciprocal modulation of adult beta cell maturity by activin A and follistatin

2010

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Aims/hypothesis The functional maturity of pancreatic beta cells is impaired in diabetes mellitus. We sought to define factors that can influence adult beta cell maturation status and function. Methods MIN6 cells labelled with a Pdx1 monomeric red fluorescent protein-Ins1 enhanced green fluorescent protein dual reporter lentivirus were used to screen candidate growth and/or differentiation factors using image-based approaches with confirmation by real-time RT-PCR and assays of beta cell function using primary mouse islets.Results Activin A strikingly decreased the number of mature beta cells and increased the number of immature beta cells. While activins are critical for pancreatic morphogenesis, their role in adult beta cells remains controversial. In primary islets and MIN6 cells, activin A significantly decreased the expression of insulin and several genes associated with beta cell maturity (e.g. Pdx1, Mafa, Glut2 [also known as Slc2a2]). Genes found in immature beta cells (e.g. Mafb) tended to be upregulated by activin A. Insulin secretion was also reduced by activin A. In addition, activin A-treated MIN6 cells proliferated faster than non-treated cells. The effects of endogenous activin A on beta cells were completely reversed by exogenous follistatin. Conclusions/interpretation These results suggest that autocrine and/or paracrine activin A signalling exerts a suppressive effect on adult beta cell maturation and function. Thus, the maturation state of adult beta cells can be modulated by external factors in culture. Interventions inhibiting activin or its signalling pathways may improve beta cell function. Understanding of maturation and plasticity of adult pancreatic tissue has significant implications for islet regeneration and for in vitro generation of functional beta cells.

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Section: Discussionsupporting

confidence: 88%

Reciprocal modulation of adult beta cell maturity by activin A and follistatin

2010

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“…To help understand the molecular mechanisms underlying these histological and functional differences, we quantified the levels of the insulin (Ins2) and Pdx1 mRNAs. Pancreatic duodenal homeobox 1 (PDX1) is involved in pancreatic development and differentiation, and transcriptionally activates many beta cell genes encoding proteins involved in glucose-stimulated insulin secretion, including glucokinase, glucose transporter 2, as well as insulin itself [21]. As shown in Fig.…”

Section: Resultsmentioning

confidence: 99%

Identification of ALOX5 as a gene regulating adiposity and pancreatic function

et al. 2008

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Aims/hypothesis We previously used an integrative genetics approach to demonstrate that 5-lipoxygenase (5-LO) deficiency in mice (Alox5 −/− ) protects against atherosclerosis despite increasing lipid levels and fat mass. In the present study, we sought to further examine the role of 5-LO in adiposity and pancreatic function. Methods Alox5 −/− and wild-type (WT) mice were characterised with respect to adiposity and glucose/insulin metabolism using in vivo and in vitro approaches. The role of ALOX5 in pancreatic function in human islets was assessed through short interfering RNA (siRNA) knockdown experiments. Results Beginning at 12 weeks of age, Alox5 −/− mice had significantly increased fat mass, plasma leptin levels and fasting glucose levels, but lower fasting insulin levels (p< 0.05). Although Alox5 −/− mice did not exhibit insulin resistance, they had impaired insulin secretion in response to a bolus glucose injection. Histological analyses revealed Diabetologia (2008) that Alox5 −/− mice had increased islet area, beta cell nuclear size, and numbers of beta cells/mm 2 islet (p < 0.05), indicative of both hyperplasia and hypertrophy. Basal and stimulated insulin secretion in isolated Alox5 −/− islets were significantly lower than in WT islets (p <0.05) and accompanied by a three-to fivefold decrease in the expression of the genes encoding insulin and pancreatic duodenal homeobox 1 (Pdx1). Direct perturbation of ALOX5 in isolated human islets with siRNA decreased insulin and PDX1 gene expression by 50% and insulin secretion by threefold (p<0.05). Conclusions/interpretation These results provide strong evidence for pleiotropic metabolic effects of 5-LO on adiposity and pancreatic function and may have important implications for therapeutic strategies targeting this pathway for the treatment of cardiovascular disease.

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“…2). Pdx1 haploinsufficiency does not appear to physically or functionally impinge upon pancreas development in Pdx1+/− mice [12,13], however, such mice exhibit strikingly impaired glucose tolerance and glucose-stimulated insulin secretion with age [56,57]. Similarly impaired β cell function in the setting of Pdx1 deficiency has been observed in several other animal models (rat, fish, and sand rat [58][59][60][61][62]), as well as in humans with single allelic mutations in Ipf1 (where the development of impaired glucose responsiveness and frank diabetes occurs) [17][18][19][20][21].…”

Section: Role Of Pdx1 In the Adult Pancreasmentioning

confidence: 99%

“…Although subtle developmental defects cannot be ruled out, these observations suggest a dramatically different requirement for Pdx1 gene dosage in the developing pancreas vs. the mature β cell, the latter of which may require more tightly regulated transcription and/or translation. In this regard, in some mouse models (and quite possibly in obese humans) the progressive loss of Pdx1 protein levels with age might account for the increasing incidence of β cell dysfunction and impaired glucose tolerance [22,57,65,66].…”

Section: Role Of Pdx1 In the Adult Pancreasmentioning

confidence: 99%

“…Based upon these studies, several mechanisms have been postulated: (a) increased β cell apoptosis via and Bcl-2), with resulting loss of downregulation of anti-apoptotic genes (Bcl XL functional cell mass [56,67], (b) loss of activity of key Pdx1 target genes whose products are involved in glucose-stimulated insulin transcription and secretion (including Glut2, glucokinase, MafA, Nkx6.1, insulin) [57,63,[68][69][70][71][72][73][74][75][76], and (d) loss of new β cell formation/regeneration [64,77]; in this regard, studies suggest that the action of glucagon-like peptide 1 (GLP1) in enhancing β cell growth and formation in the adult may rely upon activation of Pdx1 in β cells and potential precursor cell types, such as those residing within ducts [74,[78][79][80][81][82].…”

Section: Role Of Pdx1 In the Adult Pancreasmentioning

confidence: 99%

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A feat of metabolic proportions: Pdx1 orchestrates islet development and function in the maintenance of glucose homeostasis

Babu

Deering

Mirmira

2007

Molecular Genetics and Metabolism

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Emerging evidence over the past decade indicates a central role for transcription factors in the embryonic development of pancreatic islets and the consequent maintenance of normal glucose homeostasis. Pancreatic and duodenal homeobox 1 (Pdx1) is the best studied and perhaps most important of these factors. Whereas deletion or inactivating mutations of the Pdx1 gene causes whole pancreas agenesis in both mice and humans, even haploinsufficiency of the gene or alterations in its expression in mature islet cells causes substantial impairments in glucose tolerance and the development of a late-onset form of diabetes known as maturity onset diabetes of the young. The study of Pdx1 has revealed crucial phenotypic interrelationships of the varied cell types within the pancreas, particularly as these impinge upon cellular differentiation in the embryo and neogenesis and regeneration in the adult. In this review, we describe the actions of Pdx1 in the developing and mature pancreas and attempt to unify these actions with its known roles in modulating transcriptional complex formation and chromatin structure at the molecular genetic level.

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Reduction in Pancreatic Transcription Factor PDX-1 Impairs Glucose-stimulated Insulin Secretion

Cited by 359 publications

References 63 publications

Reciprocal modulation of adult beta cell maturity by activin A and follistatin

Reciprocal modulation of adult beta cell maturity by activin A and follistatin

Identification of ALOX5 as a gene regulating adiposity and pancreatic function

A feat of metabolic proportions: Pdx1 orchestrates islet development and function in the maintenance of glucose homeostasis

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