Suppression of Pdx-1 perturbs proinsulin processing, insulin secretion and GLP-1 signalling in INS-1 cells

Wang, Haiyan; Iezzi, Mariella; Theander, Sten; Antinozzi, Peter A.; Gauthier, Benoit R.; Halban, Philippe A.; Wollheim, Claes B.

doi:10.1007/s00125-005-1692-8

Cited by 66 publications

(57 citation statements)

References 79 publications

(114 reference statements)

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“…Since PDX-1 is essential for the regulation of a wide variety of important genes in b-cells (Waeber et al 1996, Watada et al 1996, Macfarlane et al 2000, a reduction in expression would be expected to exert deleterious effects on insulin secretory responses. Expression of dominant-negative PDX-1 in INS-1 cells has been shown to inhibit nutrient-and KCl-induced insulin secretion (Wang et al 2005). Monitoring of PDX-1 expression at the protein level in response to HNF1b confirmed that it declined markedly within 24 h, suggesting that turnover of PDX-1 protein occurs rapidly in cells overexpressing WT HNF1b.…”

Section: Discussionmentioning

confidence: 94%

Conditional expression of hepatocyte nuclear factor-1β, the maturity-onset diabetes of the young-5 gene product, influences the viability and functional competence of pancreatic β-cells

Welters

Senkel

Klein-Hitpaß

et al. 2006

Journal of Endocrinology

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Mutations in the gene encoding hepatocyte nuclear factor (HNF)1b result in maturity-onset diabetes of the young-(MODY)5, by impairing insulin secretory responses and, possibly, by reducing b-cell mass. The functional role of HNF1b in normal b-cells is poorly understood; therefore, in the present study, wild-type (WT) HNF1b, or one of two naturally occurring MODY5 mutations (an activating mutation, P328L329del, or a dominant-negative form, A263insGG) were conditionally expressed in the pancreatic b-cell line, insulin-1 (INS-1), and the functional consequences examined. Surprisingly, overexpression of the dominant-negative mutant did not modify any of the functional properties of the cells studied (including insulin secretion, cell growth and viability). By contrast, expression of WT HNF1b was associated with a time-and dose-dependent inhibition of INS-1 cell proliferation and a marked increase in apoptosis. Induction of WT HNF1b also inhibited the insulin secretory response to nutrient stimuli, membrane depolarisation or activation of protein kinases A and C and this correlated with a significant decrease in pancrease-duodenum homeobox-1 protein levels. The attenuation of insulin secretion was, however, dissociated from the inhibition of proliferation and loss of viability, since expression of the P328L329del mutant led to a reduced rate of cell proliferation, but failed to induce apoptosis or to alter insulin secretion. Taken together, the present results suggest that mature rodent b-cells are sensitive to increased expression of WT HNF1b and they imply that the levels of this protein are tightly regulated to maintain secretory competence and cell viability.

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Section: Discussionmentioning

confidence: 94%

Conditional expression of hepatocyte nuclear factor-1β, the maturity-onset diabetes of the young-5 gene product, influences the viability and functional competence of pancreatic β-cells

Welters

Senkel

Klein-Hitpaß

et al. 2006

Journal of Endocrinology

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“…Homeodomain transcription factor PDX-1 is required for cAMP generation and exendin-4 stimulation of cyclin A2. PDX-1 is required for exendin-4 effects on ␤-cell proliferation and function (6,8,21). Therefore, we examined the role of PDX-1 in exendin-4 -stimulated cyclin A2 expression.…”

Section: Exendin-4 Stimulation Of Cyclin A2mentioning

confidence: 99%

“…␤-Cell-specific ablation of PDX-1 markedly reduces GLP-1-induced ␤-cell proliferation (8), whereas other salient ␤-cell properties, such as glucokinase activity, mitochondrial metabolism, ATP generation (21), and levels of mRNA transcripts of important proteins such as IRS2, CREB, and transcription factors Nkx2.2 and Isl1, remain intact at normal levels (8,21). Consistent with these observations (5,21), the present findings confirm that PDX-1 expression is required for cAMP generation in pancreatic ␤-cells.…”

Section: Exendin-4 Stimulation Of Cyclin A2mentioning

confidence: 99%

Exendin-4 Stimulation of Cyclin A2 in β-Cell Proliferation

et al. 2008

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OBJECTIVE-␤-Cell proliferation is an important mechanism underlying ␤-cell mass adaptation to metabolic demands. We have examined effects, in particular those mediated through intracellular cAMP signaling, of the incretin hormone analog exendin-4 on cell cycle regulation in ␤-cells.RESEARCH DESIGN AND METHODS-Changes in islet protein levels of cyclins and of two critical cell cycle regulators cyclin kinase inhibitor p27 and S-phase kinase-associated protein 2 (Skp2) were assessed in mice treated with exendin-4 and in a mouse model with specific upregulation of nuclear cAMP signaling exhibiting increased ␤-cell proliferation (CBP-S436A mouse). Because cyclin A2 was stimulated by cAMP, we assessed the role of cylcin A2 in cell cycle progression in Min6 and isolated islet ␤-cells.RESULTS-Mice treated with exendin-4 showed increased ␤-cell proliferation, elevated islet protein levels of cyclin A2 with unchanged D-type cyclins, elevated PDX-1 and Skp2 levels, and reduced p27 levels. Exendin-4 stimulated cyclin A2 promoter activity via the cAMP-cAMP response element binding protein pathway. CBP-S436A islets exhibited elevated cyclin A2, reduced p27, and no changes in D-type cyclins, PDX-1, or Skp2. In cultured islets, exendin-4 increased cyclin A2 and Skp2 and reduced p27. Cyclin A2 overexpression in primary islets increased proliferation and reduced p27. In Min6 cells, cyclin A2 knockdown prevented exendin-4 -stimulated proliferation. PDX-1 knockdown reduced exendin-4 -stimulated cAMP synthesis and cyclin A2 transcription.CONCLUSIONS-Cyclin A2 is required for ␤-cell proliferation, exendin-4 stimulates cyclin A2 expression via the cAMP pathway, and exendin-4 stimulation of cAMP requires PDX-1. Diabetes 57:2371-2381, 2008 P ancreatic ␤-cell mass is dynamic and responds to variations in metabolic demand on insulin production. The inability of the endocrine pancreas to adapt to changing insulin demand (inadequate ␤-cell mass) is found both in type 1 and type 2 diabetes. Increasing ␤-cell mass by regeneration may ameliorate or correct both type 1 and 2 diabetes (1). Within the pancreas, ␤-cells regenerate predominantly by ␤-cell replication (2,3). In this context, insight into the mechanisms underlying ␤-cell proliferation and cell cycle regulation, may provide potential targets for therapy in situations of inadequate ␤-cell mass.The incretin hormone glucagon-like peptide-1 (GLP-1) and its long-acting peptide analog exendin-4 stimulate ␤-cell proliferation in vitro and in vivo (4), leading to increased ␤-cell mass in rodents and amelioration of glucose metabolism in diabetic animal models and human diabetic subjects (4). Downstream effectors of the GLP-1 signaling to the cell nucleus include 1) the epidermal growth factor receptor-phosphoinositol 3-kinase (PI 3-kinase)-protein kinase B (PKB/Akt)-forkhead box transcription factor O1 (FoxO1) pathway (5) and 2) the cAMP-protein kinase A (PKA)-cAMP response element binding protein (CREB) pathway (4). Activation of the PI 3-kinase pathway results in phosphorylation and nuclear...

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“…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%

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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Suppression of Pdx-1 perturbs proinsulin processing, insulin secretion and GLP-1 signalling in INS-1 cells

Cited by 66 publications

References 79 publications

Conditional expression of hepatocyte nuclear factor-1β, the maturity-onset diabetes of the young-5 gene product, influences the viability and functional competence of pancreatic β-cells

Conditional expression of hepatocyte nuclear factor-1β, the maturity-onset diabetes of the young-5 gene product, influences the viability and functional competence of pancreatic β-cells

Exendin-4 Stimulation of Cyclin A2 in β-Cell Proliferation

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

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