1
|
Bele S, Wokasch AS, Gannon M. Epigenetic modulation of cell fate during pancreas development. TRENDS IN DEVELOPMENTAL BIOLOGY 2023; 16:1-27. [PMID: 38873037 PMCID: PMC11173269] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Subscribe] [Scholar Register] [Indexed: 06/15/2024]
Abstract
Epigenetic modifications to DNA and its associated proteins affect cell plasticity and cell fate restrictions throughout embryonic development. Development of the vertebrate pancreas is characterized by initial is an over-lapping expression of a set of transcriptional regulators in a defined region of the posterior foregut endoderm that collectively promote pancreas progenitor specification and proliferation. As development progresses, these transcription factors segregate into distinct pancreatic lineages, with some being maintained in specific subsets of terminally differentiated pancreas cell types throughout adulthood. Here we describe the progressive stages and cell fate restrictions that occur during pancreas development and the relevant known epigenetic regulatory events that drive the dynamic expression patterns of transcription factors that regulate pancreas development. In addition, we highlight how changes in epigenetic marks can affect susceptibility to pancreas diseases (such as diabetes), adult pancreas cell plasticity, and the ability to derive replacement insulin-producing β cells for the treatment of diabetes.
Collapse
Affiliation(s)
- Shilpak Bele
- Department of Medicine, Vanderbilt University Medical Center, 2213 Garland Avenue, Nashville, TN, 37232, USA
| | - Anthony S. Wokasch
- Department of Cell and Developmental Biology, Vanderbilt University, 2213 Garland Avenue, Nashville, TN, 37232, USA
| | - Maureen Gannon
- Department of Medicine, Vanderbilt University Medical Center, 2213 Garland Avenue, Nashville, TN, 37232, USA
- Department of Cell and Developmental Biology, Vanderbilt University, 2213 Garland Avenue, Nashville, TN, 37232, USA
- Department of Veterans Affairs Tennessee Valley Authority, Research Division, 1310 24 Avenue South, Nashville, TN, 37212, USA
- Department of Molecular Physiology and Biophysics, 2213 Garland Avenue, Nashville, TN, 37232, USA
| |
Collapse
|
2
|
Ebrahim N, Shakirova K, Dashinimaev E. PDX1 is the cornerstone of pancreatic β-cell functions and identity. Front Mol Biosci 2022; 9:1091757. [PMID: 36589234 PMCID: PMC9798421 DOI: 10.3389/fmolb.2022.1091757] [Citation(s) in RCA: 28] [Impact Index Per Article: 9.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/07/2022] [Accepted: 12/01/2022] [Indexed: 12/23/2022] Open
Abstract
Diabetes has been a worldwide healthcare problem for many years. Current methods of treating diabetes are still largely directed at symptoms, aiming to control the manifestations of the pathology. This creates an overall need to find alternative measures that can impact on the causes of the disease, reverse diabetes, or make it more manageable. Understanding the role of key players in the pathogenesis of diabetes and the related β-cell functions is of great importance in combating diabetes. PDX1 is a master regulator in pancreas organogenesis, the maturation and identity preservation of β-cells, and of their role in normal insulin function. Mutations in the PDX1 gene are correlated with many pancreatic dysfunctions, including pancreatic agenesis (homozygous mutation) and MODY4 (heterozygous mutation), while in other types of diabetes, PDX1 expression is reduced. Therefore, alternative approaches to treat diabetes largely depend on knowledge of PDX1 regulation, its interaction with other transcription factors, and its role in obtaining β-cells through differentiation and transdifferentiation protocols. In this article, we review the basic functions of PDX1 and its regulation by genetic and epigenetic factors. Lastly, we summarize different variations of the differentiation protocols used to obtain β-cells from alternative cell sources, using PDX1 alone or in combination with various transcription factors and modified culture conditions. This review shows the unique position of PDX1 as a potential target in the genetic and cellular treatment of diabetes.
Collapse
Affiliation(s)
- Nour Ebrahim
- Center for Precision Genome Editing and Genetic Technologies for Biomedicine, Pirogov Russian National Research Medical University, Moscow, Russia,Moscow Institute of Physics and Technology (State University), Dolgoprudny, Russia
| | - Ksenia Shakirova
- Center for Precision Genome Editing and Genetic Technologies for Biomedicine, Pirogov Russian National Research Medical University, Moscow, Russia
| | - Erdem Dashinimaev
- Center for Precision Genome Editing and Genetic Technologies for Biomedicine, Pirogov Russian National Research Medical University, Moscow, Russia,Moscow Institute of Physics and Technology (State University), Dolgoprudny, Russia,*Correspondence: Erdem Dashinimaev,
| |
Collapse
|
3
|
Heller S, Li Z, Lin Q, Geusz R, Breunig M, Hohwieler M, Zhang X, Nair GG, Seufferlein T, Hebrok M, Sander M, Julier C, Kleger A, Costa IG. Transcriptional changes and the role of ONECUT1 in hPSC pancreatic differentiation. Commun Biol 2021; 4:1298. [PMID: 34789845 PMCID: PMC8599846 DOI: 10.1038/s42003-021-02818-3] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/21/2021] [Accepted: 10/24/2021] [Indexed: 02/07/2023] Open
Abstract
Cell type specification during pancreatic development is tightly controlled by a transcriptional and epigenetic network. The precise role of most transcription factors, however, has been only described in mice. To convey such concepts to human pancreatic development, alternative model systems such as pancreatic in vitro differentiation of human pluripotent stem cells can be employed. Here, we analyzed stage-specific RNA-, ChIP-, and ATAC-sequencing data to dissect transcriptional and regulatory mechanisms during pancreatic development. Transcriptome and open chromatin maps of pancreatic differentiation from human pluripotent stem cells provide a stage-specific pattern of known pancreatic transcription factors and indicate ONECUT1 as a crucial fate regulator in pancreas progenitors. Moreover, our data suggest that ONECUT1 is also involved in preparing pancreatic progenitors for later endocrine specification. The dissection of the transcriptional and regulatory circuitry revealed an important role for ONECUT1 within such network and will serve as resource to study human development and disease.
Collapse
Affiliation(s)
- Sandra Heller
- grid.410712.1Department of Internal Medicine I, Ulm University Hospital, Ulm, Germany
| | - Zhijian Li
- grid.1957.a0000 0001 0728 696XInstitute for Computational Genomics, RWTH Aachen University Medical School, Aachen, Germany
| | - Qiong Lin
- grid.420044.60000 0004 0374 4101Bayer AG, Research & Development, Pharmaceuticals, Bioinformatics, Berlin, Germany
| | - Ryan Geusz
- grid.266100.30000 0001 2107 4242Pediatric Diabetes Research Center (PDRC) at the University of California, San Diego, USA
| | - Markus Breunig
- grid.410712.1Department of Internal Medicine I, Ulm University Hospital, Ulm, Germany
| | - Meike Hohwieler
- grid.410712.1Department of Internal Medicine I, Ulm University Hospital, Ulm, Germany
| | - Xi Zhang
- grid.410712.1Department of Internal Medicine I, Ulm University Hospital, Ulm, Germany
| | - Gopika G. Nair
- grid.266102.10000 0001 2297 6811Diabetes Center at the University of California, San Francisco, USA
| | - Thomas Seufferlein
- grid.410712.1Department of Internal Medicine I, Ulm University Hospital, Ulm, Germany
| | - Matthias Hebrok
- grid.266102.10000 0001 2297 6811Diabetes Center at the University of California, San Francisco, USA
| | - Maike Sander
- grid.266100.30000 0001 2107 4242Pediatric Diabetes Research Center (PDRC) at the University of California, San Diego, USA
| | - Cécile Julier
- grid.4444.00000 0001 2112 9282Université de Paris, Institut Cochin, INSERM U1016, CNRS UMR-8104, Paris, France
| | - Alexander Kleger
- Department of Internal Medicine I, Ulm University Hospital, Ulm, Germany.
| | - Ivan G. Costa
- grid.1957.a0000 0001 0728 696XInstitute for Computational Genomics, RWTH Aachen University Medical School, Aachen, Germany
| |
Collapse
|
4
|
Sun ZY, Yu TY, Jiang FX, Wang W. Functional maturation of immature β cells: A roadblock for stem cell therapy for type 1 diabetes. World J Stem Cells 2021; 13:193-207. [PMID: 33815669 PMCID: PMC8006013 DOI: 10.4252/wjsc.v13.i3.193] [Citation(s) in RCA: 10] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/29/2020] [Revised: 01/19/2021] [Accepted: 02/25/2021] [Indexed: 02/06/2023] Open
Abstract
Type 1 diabetes mellitus (T1DM) is a chronic autoimmune disease caused by the specific destruction of pancreatic islet β cells and is characterized as the absolute insufficiency of insulin secretion. Current insulin replacement therapy supplies insulin in a non-physiological way and is associated with devastating complications. Experimental islet transplantation therapy has been proven to restore glucose homeostasis in people with severe T1DM. However, it is restricted by many factors such as severe shortage of donor sources, progressive loss of donor cells, high cost, etc. As pluripotent stem cells have the potential to give rise to all cells including islet β cells in the body, stem cell therapy for diabetes has attracted great attention in the academic community and the general public. Transplantation of islet β-like cells differentiated from human pluripotent stem cells (hPSCs) has the potential to be an excellent alternative to islet transplantation. In stem cell therapy, obtaining β cells with complete insulin secretion in vitro is crucial. However, after much research, it has been found that the β-like cells obtained by in vitro differentiation still have many defects, including lack of adult-type glucose stimulated insulin secretion, and multi-hormonal secretion, suggesting that in vitro culture does not allows for obtaining fully mature β-like cells for transplantation. A large number of studies have found that many transcription factors play important roles in the process of transforming immature to mature human islet β cells. Furthermore, PDX1, NKX6.1, SOX9, NGN3, PAX4, etc., are important in inducing hPSC differentiation in vitro. The absent or deficient expression of any of these key factors may lead to the islet development defect in vivo and the failure of stem cells to differentiate into genuine functional β-like cells in vitro. This article reviews β cell maturation in vivo and in vitro and the vital roles of key molecules in this process, in order to explore the current problems in stem cell therapy for diabetes.
Collapse
Affiliation(s)
- Zi-Yi Sun
- Department of Endocrinology, Xiang'an Hospital of Xiamen University, School of Medicine, Xiamen University, Xiamen 361100, Fujian Province, China
| | - Ting-Yan Yu
- Department of Endocrinology, Xiang'an Hospital of Xiamen University, School of Medicine, Xiamen University, Xiamen 361100, Fujian Province, China
| | - Fang-Xu Jiang
- Department of Endocrinology, Xiang'an Hospital of Xiamen University, School of Medicine, Xiamen University, Xiamen 361100, Fujian Province, China
| | - Wei Wang
- Department of Endocrinology, Xiang'an Hospital of Xiamen University, School of Medicine, Xiamen University, Xiamen 361100, Fujian Province, China.
| |
Collapse
|
5
|
Sun ZY, Yu TY, Jiang FX, Wang W. Functional maturation of immature β cells: A roadblock for stem cell therapy for type 1 diabetes. World J Stem Cells 2021; 13:193-207. [PMID: 33815669 DOI: 10.4252/wjsc.v13.i3.193] [cited] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/29/2020] [Revised: 01/19/2021] [Accepted: 02/25/2021] [Indexed: 01/26/2025] Open
Abstract
Type 1 diabetes mellitus (T1DM) is a chronic autoimmune disease caused by the specific destruction of pancreatic islet β cells and is characterized as the absolute insufficiency of insulin secretion. Current insulin replacement therapy supplies insulin in a non-physiological way and is associated with devastating complications. Experimental islet transplantation therapy has been proven to restore glucose homeostasis in people with severe T1DM. However, it is restricted by many factors such as severe shortage of donor sources, progressive loss of donor cells, high cost, etc. As pluripotent stem cells have the potential to give rise to all cells including islet β cells in the body, stem cell therapy for diabetes has attracted great attention in the academic community and the general public. Transplantation of islet β-like cells differentiated from human pluripotent stem cells (hPSCs) has the potential to be an excellent alternative to islet transplantation. In stem cell therapy, obtaining β cells with complete insulin secretion in vitro is crucial. However, after much research, it has been found that the β-like cells obtained by in vitro differentiation still have many defects, including lack of adult-type glucose stimulated insulin secretion, and multi-hormonal secretion, suggesting that in vitro culture does not allows for obtaining fully mature β-like cells for transplantation. A large number of studies have found that many transcription factors play important roles in the process of transforming immature to mature human islet β cells. Furthermore, PDX1, NKX6.1, SOX9, NGN3, PAX4, etc., are important in inducing hPSC differentiation in vitro. The absent or deficient expression of any of these key factors may lead to the islet development defect in vivo and the failure of stem cells to differentiate into genuine functional β-like cells in vitro. This article reviews β cell maturation in vivo and in vitro and the vital roles of key molecules in this process, in order to explore the current problems in stem cell therapy for diabetes.
Collapse
Affiliation(s)
- Zi-Yi Sun
- Department of Endocrinology, Xiang'an Hospital of Xiamen University, School of Medicine, Xiamen University, Xiamen 361100, Fujian Province, China
| | - Ting-Yan Yu
- Department of Endocrinology, Xiang'an Hospital of Xiamen University, School of Medicine, Xiamen University, Xiamen 361100, Fujian Province, China
| | - Fang-Xu Jiang
- Department of Endocrinology, Xiang'an Hospital of Xiamen University, School of Medicine, Xiamen University, Xiamen 361100, Fujian Province, China
| | - Wei Wang
- Department of Endocrinology, Xiang'an Hospital of Xiamen University, School of Medicine, Xiamen University, Xiamen 361100, Fujian Province, China.
| |
Collapse
|
6
|
Modulation of Insulin Sensitivity by Insulin-Degrading Enzyme. Biomedicines 2021; 9:biomedicines9010086. [PMID: 33477364 PMCID: PMC7830943 DOI: 10.3390/biomedicines9010086] [Citation(s) in RCA: 35] [Impact Index Per Article: 8.8] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/08/2020] [Revised: 01/14/2021] [Accepted: 01/15/2021] [Indexed: 12/15/2022] Open
Abstract
Insulin-degrading enzyme (IDE) is a highly conserved and ubiquitously expressed metalloprotease that degrades insulin and several other intermediate-size peptides. For many decades, IDE had been assumed to be involved primarily in hepatic insulin clearance, a key process that regulates availability of circulating insulin levels for peripheral tissues. Emerging evidence, however, suggests that IDE has several other important physiological functions relevant to glucose and insulin homeostasis, including the regulation of insulin secretion from pancreatic β-cells. Investigation of mice with tissue-specific genetic deletion of Ide in the liver and pancreatic β-cells (L-IDE-KO and B-IDE-KO mice, respectively) has revealed additional roles for IDE in the regulation of hepatic insulin action and sensitivity. In this review, we discuss current knowledge about IDE’s function as a regulator of insulin secretion and hepatic insulin sensitivity, both evaluating the classical view of IDE as an insulin protease and also exploring evidence for several non-proteolytic functions. Insulin proteostasis and insulin sensitivity have both been highlighted as targets controlling blood sugar levels in type 2 diabetes, so a clearer understanding the physiological functions of IDE in pancreas and liver could led to the development of novel therapeutics for the treatment of this disease.
Collapse
|
7
|
Kropp PA, Rushing GV, Brockman AA, Yu ENZ, Ihrie RA, Gannon M. Unexpected effects of ivermectin and selamectin on inducible Cre ER activity in mice. Lab Anim Res 2020; 36:36. [PMID: 33042783 PMCID: PMC7542348 DOI: 10.1186/s42826-020-00069-7] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/18/2020] [Accepted: 09/28/2020] [Indexed: 11/10/2022] Open
Abstract
BACKGROUND Anti-parasitics are frequently used in research animal facilities to treat a multitude of common infections, with pinworms and fur mites being amongst the most common. Ivermectin and selamectin are common oral and topical treatments for these infections, respectively. Although commonly thought to be innocuous to both the research animals and any transgenic elements that the animals may carry, evidence exists that ivermectin is capable of activating the recombinase activity of at least one CreER. The goal of the current study was to determine if there was an effect of either anti-parasitic agent on the activity of CreER proteins in transgenic mice. CASE PRESENTATION We analyzed the offspring of transgenic mice exposed to either ivermectin or selamectin during pregnancy and nursing. Through analysis of reporter genes co-expressed with multiple, independently generated transgenic CreER drivers, we report here that ivermectin and selamectin both alter recombinase activity and thus may have unintended consequences on gene inactivation studies in mice. CONCLUSIONS Although the mechanisms by which ivermectin and selamectin affect CreER activity in the offspring of treated dams remain unclear, the implications are important nonetheless. Treatment of pregnant transgenic mice with these anti-parasitics has the potential to alter transgene activity in the offspring. Special considerations should be made when planning treatment of transgenic mice with either of these pharmacologics.
Collapse
Affiliation(s)
- Peter A. Kropp
- Department of Molecular Physiology and Biophysics, Vanderbilt University, Nashville, TN USA
- Present Address: Laboratory of Biochemistry and Genetics, National Institutes of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Bethesda, MD 20886 USA
| | | | - Asa A. Brockman
- Department of Cell and Developmental Biology, Vanderbilt University, Nashville, TN USA
| | - Erin N. Z. Yu
- Department of Pathology, Immunology and Microbiology, Vanderbilt University Medical Center, Nashville, TN USA
| | - Rebecca A. Ihrie
- Neuroscience Program, Vanderbilt University, Nashville, TN USA
- Department of Cell and Developmental Biology, Vanderbilt University, Nashville, TN USA
- Department of Neurological Surgery, Vanderbilt University Medical Center, Nashville, TN USA
| | - Maureen Gannon
- Department of Molecular Physiology and Biophysics, Vanderbilt University, Nashville, TN USA
- Department of Cell and Developmental Biology, Vanderbilt University, Nashville, TN USA
- Department of Medicine, Vanderbilt University Medical Center, Nashville, TN USA
- Department of Veteran’s Affairs, Tennessee Valley Health Authority, Nashville, TN USA
| |
Collapse
|
8
|
Yao S, Zhang J, Zhan Y, Shi Y, Yu Y, Zheng L, Xu N, Luo G. Insulin Resistance in Apolipoprotein M Knockout Mice is Mediated by the Protein Kinase Akt Signaling Pathway. Endocr Metab Immune Disord Drug Targets 2020; 20:771-780. [PMID: 31702495 PMCID: PMC7360917 DOI: 10.2174/1871530319666191023125820] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/24/2019] [Revised: 09/12/2019] [Accepted: 09/13/2019] [Indexed: 12/11/2022]
Abstract
BACKGROUND Previous clinical studies have suggested that apolipoprotein M (apoM) is involved in glucose metabolism and plays a causative role in insulin sensitivity. OBJECTIVE The potential mechanism of apoM on modulating glucose homeostasis is explored and differentially expressed genes are analyzed by employing ApoM deficient (ApoM-/- ) and wild type (WT) mice. METHODS The metabolism of glucose in the hepatic tissues of high-fat diet ApoM-/- and WT mice was measured by a glycomics approach. Bioinformatic analysis was applied for analyzing the levels of differentially expressed mRNAs in the liver tissues of these mice. The insulin sensitivity of ApoM-/- and WT mice was compared using the insulin tolerance test and the phosphorylation levels of protein kinase Akt (AKT) and insulin stimulation in different tissues were examined by Western blot. RESULTS The majority of the hepatic glucose metabolites exhibited lower concentration levels in the ApoM-/- mice compared with those of the WT mice. Gene Ontology (GO) classification and Kyoto Encyclopedia of Genes and Genomes (KEGG) enrichment analysis indicated that ApoM deficiency affected the genes associated with the metabolism of glucose. The insulin tolerance test suggested that insulin sensitivity was impaired in ApoM-/- mice. The phosphorylation levels of AKT in muscle and adipose tissues of ApoM-/- mice were significantly diminished in response to insulin stimulation compared with those noted in WT mice. CONCLUSION ApoM deficiency led to the disorders of glucose metabolism and altered genes related to glucose metabolism in mice liver. In vivo data indicated that apoM might augment insulin sensitivity by AKT-dependent mechanism.
Collapse
Affiliation(s)
| | | | | | | | | | | | - Ning Xu
- Address correspondence to these two authors at the Comprehensive Laboratory, the Third Affiliated Hospital of Soochow University, 213003, Changzhou, China; Tel: +86-0519-68870619; E-mail: , and the Section of Clinical Chemistry & Pharmacology, Institute of Laboratory Medicine, Lunds University, S-22185 Lund, Sweden; E-mail:
| | - Guanghua Luo
- Address correspondence to these two authors at the Comprehensive Laboratory, the Third Affiliated Hospital of Soochow University, 213003, Changzhou, China; Tel: +86-0519-68870619; E-mail: , and the Section of Clinical Chemistry & Pharmacology, Institute of Laboratory Medicine, Lunds University, S-22185 Lund, Sweden; E-mail:
| |
Collapse
|
9
|
Fernández-Díaz CM, Merino B, López-Acosta JF, Cidad P, de la Fuente MA, Lobatón CD, Moreno A, Leissring MA, Perdomo G, Cózar-Castellano I. Pancreatic β-cell-specific deletion of insulin-degrading enzyme leads to dysregulated insulin secretion and β-cell functional immaturity. Am J Physiol Endocrinol Metab 2019; 317:E805-E819. [PMID: 31479304 PMCID: PMC7132327 DOI: 10.1152/ajpendo.00040.2019] [Citation(s) in RCA: 19] [Impact Index Per Article: 3.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/17/2022]
Abstract
Inhibition of insulin-degrading enzyme (IDE) has been proposed as a possible therapeutic target for type 2 diabetes treatment. However, many aspects of IDE's role in glucose homeostasis need to be clarified. In light of this, new preclinical models are required to elucidate the specific role of this protease in the main tissues related to insulin handling. To address this, here we generated a novel line of mice with selective deletion of the Ide gene within pancreatic beta-cells, B-IDE-KO mice, which have been characterized in terms of multiple metabolic end points, including blood glucose, plasma C-peptide, and intraperitoneal glucose tolerance tests. In addition, glucose-stimulated insulin secretion was quantified in isolated pancreatic islets and beta-cell differentiation markers and insulin secretion machinery were characterized by RT-PCR. Additionally, IDE was genetically and pharmacologically inhibited in INS-1E cells and rodent and human islets, and insulin secretion was assessed. Our results show that, in vivo, life-long deletion of IDE from beta-cells results in increased plasma C-peptide levels. Corroborating these findings, isolated islets from B-IDE-KO mice showed constitutive insulin secretion, a hallmark of beta-cell functional immaturity. Unexpectedly, we found 60% increase in Glut1 (a high-affinity/low-Km glucose transporter), suggesting increased glucose transport into the beta-cell at low glucose levels, which may be related to constitutive insulin secretion. In parallel, IDE inhibition in INS-1E and islet cells resulted in impaired insulin secretion after glucose challenge. We conclude that IDE is required for glucose-stimulated insulin secretion. When IDE is inhibited, insulin secretion machinery is perturbed, causing either inhibition of insulin release at high glucose concentrations or constitutive secretion.
Collapse
Affiliation(s)
- Cristina M Fernández-Díaz
- Instituto de Biología y Genética Molecular, Universidad de Valladolid-Consejo Superior de Investigaciones Científicas, Valladolid, Spain
| | - Beatriz Merino
- Instituto de Biología y Genética Molecular, Universidad de Valladolid-Consejo Superior de Investigaciones Científicas, Valladolid, Spain
| | - José F López-Acosta
- Instituto de Biología y Genética Molecular, Universidad de Valladolid-Consejo Superior de Investigaciones Científicas, Valladolid, Spain
| | - Pilar Cidad
- Instituto de Biología y Genética Molecular, Universidad de Valladolid-Consejo Superior de Investigaciones Científicas, Valladolid, Spain
| | - Miguel A de la Fuente
- Instituto de Biología y Genética Molecular, Universidad de Valladolid-Consejo Superior de Investigaciones Científicas, Valladolid, Spain
| | - Carmen D Lobatón
- Instituto de Biología y Genética Molecular, Universidad de Valladolid-Consejo Superior de Investigaciones Científicas, Valladolid, Spain
| | - Alfredo Moreno
- Instituto de Biología y Genética Molecular, Universidad de Valladolid-Consejo Superior de Investigaciones Científicas, Valladolid, Spain
| | - Malcolm A Leissring
- Institute for Memory Impairments and Neurological Disorders, University of California, Irvine, California
| | - Germán Perdomo
- Departmento de Ciencias de la Salud, Facultad de Ciencias de la Salud, Universidad de Burgos, Burgos, Spain
| | - Irene Cózar-Castellano
- Instituto de Biología y Genética Molecular, Universidad de Valladolid-Consejo Superior de Investigaciones Científicas, Valladolid, Spain
- Centro de Investigación Biomédica en Red de Diabetes y Enfermedades Metabólicas Asociadas, Madrid, Spain
| |
Collapse
|