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Beta cells AND Pax4

Stephanie Robyn Johnson, Paul Leo, Louise Sonia Conwell, Mark Harris, Matthew Arthur Brown, Emma Letitia Duncan
Maturity-onset diabetes of the young (MODY) is the commonest form of monogenic diabetes, resulting from dominant mutations in one of fourteen genes that regulate beta-cell function (HNF4A, GCK, HNF1A, PDX1, HNF1B, NEUROD1, KLF11, CEL, PAX4, INS, BLK, ABCC8,KCNJ11 and APPL1 1,2 ). MODY accounts for 2-2.5% of childhood diabetes 3 , yet MODY genetic screening is uncommon, even in highly suggestive families, and when performed often limited to the commonest genes (e.g.HNF1A and GCK) 4 .
May 4, 2018: Journal of Diabetes
Jose M Mellado-Gil, Esther Fuente-Martín, Petra I Lorenzo, Nadia Cobo-Vuilleumier, Livia López-Noriega, Alejandro Martín-Montalvo, Irene de Gracia Herrera Gómez, Maria Ceballos-Chávez, Laura Gómez-Jaramillo, Antonio Campos-Caro, Silvana Y Romero-Zerbo, Júlia Rodríguez-Comas, Joan-Marc Servitja, Gemma Rojo-Martinez, Abdelkrim Hmadcha, Bernat Soria, Marco Bugliani, Piero Marchetti, Francisco J Bérmudez-Silva, Jose C Reyes, Manuel Aguilar-Diosdado, Benoit R Gauthier
HMG20A (also known as iBRAF) is a chromatin factor involved in neuronal differentiation and maturation. Recently small nucleotide polymorphisms (SNPs) in the HMG20A gene have been linked to type 2 diabetes mellitus (T2DM) yet neither expression nor function of this T2DM candidate gene in islets is known. Herein we demonstrate that HMG20A is expressed in both human and mouse islets and that levels are decreased in islets of T2DM donors as compared to islets from non-diabetic donors. In vitro studies in mouse and human islets demonstrated that glucose transiently increased HMG20A transcript levels, a result also observed in islets of gestating mice...
February 15, 2018: Cell Death & Disease
Tianyi Xu, Yiru Shi, Jiangbo Liu, Yun Liu, Ailin Zhu, Cui Xie, Yan Zhang, Yan Chen, Lirong Ren
Objective The rs10229583 polymorphism near paired box gene 4 ( PAX4) is associated with insulin resistance and type 2 diabetes. Mutations in the PAX4 gene may be associated with impaired differentiation/development of pancreatic islet beta cells during fetal development and, consequently, a compromised insulin response to high blood glucose. To ascertain whether this polymorphism plays a role in gestational diabetes mellitus (GDM), we investigated the genotypic and allele frequency differences between GDM and normal pregnancies...
January 2018: Journal of International Medical Research
Anshu Sharma, Rajni Rani
BACKGROUND: Type 1 diabetes (T1D) is a multifactorial autoimmune disorder where pancreatic beta cells are lost before the clinical manifestations of the disease. Administration of mesenchymal stem cells (MSCs) or MSCs differentiated into insulin-producing cells (IPCs) have yielded limited success when used therapeutically. We have evaluated the immunoprophylactic potentials of precursors to insulin-producing cells (pIPCs) and IPCs in nonobese diabetic (NOD) mice to ask a basic question: do we need to differentiate MSCs into IPCs or will pIPCs suffice to attenuate autoimmune responses in T1D? METHODS: Bone marrow-derived MSCs from Balb/c mice were characterized following the International Society for Cellular Therapy (ISCT) guidelines...
July 12, 2017: Stem Cell Research & Therapy
Ediz Coskun, Merve Ercin, Selda Gezginci-Oktayoglu
In this study, we aimed to research the effects of class-I HDACs and glucose on differentiation of pancreatic islet derived mesenchymal stem cells (PI-MSCs) to beta cells. Beta cell differentiation determined by flow cytometric analysis and gene expression levels of PDX1, PAX4, PAX6, NKX6.1, NGN3, INS2, and GLUT2. As a result the valproic acid, is an inhibitor of class-I HDACs, caused the highest beta cell differentiation in PI-MSCs. However, the cells in this group were at early stages of differentiation. Glucose co-administration to this group carried the differentiation to higher levels, but these newly formed beta cells were not functional...
January 2018: Journal of Cellular Biochemistry
Maria J Lima, Kenneth R Muir, Hilary M Docherty, Neil W A McGowan, Shareen Forbes, Yves Heremans, Harry Heimberg, John Casey, Kevin Docherty
Transcription factor mediated lineage reprogramming of human pancreatic exocrine tissue could conceivably provide an unlimited supply of islets for transplantation in the treatment of diabetes. Exocrine tissue can be efficiently reprogrammed to islet-like cells using a cocktail of transcription factors: Pdx1, Ngn3, MafA and Pax4 in combination with growth factors. We show here that overexpression of exogenous Pax4 in combination with suppression of the endogenous transcription factor ARX considerably enhances the production of functional insulin-secreting β-like cells with concomitant suppression of α-cells...
2016: PloS One
José Manuel Mellado-Gil, Carmen María Jiménez-Moreno, Alejandro Martin-Montalvo, Ana Isabel Alvarez-Mercado, Esther Fuente-Martin, Nadia Cobo-Vuilleumier, Petra Isabel Lorenzo, Eva Bru-Tari, Irene de Gracia Herrera-Gómez, Livia López-Noriega, Javier Pérez-Florido, Javier Santoyo-López, Andreas Spyrantis, Paolo Meda, Bernhard O Boehm, Ivan Quesada, Benoit R Gauthier
AIMS/HYPOTHESIS: A strategy to enhance pancreatic islet functional beta cell mass (BCM) while restraining inflammation, through the manipulation of molecular and cellular targets, would provide a means to counteract the deteriorating glycaemic control associated with diabetes mellitus. The aims of the current study were to investigate the therapeutic potential of such a target, the islet-enriched and diabetes-linked transcription factor paired box 4 (PAX4), to restrain experimental autoimmune diabetes (EAD) in the RIP-B7...
April 2016: Diabetologia
Marina Lizio, Yuri Ishizu, Masayoshi Itoh, Timo Lassmann, Akira Hasegawa, Atsutaka Kubosaki, Jessica Severin, Hideya Kawaji, Yukio Nakamura, Harukazu Suzuki, Yoshihide Hayashizaki, Piero Carninci, Alistair R R Forrest
Mammals are composed of hundreds of different cell types with specialized functions. Each of these cellular phenotypes are controlled by different combinations of transcription factors. Using a human non islet cell insulinoma cell line (TC-YIK) which expresses insulin and the majority of known pancreatic beta cell specific genes as an example, we describe a general approach to identify key cell-type-specific transcription factors (TFs) and their direct and indirect targets. By ranking all human TFs by their level of enriched expression in TC-YIK relative to a broad collection of samples (FANTOM5), we confirmed known key regulators of pancreatic function and development...
2015: Frontiers in Genetics
Sergiu Şuşman, Dan Rus-Ciucă, Olga Soriţău, Răzvan Ciortea, Mihai Gîrlovanu, Dan Mihu, Carmen Mihaela Mihu
OBJECTIVES: The apparition of sugar diabetes is produced by the decrease of the number and capacity of beta cells to secrete insulin. Cell mass recovery through cell therapy might be one of the solutions for treating this disease. The use of various cell sources of different differentiation grades has been tried over the last years. Decoding the molecular mechanisms of the pancreatic morphogenesis is essential for obtaining cells having a phenotype, which would be very similar to the mature cells located in the pancreatic endocrine component...
2015: Romanian Journal of Morphology and Embryology, Revue Roumaine de Morphologie et Embryologie
Ling Chen, Jing Zhang, Zhuo Zhang, Yaping Chu, Bing Song, Wang Cai
BACKGROUND/AIMS: The lack of available beta cells greatly limits the use of beta cell transplantation as a therapy for diabetes. Thus, generation of beta cells from other sources is substantially required. Pax4 has been shown to induce reprograming of alpha cells into beta cells during embryogenesis. Nevertheless, whether expression of Pax4 in adult alpha cells could trigger this alpha-to-beta cell reprogramming is unknown. METHODS: Here we generated an adeno-associated virus carrying Pax4 and GFP under a CMV promoter (AAV-Pax4)...
2015: Cellular Physiology and Biochemistry
Prabhu Mathiyalagan, Samuel T Keating, Keith Al-Hasani, Assam El-Osta
SIGNIFICANCE: Type 1 diabetes (T1D) results from cell-mediated autoimmune destruction of insulin-secreting pancreatic beta cells (β-cells). In the context of T1D, the scarcity of organ donors has driven research to alternate sources of functionally competent, insulin-secreting β-cells as substitute for donor islets to meet the clinical need for transplantation therapy. RECENT ADVANCES: Experimental evidence of an inherent plasticity of pancreatic cells has fuelled interest in in vivo regeneration of β-cells...
June 1, 2015: Antioxidants & Redox Signaling
Caroline B Sangan, Ramiro Jover, Harry Heimberg, David Tosh
There is currently a shortage of organ donors available for pancreatic beta cell transplantation into diabetic patients. An alternative source of beta cells is pre-existing pancreatic cells. While we know that beta cells can arise directly from alpha cells during pancreatic regeneration we do not understand the molecular basis for the switch in phenotype. The aim of the present study was to investigate if hepatocyte nuclear factor 4 alpha (HNF4α), a transcription factor essential for a normal beta cell phenotype, could induce the reprogramming of alpha cells towards potential beta cells...
January 5, 2015: Molecular and Cellular Endocrinology
Jennifer R Kulzer, Michael L Stitzel, Mario A Morken, Jeroen R Huyghe, Christian Fuchsberger, Johanna Kuusisto, Markku Laakso, Michael Boehnke, Francis S Collins, Karen L Mohlke
Genome-wide association studies (GWASs) have identified more than 70 loci associated with type 2 diabetes (T2D), but for most, the underlying causal variants, associated genes, and functional mechanisms remain unknown. At a T2D- and fasting-proinsulin-associated locus on 11q13.4, we have identified a functional regulatory DNA variant, a candidate target gene, and a plausible underlying molecular mechanism. Fine mapping, conditional analyses, and exome array genotyping in 8,635 individuals from the Metabolic Syndrome in Men study confirmed a single major association signal between fasting proinsulin and noncoding variants (p = 7...
February 6, 2014: American Journal of Human Genetics
Anahita Shaer, Negar Azarpira, Akbar Vahdati, Mohammad Hosein Karimi, Mehrdad Shariati
OBJECTIVES: In diabetes mellitus type 1, beta cells are mostly destroyed; while in diabetes mellitus type 2, beta cells are reduced by 40% to 60%. We hope that soon, stem cells can be used in diabetes therapy via pancreatic beta cell replacement. Induced pluripotent stem cells are a kind of stem cell taken from an adult somatic cell by "stimulating" certain genes. These induced pluripotent stem cells may be a promising source of cell therapy. This study sought to produce isletlike clusters of insulin-producing cells taken from induced pluripotent stem cells...
February 2015: Experimental and Clinical Transplantation
Blair K Gage, Travis D Webber, Timothy J Kieffer
Human embryonic stem cells (hESCs) have the ability to form cells derived from all three germ layers, and as such have received significant attention as a possible source for insulin-secreting pancreatic beta-cells for diabetes treatment. While considerable advances have been made in generating hESC-derived insulin-producing cells, to date in vitro-derived glucose-responsive beta-cells have remained an elusive goal. With the objective of increasing the in vitro formation of pancreatic endocrine cells, we examined the effect of varying initial cell seeding density from 1...
2013: PloS One
Rémy Bonnavion, Rami Jaafar, Julie Kerr-Conte, Fouzia Assade, Esther van Stralen, Emmanuelle Leteurtre, Célio Pouponnot, Sofia Gargani, François Pattou, Philippe Bertolino, Martine Cordier-Bussat, Jieli Lu, Chang Xian Zhang
Pax4 and MafA (v-maf musculoaponeurotic fibrosarcoma oncogene homolog A) are two transcription factors crucial for normal functions of islet beta cells in the mouse. Intriguingly, recent studies indicate the existence of notable difference between human and rodent islet in terms of gene expression and functions. To better understand the biological role of human PAX4 and MAFA, we investigated their expression in normal and diseased human islets, using validated antibodies. PAX4 was detected in 43.0±5.0% and 39...
2013: PloS One
Sudhanshu P Raikwar, Nicholas Zavazava
Pluripotent embryonic stem (ES) cells and induced pluripotent stem (iPS) cells recently developed in our laboratory can be used to generate the much needed insulin producing cells (IPCs) for the treatment of type 1 diabetes. However, currently available differentiation protocols generate IPCs at a very low frequency. More importantly, it is difficult to purify the IPCs from the mixed cell population due to the lack of well characterized pancreatic beta cell-specific cell surface markers. Subsequently, multiple studies have been published with limited success...
2013: Methods in Molecular Biology
R C W Ma, C Hu, C H Tam, R Zhang, P Kwan, T F Leung, G N Thomas, M J Go, K Hara, X Sim, J S K Ho, C Wang, H Li, L Lu, Y Wang, J W Li, Y Wang, V K L Lam, J Wang, W Yu, Y J Kim, D P Ng, H Fujita, K Panoutsopoulou, A G Day-Williams, H M Lee, A C W Ng, Y-J Fang, A P S Kong, F Jiang, X Ma, X Hou, S Tang, J Lu, T Yamauchi, S K W Tsui, J Woo, P C Leung, X Zhang, N L S Tang, H Y Sy, J Liu, T Y Wong, J Y Lee, S Maeda, G Xu, S S Cherny, T F Chan, M C Y Ng, K Xiang, A P Morris, S Keildson, R Hu, L Ji, X Lin, Y S Cho, T Kadowaki, E S Tai, E Zeggini, M I McCarthy, K L Hon, L Baum, B Tomlinson, W Y So, Y Bao, J C N Chan, W Jia
AIMS/HYPOTHESIS: Most genetic variants identified for type 2 diabetes have been discovered in European populations. We performed genome-wide association studies (GWAS) in a Chinese population with the aim of identifying novel variants for type 2 diabetes in Asians. METHODS: We performed a meta-analysis of three GWAS comprising 684 patients with type 2 diabetes and 955 controls of Southern Han Chinese descent. We followed up the top signals in two independent Southern Han Chinese cohorts (totalling 10,383 cases and 6,974 controls), and performed in silico replication in multiple populations...
June 2013: Diabetologia
Qing Le Liang, Zhengying Mo, Xue Feng Li, Xiao Xun Wang, Rui Ming Li
Success in generating insulin-producing cells (IPCs) from human embryonic stem (hES) cells by genetic manipulation has recently revealed a new therapeutic potential for diabetes. However, clinical application has been hampered by the viral genome integration and the risk of insertion mutagenesis that are entailed. Herein, we report the induction of hEC into IPCs by direct delivery of human Pdx1 proteins per se. Recombinant human Pdx1 proteins (hPdx1), which have an Antennapedia-like protein transduction domain sequence in their structure, can be efficiently translocated into hES cells and function as pancreatic transcription factor...
January 2013: Cell Biology International
P Rahnamay Moshtagh, S Hojati Emami, Ali M Sharifi
Stem cells with the ability to differentiate into insulin-producing cells (IPCs) are becoming the most promising therapy for diabetes mellitus and reduce the major limitations of availability and allogeneic rejection of beta cell transplantations. Mesenchymal stem cells (MSCs) are pluripotent stromal cells with the ability to proliferate and differentiate into a variety of cell types including endocrine cells of the pancreas. This study sought to inspect the in vitro differentiation of human adipose-derived tissue stem cells into IPCs which could provide an abundant source of cells for the purpose of diabetic cell therapy in addition to avoid immunological rejection...
September 2013: Journal of Physiology and Biochemistry
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