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Hao M, Sebag SC, Qian Q, Yang L. Lysosomal physiology and pancreatic lysosomal stress in diabetes mellitus. EGASTROENTEROLOGY 2024; 2:e100096. [PMID: 39512752 PMCID: PMC11542681 DOI: 10.1136/egastro-2024-100096] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Indexed: 11/15/2024]
Abstract
Endocrine and exocrine functions of the pancreas control nutritional absorption, utilisation and systemic metabolic homeostasis. Under basal conditions, the lysosome is pivotal in regulating intracellular organelles and metabolite turnover. In response to acute or chronic stress, the lysosome senses metabolic flux and inflammatory challenges, thereby initiating the adaptive programme to re-establish cellular homeostasis. A growing body of evidence has demonstrated the pathophysiological relevance of the lysosomal stress response in metabolic diseases in diverse sets of tissues/organs, such as the liver and the heart. In this review, we discuss the pathological relevance of pancreatic lysosome stress in diabetes mellitus. We begin by summarising lysosomal biology, followed by exploring the immune and metabolic functions of lysosomes and finally discussing the interplay between lysosomal stress and the pathogenesis of pancreatic diseases. Ultimately, our review aims to enhance our understanding of lysosomal stress in disease pathogenesis, which could potentially lead to the discovery of innovative treatment methods for these conditions.
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Affiliation(s)
- Meihua Hao
- Department of Anatomy and Cell Biology, Fraternal Order of Eagles Diabetes Research Center, Pappajohn Biomedical Institute, University of Iowa Carver College of Medicine, Iowa City, Iowa, USA
| | - Sara C Sebag
- Department of Anatomy and Cell Biology, Fraternal Order of Eagles Diabetes Research Center, Pappajohn Biomedical Institute, University of Iowa Carver College of Medicine, Iowa City, Iowa, USA
| | - Qingwen Qian
- Department of Anatomy and Cell Biology, Fraternal Order of Eagles Diabetes Research Center, Pappajohn Biomedical Institute, University of Iowa Carver College of Medicine, Iowa City, Iowa, USA
| | - Ling Yang
- Department of Anatomy and Cell Biology, Fraternal Order of Eagles Diabetes Research Center, Pappajohn Biomedical Institute, University of Iowa Carver College of Medicine, Iowa City, Iowa, USA
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2
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Dale DJ, Rutan CD, Mastracci TL. Development of the Pancreatic Ducts and Their Contribution to Organogenesis. ADVANCES IN ANATOMY, EMBRYOLOGY, AND CELL BIOLOGY 2024; 239:31-55. [PMID: 39283481 PMCID: PMC11934529 DOI: 10.1007/978-3-031-62232-8_2] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 09/25/2024]
Abstract
The pancreas is a dual-function organ, with exocrine cells that aid in digestion and endocrine cells that regulate glucose homeostasis. These cell types share common progenitors and arise from the embryonic ducts. Early signaling events in the embryonic ducts shape the neonatal, adolescent, and adult exocrine and endocrine pancreas. This chapter discusses recent advances in the tools used to study the ducts and our current understanding of how ductal development contributes to pancreatic organogenesis.
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Affiliation(s)
- Dorian J Dale
- Department of Biology, Indiana University-Indianapolis, Indianapolis, IN, USA
| | - Caleb D Rutan
- Department of Biology, Indiana University-Indianapolis, Indianapolis, IN, USA
| | - Teresa L Mastracci
- Department of Biology, Indiana University-Indianapolis, Indianapolis, IN, USA.
- Department of Biochemistry and Molecular Biology, Indiana University School of Medicine, Indianapolis, IN, USA.
- Center for Diabetes and Metabolic Disease, Indiana University School of Medicine, Indianapolis, IN, USA.
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Yskout M, Vliebergh J, Bor H, Dupont L, Lorent N, Van Bleyenbergh P, Gillard P, Van der Schueren B, Mertens A, Mathieu C, Vangoitsenhoven R. Hypoglycaemia after Initiation of CFTR Modulator Therapy in a Cystic Fibrosis Patient without Diabetes. Case Rep Endocrinol 2023; 2023:9769119. [PMID: 38161769 PMCID: PMC10757659 DOI: 10.1155/2023/9769119] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/29/2022] [Revised: 11/20/2023] [Accepted: 11/30/2023] [Indexed: 01/03/2024] Open
Abstract
Introduction Cystic fibrosis transmembrane regulator (CFTR) modulator therapies improve respiratory function and glycaemic control in patients with cystic fibrosis (CF). The direct effect of CFTR modulator therapies on pancreatic function in patients without preexisting diabetes remains unclear. Case Presentation. An 18-year-old female with CF caused by F508del/F508del mutation, who had no diabetes, developed postprandial hypoglycaemias 6 months after initiation of elexacaftor, tezacaftor, and ivacaftor combination therapy (ETI). Symptoms were persisted after brief discontinuation of ETI, but her symptoms and time-in-hypoglycaemia had improved remarkably by avoiding high glycaemic index-foods. Discussion. This case of hypoglycaemia associated with CFTR modulator therapy in a patient without preexisting diabetes suggests that CFTR modulator therapy has the potential to directly affect glucose homeostasis. There might be an improvement in insulin secretion as well as a reduction in systemic insulin resistance. Conclusion Treatment of CF patients without diabetes with CFTR modulator therapies can cause recurrent hypoglycaemic episodes which resolve with dietary measures.
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Affiliation(s)
| | | | - Hakan Bor
- Nutrition and Dietetic, Gumushane University, Gumushane, Türkiye
- Chronic Diseases and Metabolism, KU Leuven, Leuven, Belgium
| | - Lieven Dupont
- Chronic Diseases and Metabolism, KU Leuven, Leuven, Belgium
- Pneumology, UZ Leuven, Leuven, Belgium
| | - Natalie Lorent
- Chronic Diseases and Metabolism, KU Leuven, Leuven, Belgium
- Pneumology, UZ Leuven, Leuven, Belgium
| | - Pascal Van Bleyenbergh
- Chronic Diseases and Metabolism, KU Leuven, Leuven, Belgium
- Pneumology, UZ Leuven, Leuven, Belgium
| | - Pieter Gillard
- UZ Leuven, Endocrinology, Leuven, Belgium
- Chronic Diseases and Metabolism, KU Leuven, Leuven, Belgium
| | - Bart Van der Schueren
- UZ Leuven, Endocrinology, Leuven, Belgium
- Chronic Diseases and Metabolism, KU Leuven, Leuven, Belgium
| | - Ann Mertens
- UZ Leuven, Endocrinology, Leuven, Belgium
- Chronic Diseases and Metabolism, KU Leuven, Leuven, Belgium
| | - Chantal Mathieu
- UZ Leuven, Endocrinology, Leuven, Belgium
- Chronic Diseases and Metabolism, KU Leuven, Leuven, Belgium
| | - Roman Vangoitsenhoven
- UZ Leuven, Endocrinology, Leuven, Belgium
- Chronic Diseases and Metabolism, KU Leuven, Leuven, Belgium
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Ciochina M, Balaban DV, Manucu G, Jinga M, Gheorghe C. The Impact of Pancreatic Exocrine Diseases on the β-Cell and Glucose Metabolism-A Review with Currently Available Evidence. Biomolecules 2022; 12:biom12050618. [PMID: 35625546 PMCID: PMC9139037 DOI: 10.3390/biom12050618] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/22/2022] [Revised: 04/17/2022] [Accepted: 04/19/2022] [Indexed: 02/07/2023] Open
Abstract
Pancreatic exocrine and endocrine dysfunctions often come together in the course of pancreatic diseases as interdependent manifestations of the same organ. However, the mechanisms underlying the bidirectional connection of the exocrine and endocrine pancreas are not fully understood. In this review, we aimed to synthetize the current knowledge regarding the effects of several exocrine pancreatic pathologies on the homeostasis of β-cells, with a special interest in the predisposition toward diabetes mellitus (DM). We focused on the following pancreatic exocrine diseases: chronic pancreatitis, acute pancreatitis, cystic fibrosis, pancreatic cancer, pancreatic resections, and autoimmune pancreatitis. We discuss the pathophysiologic mechanisms behind the impact on β-cell function and evolution into DM, as well as the associated risk factors in progression to DM, and we describe the most relevant and statistically significant findings in the literature. An early and correct diagnosis of DM in the setting of pancreatic exocrine disorders is of paramount importance for anticipating the disease's course and its therapeutical needs.
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Affiliation(s)
- Marina Ciochina
- Faculty of Medicine, Carol Davila University of Medicine and Pharmacy, 050474 Bucharest, Romania; (D.V.B.); (M.J.); (C.G.)
- Correspondence:
| | - Daniel Vasile Balaban
- Faculty of Medicine, Carol Davila University of Medicine and Pharmacy, 050474 Bucharest, Romania; (D.V.B.); (M.J.); (C.G.)
- Gastroenterology Department, Central Military Emergency University Hospital, 010825 Bucharest, Romania;
| | - George Manucu
- Gastroenterology Department, Central Military Emergency University Hospital, 010825 Bucharest, Romania;
| | - Mariana Jinga
- Faculty of Medicine, Carol Davila University of Medicine and Pharmacy, 050474 Bucharest, Romania; (D.V.B.); (M.J.); (C.G.)
- Gastroenterology Department, Central Military Emergency University Hospital, 010825 Bucharest, Romania;
| | - Cristian Gheorghe
- Faculty of Medicine, Carol Davila University of Medicine and Pharmacy, 050474 Bucharest, Romania; (D.V.B.); (M.J.); (C.G.)
- Gastroenterology Department, Fundeni Clinical Institute, 022328 Bucharest, Romania
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5
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Butnariu LI, Țarcă E, Cojocaru E, Rusu C, Moisă ȘM, Leon Constantin MM, Gorduza EV, Trandafir LM. Genetic Modifying Factors of Cystic Fibrosis Phenotype: A Challenge for Modern Medicine. J Clin Med 2021; 10:5821. [PMID: 34945117 PMCID: PMC8707808 DOI: 10.3390/jcm10245821] [Citation(s) in RCA: 21] [Impact Index Per Article: 5.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/20/2021] [Revised: 12/06/2021] [Accepted: 12/07/2021] [Indexed: 12/13/2022] Open
Abstract
Cystic fibrosis (CF) is a monogenic autosomal recessive disease caused by cystic fibrosis transmembrane conductance regulator (CFTR) gene mutations. CF is characterized by a high phenotypic variability present even in patients with the same genotype. This is due to the intervention of modifier genes that interact with both the CFTR gene and environmental factors. The purpose of this review is to highlight the role of non-CFTR genetic factors (modifier genes) that contribute to phenotypic variability in CF. We analyzed literature data starting with candidate gene studies and continuing with extensive studies, such as genome-wide association studies (GWAS) and whole exome sequencing (WES). The results of both types of studies revealed that the number of modifier genes in CF patients is impressive. Their identification offers a new perspective on the pathophysiological mechanisms of the disease, paving the way for the understanding of other genetic disorders. In conclusion, in the future, genetic analysis, such as GWAS and WES, should be performed routinely. A challenge for future research is to integrate their results in the process of developing new classes of drugs, with a goal to improve the prognosis, increase life expectancy, and enhance quality of life among CF patients.
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Affiliation(s)
- Lăcrămioara Ionela Butnariu
- Department of Medical Genetics, Faculty of Medicine, “Grigore T. Popa” University of Medicine and Pharmacy, 700115 Iasi, Romania; (L.I.B.); (C.R.); (E.V.G.)
| | - Elena Țarcă
- Department of Surgery II—Pediatric Surgery, “Grigore T. Popa” University of Medicine and Pharmacy, 700115 Iaşi, Romania
| | - Elena Cojocaru
- Department of Morphofunctional Sciences I, “Grigore T. Popa” University of Medicine and Pharmacy, 700115 Iaşi, Romania
| | - Cristina Rusu
- Department of Medical Genetics, Faculty of Medicine, “Grigore T. Popa” University of Medicine and Pharmacy, 700115 Iasi, Romania; (L.I.B.); (C.R.); (E.V.G.)
| | - Ștefana Maria Moisă
- Department of Mother and Child, Faculty of Medicine, “Grigore T. Popa” University of Medicine and Pharmacy, 700115 Iasi, Romania; (Ș.M.M.); (L.M.T.)
| | | | - Eusebiu Vlad Gorduza
- Department of Medical Genetics, Faculty of Medicine, “Grigore T. Popa” University of Medicine and Pharmacy, 700115 Iasi, Romania; (L.I.B.); (C.R.); (E.V.G.)
| | - Laura Mihaela Trandafir
- Department of Mother and Child, Faculty of Medicine, “Grigore T. Popa” University of Medicine and Pharmacy, 700115 Iasi, Romania; (Ș.M.M.); (L.M.T.)
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Semaniakou A, Chappe F, Anini Y, Chappe V. VIP reduction in the pancreas of F508del homozygous CF mice and early signs of Cystic Fibrosis Related Diabetes (CFRD). J Cyst Fibros 2021; 20:881-890. [PMID: 34034984 DOI: 10.1016/j.jcf.2021.05.006] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/08/2020] [Revised: 04/30/2021] [Accepted: 05/04/2021] [Indexed: 12/19/2022]
Abstract
Vasoactive intestinal peptide (VIP), a 28-amino acid neuropeptide with potent anti-inflammatory, bronchodilatory and immunomodulatory functions, is secreted by intrinsic neurons innervating all exocrine glands, including the pancreas, in which it exerts a regulatory function in the secretion of insulin and glucagon. Cystic fibrosis-related diabetes (CFRD) is the most common co-morbidity associated with cystic fibrosis (CF), impacting approximately 50% of adult patients. We recently demonstrated a 50% reduction of VIP abundance in the lungs, duodenum and sweat glands of C57Bl/6 CF mice homozygous for the F508del-CFTR disease-causing mutation. VIP deficiency resulted from a reduction in VIPergic and cholinergic innervation, starting before signs of CF disease were observed. As VIP functions as a neuromodulator with insulinotropic effect on pancreatic beta cells, we sought to study changes in VIP in the pancreas of CF mice. Our goal was to examine VIP content and VIPergic innervation in the pancreas of 8- and 17-week-old F508del-CFTR homozygous mice and to determine whether changes in VIP levels would contribute to CFRD development. Our data showed that a decreased amount of VIP and reduced innervation are found in CF mice pancreas, and that these mice also exhibited reduced insulin secretion, up-regulation of glucagon production and high random blood glucose levels compared to same-age wild-type mice. We propose that low level of VIP, due to reduced innervation of the CF pancreas and starting at an early disease stage, contributes to changes in insulin and glucagon secretion that can lead to CFRD development.
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Affiliation(s)
- Anna Semaniakou
- Department of Physiology & Biophysics, Faculty of Medicine, Dalhousie University, Halifax, NS, Canada
| | - Frederic Chappe
- Department of Physiology & Biophysics, Faculty of Medicine, Dalhousie University, Halifax, NS, Canada
| | - Younes Anini
- Department of Physiology & Biophysics, Faculty of Medicine, Dalhousie University, Halifax, NS, Canada; Obstetrics and Gynecology, Faculty of Medicine, Dalhousie University, Halifax, NS, Canada
| | - Valerie Chappe
- Department of Physiology & Biophysics, Faculty of Medicine, Dalhousie University, Halifax, NS, Canada.
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Ziegler R, Heinemann L, Freckmann G, Schnell O, Hinzmann R, Kulzer B. Intermittent Use of Continuous Glucose Monitoring: Expanding the Clinical Value of CGM. J Diabetes Sci Technol 2021; 15:684-694. [PMID: 32064909 PMCID: PMC8120049 DOI: 10.1177/1932296820905577] [Citation(s) in RCA: 13] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/11/2022]
Abstract
In addition to the continuous use, the intermittent use of continuous glucose monitoring (CGM) is an application of CGM, expanding the typical medical use cases. There are a variety of reasons and occasions that speak in favor of using CGM only for a limited time. To date, these circumstances have not been sufficiently discussed. In this article, we define discontinuous or intermittent CGM use, provide reasons for using it, and expand on the benefits and possibilities of using CGM on a temporary basis. We aim to draw attention to this important topic in the discussion of CGM use and give examples for a different method of CGM use. As well, we would like to foster the allocation of CGM to the right patient groups and indications, especially in cases of limited resources. From a global point of view, intermittent CGM use is more likely to occur than continuous use, primarily for economic reasons.
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Affiliation(s)
- Ralph Ziegler
- Diabetes Clinic for Children and
Adolescents, Muenster, Germany
- Ralph Ziegler, MD, Diabetes Clinic
for Children and Adolescents Mondstr. 148, Muenster 48155, Germany.
| | | | - Guido Freckmann
- Institut für Diabetes-Technologie,
Forschungs- und Entwicklungsgesellschaft mbH an der Universität Ulm,
Germany
| | - Oliver Schnell
- Forschergruppe Diabetes e.V.,
Helmholtz Zentrum, Munich, Germany
| | | | - Bernd Kulzer
- Diabetes Center Bad Mergentheim,
Research Institute of the Diabetes Academy, Bad Mergentheim, University
Bamberg, Germany
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Iafusco F, Maione G, Rosanio FM, Mozzillo E, Franzese A, Tinto N. Cystic Fibrosis-Related Diabetes (CFRD): Overview of Associated Genetic Factors. Diagnostics (Basel) 2021; 11:diagnostics11030572. [PMID: 33810109 PMCID: PMC8005125 DOI: 10.3390/diagnostics11030572] [Citation(s) in RCA: 12] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/06/2021] [Accepted: 03/19/2021] [Indexed: 12/21/2022] Open
Abstract
Cystic fibrosis (CF) is the most common autosomal recessive disease in the Caucasian population and is caused by mutations in the CF transmembrane conductance regulator (CFTR) gene that encodes for a chloride/bicarbonate channel expressed on the membrane of epithelial cells of the airways and of the intestine, as well as in cells with exocrine and endocrine functions. A common nonpulmonary complication of CF is cystic fibrosis-related diabetes (CFRD), a distinct form of diabetes due to insulin insufficiency or malfunction secondary to destruction/derangement of pancreatic betacells, as well as to other factors that affect their function. The prevalence of CFRD increases with age, and 40–50% of CF adults develop the disease. Several proposed hypotheses on how CFRD develops have emerged, including exocrine-driven fibrosis and destruction of the entire pancreas, as well as contrasting theories on the direct or indirect impact of CFTR mutation on islet function. Among contributors to the development of CFRD, in addition to CFTR genotype, there are other genetic factors related and not related to type 2 diabetes. This review presents an overview of the current understanding on genetic factors associated with glucose metabolism abnormalities in CF.
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Affiliation(s)
- Fernanda Iafusco
- Department of Molecular Medicine and Medical Biotechnology, University of Naples “Federico II”, 80131 Naples, Italy; (F.I.); (G.M.)
- CEINGE Advanced Biotechnology, 80131 Naples, Italy
| | - Giovanna Maione
- Department of Molecular Medicine and Medical Biotechnology, University of Naples “Federico II”, 80131 Naples, Italy; (F.I.); (G.M.)
- CEINGE Advanced Biotechnology, 80131 Naples, Italy
| | - Francesco Maria Rosanio
- Regional Center of Pediatric Diabetology, Department of Translational Medical Sciences, Section of Pediatrics, University of Naples “Federico II”, 80131 Naples, Italy; (F.M.R.); (E.M.); (A.F.)
| | - Enza Mozzillo
- Regional Center of Pediatric Diabetology, Department of Translational Medical Sciences, Section of Pediatrics, University of Naples “Federico II”, 80131 Naples, Italy; (F.M.R.); (E.M.); (A.F.)
| | - Adriana Franzese
- Regional Center of Pediatric Diabetology, Department of Translational Medical Sciences, Section of Pediatrics, University of Naples “Federico II”, 80131 Naples, Italy; (F.M.R.); (E.M.); (A.F.)
| | - Nadia Tinto
- Department of Molecular Medicine and Medical Biotechnology, University of Naples “Federico II”, 80131 Naples, Italy; (F.I.); (G.M.)
- CEINGE Advanced Biotechnology, 80131 Naples, Italy
- Correspondence:
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Gojsina B, Minic P, Todorovic S, Soldatovic I, Sovtic A. Continuous Glucose Monitoring as a Valuable Tool in the Early Detection of Diabetes Related to Cystic Fibrosis. Front Pediatr 2021; 9:659728. [PMID: 34307249 PMCID: PMC8298893 DOI: 10.3389/fped.2021.659728] [Citation(s) in RCA: 10] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/28/2021] [Accepted: 06/09/2021] [Indexed: 01/13/2023] Open
Abstract
Aims: We evaluated the impact of cystic fibrosis-related diabetes (CFRD) on lung disease and nutritional status. Study Design: The retrospective cohort study evaluated the subjects' medical records from 2004 to 2019. All participants older than 10 years diagnosed by a 30-minutely sampled OGTT formed OGTT-CFRD subgroup. The participants diagnosed with continuous glucose monitoring (CGM) (at least two peaks above 11.1 mmol/l and more than 10% of recorded time above 7.8 mmol/l) formed a CFRD-CGM subgroup. The participants without CFRD formed a non-CFRD group. The longitudinal follow-up was made 2 years before and 3 years after insulin therapy initiation. Results: Of 144 participants included, aged 10-55 years (44% males), 28 (19.4%) had CFRD. The HbA1c was significantly lower in the CGM-CFRD in comparison to the OGTT-CFRD subgroup (5.9 ± 0.62 and 7.3 ± 1.7% respectfully; p = 0.04). Subjects with CFRD were malnourished in comparison to non-CFRD, with significant improvements with insulin replacement therapy in regard to BMI Z-score (-1.4 ± 1.3 vs. -0.5 ± 1.2%, p = 0.04) and pulmonary exacerbation score (p = 0.02). In OGTT-CFRD subgroup there is an increase in FEV1 (62.7 ± 26.3 to 65.1 ± 21.7%, p = 0.7) and decrease in FVC (from 76.4 ± 24.2 to 71.2 ± 20%, p = 0.003) from diagnosis to second year of follow-up. In CGM-CFRD subgroup there was a decrease in FEV1 (from 58.2 ± 28.2 to 52.8 ± 25.9%, p = 0.2) and FVC-values (from 72.4 ± 26.5 to 67.4 ± 29.1%, p = 0.08).Chronic Pseudomonas aeruginosa infection was more prevalent in the CFRD group (p = 0.003). Conclusion: Continuous glucose monitoring is a useful tool for insight of glucose impairment and diagnosis of CFRD. Early recognition of CFRD and therapeutic intervention has favorable effects on clinical course of the disease.
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Affiliation(s)
- Bojana Gojsina
- Department of Pulmonology, The Institute for Health Protection of Mother and Child Serbia, Belgrade, Serbia
| | - Predrag Minic
- Department of Pulmonology, The Institute for Health Protection of Mother and Child Serbia, Belgrade, Serbia.,Faculty of Medicine, University of Belgrade, Belgrade, Serbia
| | - Sladjana Todorovic
- Department of Endocrinology, The Institute for Health Protection of Mother and Child Serbia, Belgrade, Serbia
| | - Ivan Soldatovic
- Institute for Medical Statistics and Informatics, Faculty of Medicine, University of Belgrade, Belgrade, Serbia
| | - Aleksandar Sovtic
- Department of Pulmonology, The Institute for Health Protection of Mother and Child Serbia, Belgrade, Serbia.,Faculty of Medicine, University of Belgrade, Belgrade, Serbia
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10
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Ogbolu C, Arregui-Fresneda I, Daniels T, Holt RIG. Some young adults with cystic fibrosis-related diabetes may safely stop insulin without any adverse clinical sequelae. Diabet Med 2020; 37:1205-1208. [PMID: 32115764 DOI: 10.1111/dme.14288] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Accepted: 02/26/2020] [Indexed: 11/28/2022]
Affiliation(s)
- C Ogbolu
- Human Development and Health, Faculty of Medicine, University of Southampton, Southampton, UK
| | - I Arregui-Fresneda
- Southampton NHS Foundation Trust, Wessex Adult Cystic Fibrosis Service, Southampton, UK
| | - T Daniels
- Southampton NHS Foundation Trust, Wessex Adult Cystic Fibrosis Service, Southampton, UK
| | - R I G Holt
- Human Development and Health, Faculty of Medicine, University of Southampton, Southampton, UK
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11
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Pozo L, Bello F, Mendez Y, Surani S. Cystic fibrosis-related diabetes: The unmet need. World J Diabetes 2020; 11:213-217. [PMID: 32547695 PMCID: PMC7284020 DOI: 10.4239/wjd.v11.i6.213] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/09/2020] [Revised: 04/14/2020] [Accepted: 04/25/2020] [Indexed: 02/06/2023] Open
Abstract
Cystic fibrosis (CF) is a common autosomal recessive disease. Life expectancy of patients with CF continues to improve mainly driven by the evolving therapies for CF-related organ dysfunction. The prevalence of CF-related diabetes (CFRD) increases exponentially as patients’ age. Clinical care guidelines for CFRD from 2010, recommend insulin as the mainstay of treatment. Many patients with CFRD may not require exogenous insulin due to the heterogeneity of this clinical entity. Maintenance of euglycemia by enhancing endogenous insulin production, secretion and degradation with novel pharmacological therapies like glucagon-like peptide-1 agonist is an option that remains to be fully explored. As such, the scope of this article will focus on our perspective of glucagon-like peptide-1 receptor agonist in the context of CFRD. Other potential options such as sodium-glucose cotransporter-2 and dipeptidyl peptidase 4 inhibitors and their impact on this patient population is limited and further studies are required.
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Affiliation(s)
- Leonardo Pozo
- Internal Medicine, University of Texas Rio Grande Valley, Edinburg, TX 78539, United States
| | - Fatimah Bello
- Internal Medicine, University of Texas Rio Grande Valley, Edinburg, TX 78539, United States
| | - Yamely Mendez
- Research Department, Baylor College of Medicine, Houston, Texas. 77030, United States
| | - Salim Surani
- Medical Critical Care Services, Corpus Christi Medical Center, Corpus Christi, TX 78404, United States
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12
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Kempegowda P, Sunsoa H, Chandan JS, Quinn LM, Amrelia PM, Atta SN, Amir S, Teh YS, Chaudhry S, de Bray A, Rashid R, Whitehouse JL, Nash EF, Syed A. Retinopathy and microalbuminuria are common microvascular complications in cystic fibrosis-related diabetes. Ther Adv Endocrinol Metab 2020; 11:2042018820966428. [PMID: 35154634 PMCID: PMC8832295 DOI: 10.1177/2042018820966428] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/08/2020] [Accepted: 09/24/2020] [Indexed: 11/21/2022] Open
Abstract
AIMS To study the prevalence of microvascular complications and renal changes associated with cystic fibrosis-related diabetes (CFRD). METHODS This retrospective cohort study was conducted at the West Midlands Adult Cystic Fibrosis centre, United Kingdom. Data regarding age, sex, microalbuminuria, retinopathy neuropathy, and biochemical results were collected for all people with CFRD who had an annual review from 1 January 2018 to 31 December 2018 at the centre. Descriptive statistics were analysed using STATAv15.1. RESULTS A total of 189 patients were included, of which 56.6% were male and median age (interquartile range) was 33 (27-39) years; 79.4% (150/189) had their annual review in 2018. Those with a biochemically impaired renal function numbered 7.2% (13/180) and 22.7% (32/141) had microalbuminuria; 17.2% (10/58) had diabetes related retinopathy. No one in our cohort had diabetic ulcers; however, 10.3% (13/126) had absent foot pulses. CONCLUSION We found a higher prevalence of microalbuminuria compared with retinopathy in a large cohort of cystic fibrosis adults. This study demonstrates the need for regular specialist follow-up to facilitate early identification of such complications and a long-term prospective cohort to understand underlying mechanisms.
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Affiliation(s)
| | - Harbinder Sunsoa
- West Midlands Adult CF Centre, University
Hospitals Birmingham NHS Foundation Trust, Birmingham, UK
| | - Joht S. Chandan
- Institute of Immunology and Immunotherapy,
University of Birmingham, Birmingham, UK
| | | | - Prashant M. Amrelia
- Department of Diabetes and Endocrinology,
University Hospitals Birmingham NHS Foundation Trust, UK
| | - Syed Noman Atta
- Department of Diabetes and Endocrinology,
University Hospitals Birmingham NHS Foundation Trust, UK
| | - Sidrah Amir
- Department of Diabetes and Endocrinology,
University Hospitals Birmingham NHS Foundation Trust, UK
| | - Yee Suh Teh
- Department of Diabetes and Endocrinology,
University Hospitals Birmingham NHS Foundation Trust, UK
| | - Sabba Chaudhry
- Department of Diabetes and Endocrinology,
University Hospitals Birmingham NHS Foundation Trust, UK
| | - Anne de Bray
- Department of Diabetes and Endocrinology,
University Hospitals Birmingham NHS Foundation Trust, UK
- Institute of Metabolism and Systems Research,
University of Birmingham, Birmingham, UK
| | - Rifat Rashid
- West Midlands Adult CF Centre, University
Hospitals Birmingham NHS Foundation Trust, Birmingham, UK
| | - Joanna L. Whitehouse
- West Midlands Adult CF Centre, University
Hospitals Birmingham NHS Foundation Trust, Birmingham, UK
| | - Edward F. Nash
- West Midlands Adult CF Centre, University
Hospitals Birmingham NHS Foundation Trust, Birmingham, UK
| | - Ateeq Syed
- Department of Diabetes and Endocrinology,
University Hospitals Birmingham NHS Foundation Trust, UK
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13
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Cystic Fibrosis-Related Diabetes Screening in Adults: A Gap Analysis and Evaluation of Accuracy of Glycated Hemoglobin Levels. Can J Diabetes 2019; 43:13-18. [DOI: 10.1016/j.jcjd.2018.04.008] [Citation(s) in RCA: 20] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/15/2018] [Accepted: 04/30/2018] [Indexed: 12/23/2022]
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14
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Colomba J, Boudreau V, Lehoux-Dubois C, Desjardins K, Coriati A, Tremblay F, Rabasa-Lhoret R. The main mechanism associated with progression of glucose intolerance in older patients with cystic fibrosis is insulin resistance and not reduced insulin secretion capacity. J Cyst Fibros 2019; 18:551-556. [PMID: 30711385 DOI: 10.1016/j.jcf.2019.01.009] [Citation(s) in RCA: 39] [Impact Index Per Article: 6.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/21/2018] [Revised: 11/02/2018] [Accepted: 01/21/2019] [Indexed: 02/08/2023]
Abstract
BACKGROUND Aging cystic fibrosis (CF) patients are at high risk of developing CF-related diabetes (CFRD). Decrease in insulin secretion over time is the main hypothesis to explain this increasing prevalence but mechanisms are still not well elucidated. The objective is to assess evolution of glucose tolerance and insulin secretion/sensitivity in aging CF patients. METHODS This is a retro-prospective observational analysis in the older adult CF patients from the Montreal Cystic Fibrosis Cohort (n = 46; at least 35 years old at follow-up) and followed for at least 4 years. Baseline and follow-up (last visit to date) 2-h oral glucose tolerance test (OGTT with glucose and insulin measurements every 30 min) were performed. Pulmonary function test (FEV1) and anthropometric data were measured the same day. Insulin sensitivity was measured by the Stumvoll index. RESULTS After a mean follow-up of 9.9 ± 2.6 years, mean age at follow-up was 43.5 ± 8.1 years old. An increase of body weight (+2.6 ± 6.5 kg, p = 0.01) and a decrease in pulmonary function (FEV1; 73.4 ± 21.2% to 64.5 ± 22.4%, p ≤ 0.001) were observed. Overall, insulin secretion is maintained at follow-up but all OGTT glucose values increased (for all values, p ≤ 0.028). At follow-up, 28.3% of patients had a normal glucose tolerance while 71.7% had abnormal glucose tolerance (AGT). AGT patients decreased their insulin sensitivity over time (p = 0.029) while it remained the same in NGT patients (p = 0.917). CONCLUSION In older CF patients, the progression of impaired glucose tolerance is occurring with stable insulin secretion but reduced insulin sensitivity.
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Affiliation(s)
- Johann Colomba
- Institut de Recherches Cliniques de Montréal, 110 avenue des Pins Ouest, Montréal H2W 1R7, Québec, Canada; Department of Nutrition, l'Université de Montréal, 2900 Boulevard Edouard-Montpetit, Montréal, QC H3T 1J4, Québec, Canada
| | - Valérie Boudreau
- Institut de Recherches Cliniques de Montréal, 110 avenue des Pins Ouest, Montréal H2W 1R7, Québec, Canada; Department of Nutrition, l'Université de Montréal, 2900 Boulevard Edouard-Montpetit, Montréal, QC H3T 1J4, Québec, Canada
| | - Catherine Lehoux-Dubois
- Institut de Recherches Cliniques de Montréal, 110 avenue des Pins Ouest, Montréal H2W 1R7, Québec, Canada; Department of Nutrition, l'Université de Montréal, 2900 Boulevard Edouard-Montpetit, Montréal, QC H3T 1J4, Québec, Canada
| | - Katherine Desjardins
- Institut de Recherches Cliniques de Montréal, 110 avenue des Pins Ouest, Montréal H2W 1R7, Québec, Canada
| | - Adèle Coriati
- Institut de Recherches Cliniques de Montréal, 110 avenue des Pins Ouest, Montréal H2W 1R7, Québec, Canada
| | - François Tremblay
- Cystic Fibrosis Clinic, Centre Hospitalier de l'Université de Montréal (CHUM), 1051 Rue Sanguinet, Montréal, QC H2X 3E4, Québec, Canada; Department of Medicine, Université de Montréal, 2900 Boulevard Edouard-Montpetit, Montréal, QC H3T 1J4, Québec, Canada
| | - Rémi Rabasa-Lhoret
- Institut de Recherches Cliniques de Montréal, 110 avenue des Pins Ouest, Montréal H2W 1R7, Québec, Canada; Department of Nutrition, l'Université de Montréal, 2900 Boulevard Edouard-Montpetit, Montréal, QC H3T 1J4, Québec, Canada; Cystic Fibrosis Clinic, Centre Hospitalier de l'Université de Montréal (CHUM), 1051 Rue Sanguinet, Montréal, QC H2X 3E4, Québec, Canada; Department of Medicine, Université de Montréal, 2900 Boulevard Edouard-Montpetit, Montréal, QC H3T 1J4, Québec, Canada.
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15
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Staufer K, Halilbasic E, Hillebrand P, Harm S, Schwarz S, Jaksch P, Kivaranovic D, Klepetko W, Trauner M, Kazemi-Shirazi L. Impact of nutritional status on pulmonary function after lung transplantation for cystic fibrosis. United European Gastroenterol J 2018; 6:1049-1055. [PMID: 30228893 DOI: 10.1177/2050640618778381] [Citation(s) in RCA: 12] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/26/2018] [Accepted: 04/25/2018] [Indexed: 12/17/2022] Open
Abstract
Background Nutritional status is an important prognostic factor in patients with cystic fibrosis (CF) prior to lung transplantation. Objective To investigate the impact of nutritional status on pulmonary function in CF transplant recipients. Methods Adult double lung transplanted CF patients were consecutively included. The predictive value of nutritional status on lung function - measured by spirometry - was longitudinally assessed by body composition serially evaluated by a three-compartment model bioelectrical impedance analysis (BIA) in comparison to body mass index (BMI). Results Overall, 147 spirometries and 147 BIAs were performed in 58 patients (59% female, median age: 30.1 years, median BMI: 19.6 kg/m2). Malnourished patients (BMI < 18.5 kg/m2; 27.6%) had a significantly reduced lung function compared to normal/overweight patients (forced expiratory volume in 1 second in percent (FEV1%pred), 57% vs 77%; p = 0.024). BMI, as well as the BIA parameters phase angle, total body water, fat free mass, body cell mass (BCM) and extracellular mass (ECM)/BCM ratio, were univariate predictors of FEV1%pred. When included in a linear mixed model, ECM/BCM ratio remained the only significant predictor of lung function (p = 0.012). Conclusion Nutritional status assessed by BIA predicted lung function in CF transplant recipients. Serial BIA measurements to monitor patients' nutritional status might help to improve or maintain lung function.
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Affiliation(s)
- Katharina Staufer
- Department of Surgery, Division of Transplantation, Medical University of Vienna, Vienna, Austria.,Department of Internal Medicine III, Division of Gastroenterology and Hepatology, Medical University of Vienna, Vienna, Austria
| | - Emina Halilbasic
- Department of Internal Medicine III, Division of Gastroenterology and Hepatology, Medical University of Vienna, Vienna, Austria
| | - Peter Hillebrand
- Department of Internal Medicine III, Division of Gastroenterology and Hepatology, Medical University of Vienna, Vienna, Austria
| | - Solveig Harm
- Department of Internal Medicine III, Division of Gastroenterology and Hepatology, Medical University of Vienna, Vienna, Austria
| | - Stefan Schwarz
- Department of Surgery, Division of Thoracic Surgery, Medical University of Vienna, Vienna, Austria
| | - Peter Jaksch
- Department of Surgery, Division of Thoracic Surgery, Medical University of Vienna, Vienna, Austria
| | - Danijel Kivaranovic
- Section for Medical Statistics, Centre for Medical Statistics, Informatics, and Intelligent Systems, Medical University of Vienna, Vienna, Austria
| | - Walter Klepetko
- Department of Surgery, Division of Thoracic Surgery, Medical University of Vienna, Vienna, Austria
| | - Michael Trauner
- Department of Internal Medicine III, Division of Gastroenterology and Hepatology, Medical University of Vienna, Vienna, Austria
| | - Lili Kazemi-Shirazi
- Department of Internal Medicine III, Division of Gastroenterology and Hepatology, Medical University of Vienna, Vienna, Austria
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16
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Santos-Carballal B, Fernández Fernández E, Goycoolea FM. Chitosan in Non-Viral Gene Delivery: Role of Structure, Characterization Methods, and Insights in Cancer and Rare Diseases Therapies. Polymers (Basel) 2018; 10:E444. [PMID: 30966479 PMCID: PMC6415274 DOI: 10.3390/polym10040444] [Citation(s) in RCA: 77] [Impact Index Per Article: 11.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/09/2018] [Revised: 04/04/2018] [Accepted: 04/11/2018] [Indexed: 12/23/2022] Open
Abstract
Non-viral gene delivery vectors have lagged far behind viral ones in the current pipeline of clinical trials of gene therapy nanomedicines. Even when non-viral nanovectors pose less safety risks than do viruses, their efficacy is much lower. Since the early studies to deliver pDNA, chitosan has been regarded as a highly attractive biopolymer to deliver nucleic acids intracellularly and induce a transgenic response resulting in either upregulation of protein expression (for pDNA, mRNA) or its downregulation (for siRNA or microRNA). This is explained as the consequence of a multi-step process involving condensation of nucleic acids, protection against degradation, stabilization in physiological conditions, cellular internalization, release from the endolysosome ("proton sponge" effect), unpacking and enabling the trafficking of pDNA to the nucleus or the siRNA to the RNA interference silencing complex (RISC). Given the multiple steps and complexity involved in the gene transfection process, there is a dearth of understanding of the role of chitosan's structural features (Mw and degree of acetylation, DA%) on each step that dictates the net transfection efficiency and its kinetics. The use of fully characterized chitosan samples along with the utilization of complementary biophysical and biological techniques is key to bridging this gap of knowledge and identifying the optimal chitosans for delivering a specific gene. Other aspects such as cell type and administration route are also at play. At the same time, the role of chitosan structural features on the morphology, size and surface composition of synthetic virus-like particles has barely been addressed. The ongoing revolution brought about by the recent discovery of CRISPR-Cas9 technology will undoubtedly be a game changer in this field in the short term. In the field of rare diseases, gene therapy is perhaps where the greatest potential lies and we anticipate that chitosans will be key players in the translation of research to the clinic.
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Affiliation(s)
| | - Elena Fernández Fernández
- Lung Biology Group, Department Clinical Microbiology, RCSI, Education and Research Centre, Beaumont Hospital, Dublin 9, Ireland.
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17
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Grulich-Henn J, Klose D. Understanding childhood diabetes mellitus: new pathophysiological aspects. J Inherit Metab Dis 2018; 41:19-27. [PMID: 29247329 DOI: 10.1007/s10545-017-0120-9] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/01/2017] [Accepted: 11/28/2017] [Indexed: 12/16/2022]
Abstract
Diabetes mellitus (DM) is not a single disease, but several pathophysiological conditions where synthesis, release, and/or action of insulin are disturbed. A progressive autoimmune/autoinflammatory destruction of islet cells is still considered the main pathophysiological event in the development of T1DM, but there is evidence that T1DM itself is a heterogeneous disease. More than 50 gene regions are closely associated with T1DM and a variety of epigenetic factors and metabolic patterns have been characterized, which may play a role in the development of T1DM. The pathogenesis and genetics of type 2 DM (T2DM) are distinct from T1DM. Genes associated with T2DM are distinct from those in T1DM. Characteristic metabolic patterns, different from those in T1DM were reported in T2DM, and some children with T2DM also express islet-antibodies. Huge progress has been made in the characterization of other specific types of DM, which had been considered very rare before. The molecular clarification of maturity-onset diabetes of the young (MODY) has greatly improved our understanding of the pathophysiology of DM. There are genetic overlaps between T2DM and monogenetic DM. Neonatal DM has been shown to be monogenetic in most cases, and genetic elucidation leads to more precise and individualized therapies. Cystic fibrosis related DM (CFRDM) should be considered a genuine part of cystic fibrosis, and not a complication, since pancreatic fibrosis does not sufficiently explain the pathophysiology of CFRDM. Disturbances of cystic fibrosis transmembrane conductance regulator (CFTR) as well as autoimmunity are involved in the pathogenesis of CFRDM.
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MESH Headings
- Adolescent
- Age of Onset
- Autoantibodies/immunology
- Autoimmunity
- Blood Glucose/metabolism
- Child
- Child, Preschool
- Cystic Fibrosis/epidemiology
- Cystic Fibrosis/genetics
- Cystic Fibrosis/metabolism
- Cystic Fibrosis/physiopathology
- Cystic Fibrosis Transmembrane Conductance Regulator/genetics
- Cystic Fibrosis Transmembrane Conductance Regulator/metabolism
- Diabetes Mellitus, Type 1/blood
- Diabetes Mellitus, Type 1/epidemiology
- Diabetes Mellitus, Type 1/genetics
- Diabetes Mellitus, Type 1/physiopathology
- Diabetes Mellitus, Type 2/blood
- Diabetes Mellitus, Type 2/epidemiology
- Diabetes Mellitus, Type 2/genetics
- Diabetes Mellitus, Type 2/physiopathology
- Energy Metabolism/genetics
- Genetic Predisposition to Disease
- Humans
- Infant
- Infant, Newborn
- Infant, Newborn, Diseases/blood
- Infant, Newborn, Diseases/epidemiology
- Infant, Newborn, Diseases/genetics
- Infant, Newborn, Diseases/physiopathology
- Insulin/blood
- Islets of Langerhans/immunology
- Islets of Langerhans/metabolism
- Islets of Langerhans/pathology
- Islets of Langerhans/physiopathology
- Risk Factors
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Affiliation(s)
- Juergen Grulich-Henn
- University Children´s Hospital, University of Heidelberg, Im Neuenheimer Feld 430, Heidelberg, D-69120, Germany.
| | - Daniela Klose
- University Children´s Hospital, University of Heidelberg, Im Neuenheimer Feld 430, Heidelberg, D-69120, Germany
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18
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Abstract
Cystic fibrosis (CF) is the most common autosomal recessive disorder in Caucasian populations. Individuals with CF have seen significant increases in life expectancy in the last 60 years. As a result, previously rare complications are now coming to light. The most common of these is cystic fibrosis-related diabetes (CFRD), which affects 40-50% of CF adults. CFRD significantly impacts the pulmonary function and longevity of CF patients, yet a lack of consensus on the best methods to diagnose and treat CFRD remains. We begin by reviewing our understanding of the pathogenesis of CFRD, as emerging evidence shows the cystic fibrosis transmembrane conductance regulator (CFTR) also has important roles in the release of insulin and glucagon and in the protection of β cells from oxidative stress. We then discuss how current recommended methods of CFRD diagnosis are not appropriate, as continuous glucose monitoring becomes more effective, practical, and cost-effective. Finally, we evaluate emerging treatments which have narrowed the mortality gap within the CF patient group. In the future, pharmacological potentiators and correctors directly targeting CFTR show huge promise for both CFRD and the wider CF patient groups.
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Affiliation(s)
- Kayani Kayani
- Faculty of Medicine, University of Cambridge, Cambridge, United Kingdom
| | - Raihan Mohammed
- Faculty of Medicine, University of Cambridge, Cambridge, United Kingdom
- *Correspondence: Raihan Mohammed,
| | - Hasan Mohiaddin
- Faculty of Medicine, Imperial College London, London, United Kingdom
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19
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Thomassen JC, Mueller MI, Alejandre Alcazar MA, Rietschel E, van Koningsbruggen-Rietschel S. Effect of Lumacaftor/Ivacaftor on glucose metabolism and insulin secretion in Phe508del homozygous cystic fibrosis patients. J Cyst Fibros 2017; 17:271-275. [PMID: 29249670 DOI: 10.1016/j.jcf.2017.11.016] [Citation(s) in RCA: 43] [Impact Index Per Article: 5.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/26/2017] [Revised: 10/27/2017] [Accepted: 11/29/2017] [Indexed: 12/31/2022]
Abstract
OBJECTIVE To investigate the effect of Lumacaftor/Ivacaftor on glucose metabolism and insulin secretion in patients with cystic fibrosis (CF) (Phe508del/Phe508del). METHODS A standard oral glucose tolerance test (OGTT) and an intravenous glucose tolerance test (IVGTT) were performed to investigate glucose metabolism and insulin secretion before and after 6-8weeks of treatment with Lumacaftor/Ivacaftor in 5 Phe508del-homozygous CF patients. The area under the curve (AUC) for glucose and insulin levels was calculated using the trapezoidal approximation. RESULTS 5 participants were investigated. Treatment with Lumacaftor/Ivacaftor was followed by an improvement of the 2h glucose levels in 3 patients and worsening in 2 patients. Analysis of the time course of blood glucose levels during OGTT revealed an increase of the AUC in 3 of 5 patients. In response to IVGTT, acute insulin secretion improved in 2 patients and worsened in 3. CONCLUSION The investigation could not demonstrate that treatment with Lumacaftor/Ivacaftor had a consistent impact on glucose tolerance and insulin secretion. Further adequately-powered studies examining glucose metabolism are needed to properly evaluate drug response in the endocrine pancreas and to test whether this treatment could eventually prevent the development of cystic fibrosis-related diabetes (CFRD).
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Affiliation(s)
- Jan C Thomassen
- CF Center, Children's Hospital, Faculty of Medicine, University of Cologne, Germany; Translational Experimental Pediatrics/Experimental Pulmonology, Children's Hospital, Faculty of Medicine, University of Cologne, Germany.
| | - Matthias I Mueller
- CF Center, Children's Hospital, Faculty of Medicine, University of Cologne, Germany
| | - Miguel A Alejandre Alcazar
- Translational Experimental Pediatrics/Experimental Pulmonology, Children's Hospital, Faculty of Medicine, University of Cologne, Germany
| | - Ernst Rietschel
- CF Center, Children's Hospital, Faculty of Medicine, University of Cologne, Germany
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20
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Lecube A, Simó R, Pallayova M, Punjabi NM, López-Cano C, Turino C, Hernández C, Barbé F. Pulmonary Function and Sleep Breathing: Two New Targets for Type 2 Diabetes Care. Endocr Rev 2017; 38:550-573. [PMID: 28938479 DOI: 10.1210/er.2017-00173] [Citation(s) in RCA: 57] [Impact Index Per Article: 7.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/26/2017] [Accepted: 08/29/2017] [Indexed: 02/07/2023]
Abstract
Population-based studies showing the negative impact of type 2 diabetes (T2D) on lung function are overviewed. Among the well-recognized pathophysiological mechanisms, the metabolic pathways related to insulin resistance (IR), low-grade chronic inflammation, leptin resistance, microvascular damage, and autonomic neuropathy are emphasized. Histopathological changes are exposed, and findings reported from experimental models are clearly differentiated from those described in humans. The accelerated decline in pulmonary function that appears in patients with cystic fibrosis (CF) with related abnormalities of glucose tolerance and diabetes is considered as an example to further investigate the relationship between T2D and the lung. Furthermore, a possible causal link between antihyperglycemic therapies and pulmonary function is examined. T2D similarly affects breathing during sleep, becoming an independent risk factor for higher rates of sleep apnea, leading to nocturnal hypoxemia and daytime sleepiness. Therefore, the impact of T2D on sleep breathing and its influence on sleep architecture is analyzed. Finally, the effect of improving some pathophysiological mechanisms, primarily IR and inflammation, as well as the optimization of blood glucose control on sleep breathing is evaluated. In summary, the lung should be considered by those providing care for people with diabetes and raise the central issue of whether the normalization of glucose levels can improve pulmonary function and ameliorate sleep-disordered breathing. Therefore, patients with T2D should be considered a vulnerable group for pulmonary dysfunction. However, further research aimed at elucidating how to screen for the lung impairment in the population with diabetes in a cost-effective manner is needed.
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Affiliation(s)
- Albert Lecube
- Endocrinology and Nutrition Department, Hospital Universitari Arnau de Vilanova, Institut de Recerca Biomédica de Lleida, Universitat de Lleida, Spain.,Centro de Investigación Biomédica en Red de Diabetes y Enfermedades Metabólicas Asociadas, Instituto de Salud Carlos III, Spain
| | - Rafael Simó
- Centro de Investigación Biomédica en Red de Diabetes y Enfermedades Metabólicas Asociadas, Instituto de Salud Carlos III, Spain.,Endocrinology and Nutrition Department, Hospital Universitari Vall d'Hebron, Diabetes and Metabolism Research Unit, Vall d'Hebron Institut de Recerca, Universitat Autònoma de Barcelona, Spain
| | - Maria Pallayova
- Department of Medicine, Weill Cornell Medicine.,Department of Human Physiology and Sleep Laboratory, Faculty of Medicine, Pavol Jozef Šafárik University, Slovak Republic
| | - Naresh M Punjabi
- Division of Pulmonary and Critical Care Medicine, Department of Medicine, Johns Hopkins University.,Department of Epidemiology, Bloomberg School of Public Health, Johns Hopkins University
| | - Carolina López-Cano
- Endocrinology and Nutrition Department, Hospital Universitari Arnau de Vilanova, Institut de Recerca Biomédica de Lleida, Universitat de Lleida, Spain
| | - Cecilia Turino
- Respiratory Department, Hospital Universitari Arnau de Vilanova-Santa María, Institut de Recerca Biomédica de Lleida, Universitat de Lleida, Spain
| | - Cristina Hernández
- Centro de Investigación Biomédica en Red de Diabetes y Enfermedades Metabólicas Asociadas, Instituto de Salud Carlos III, Spain.,Endocrinology and Nutrition Department, Hospital Universitari Vall d'Hebron, Diabetes and Metabolism Research Unit, Vall d'Hebron Institut de Recerca, Universitat Autònoma de Barcelona, Spain
| | - Ferran Barbé
- Respiratory Department, Hospital Universitari Arnau de Vilanova-Santa María, Institut de Recerca Biomédica de Lleida, Universitat de Lleida, Spain.,Centro de Investigación Biomédica en Red de Enfermedades Respiratorias, Instituto de Salud Carlos III, Spain
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21
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Huang WQ, Guo JH, Yuan C, Cui YG, Diao FY, Yu MK, Liu JY, Ruan YC, Chan HC. Abnormal CFTR Affects Glucagon Production by Islet α Cells in Cystic Fibrosis and Polycystic Ovarian Syndrome. Front Physiol 2017; 8:835. [PMID: 29204121 PMCID: PMC5698272 DOI: 10.3389/fphys.2017.00835] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/17/2017] [Accepted: 10/09/2017] [Indexed: 12/26/2022] Open
Abstract
Glucagon, produced by islet α cells, functions to increase blood glucose. Abnormal glucose levels are often seen in cystic fibrosis (CF), a systematic disease caused by mutations of the CF transmembrane conductance regulator (CFTR), and in polycystic ovarian syndrome (PCOS), an endocrine disorder featured with hyperandrogenism affecting 5-10% women of reproductive age. Here, we explored the role of CFTR in glucagon production in α cells and its possible contribution to glucagon disturbance in CF and PCOS. We found elevated fasting glucagon levels in CFTR mutant (DF508) mice compared to the wildtypes. Glucagon and prohormone convertase 2 (PC2) were also upregulated in CFTR inhibitor-treated or DF508 islets, as compared to the controls or wildtypes, respectively. Dihydrotestosterone (DHT)-induced PCOS rats exhibited significantly lower fasting glucagon levels with higher CFTR expression in α cells compared to that of controls. Treatment of mouse islets or αTC1-9 cells with DHT enhanced CFTR expression and reduced the levels of glucagon and PC2. The inhibitory effect of DHT on glucagon production was blocked by CFTR inhibitors in mouse islets, and mimicked by overexpressing CFTR in αTC1-9 cells with reduced phosphorylation of the cAMP/Ca2+ response element binding protein (p-CREB), a key transcription factor for glucagon and PC2. These results revealed a previously undefined role of CFTR in suppressing glucagon production in α-cells, defects in which may contribute to glucose metabolic disorder seen in CF and PCOS.
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Affiliation(s)
- Wen Qing Huang
- Epithelial Cell Biology Research Centre, School of Biomedical Sciences, Faculty of Medicine, The Chinese University of Hong Kong, Hong Kong, Hong Kong
| | - Jing Hui Guo
- Epithelial Cell Biology Research Centre, School of Biomedical Sciences, Faculty of Medicine, The Chinese University of Hong Kong, Hong Kong, Hong Kong
- Department of Pathophysiology, Key Laboratory of State Administration of Traditional Chinese Medicine of the People's Republic of China, School of Medicine, Jinan University, Guangzhou, China
| | - Chun Yuan
- State Key Laboratory of Reproductive Medicine, Clinical Center of Reproductive Medicine, First Affiliated Hospital, Nanjing Medical University, Nanjing, China
| | - Yu Gui Cui
- State Key Laboratory of Reproductive Medicine, Clinical Center of Reproductive Medicine, First Affiliated Hospital, Nanjing Medical University, Nanjing, China
| | - Fei Yang Diao
- State Key Laboratory of Reproductive Medicine, Clinical Center of Reproductive Medicine, First Affiliated Hospital, Nanjing Medical University, Nanjing, China
| | - Mei Kuen Yu
- Epithelial Cell Biology Research Centre, School of Biomedical Sciences, Faculty of Medicine, The Chinese University of Hong Kong, Hong Kong, Hong Kong
- Department of Biomedical Engineering, Faculty of Engineering, The Hong Kong Polytechnic University, Hong Kong, Hong Kong
| | - Jia Yin Liu
- State Key Laboratory of Reproductive Medicine, Clinical Center of Reproductive Medicine, First Affiliated Hospital, Nanjing Medical University, Nanjing, China
| | - Ye Chun Ruan
- Epithelial Cell Biology Research Centre, School of Biomedical Sciences, Faculty of Medicine, The Chinese University of Hong Kong, Hong Kong, Hong Kong
- Department of Biomedical Engineering, Faculty of Engineering, The Hong Kong Polytechnic University, Hong Kong, Hong Kong
| | - Hsiao Chang Chan
- Epithelial Cell Biology Research Centre, School of Biomedical Sciences, Faculty of Medicine, The Chinese University of Hong Kong, Hong Kong, Hong Kong
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22
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Sun X, Yi Y, Xie W, Liang B, Winter MC, He N, Liu X, Luo M, Yang Y, Ode KL, Uc A, Norris AW, Engelhardt JF. CFTR Influences Beta Cell Function and Insulin Secretion Through Non-Cell Autonomous Exocrine-Derived Factors. Endocrinology 2017; 158:3325-3338. [PMID: 28977592 PMCID: PMC5659686 DOI: 10.1210/en.2017-00187] [Citation(s) in RCA: 56] [Impact Index Per Article: 7.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/20/2017] [Accepted: 07/13/2017] [Indexed: 01/05/2023]
Abstract
Although β-cell dysfunction in cystic fibrosis (CF) leads to diabetes, the mechanism by which the cystic fibrosis transmembrane conductance regulator (CFTR) channel influences islet insulin secretion remains debated. We investigated the CFTR-dependent islet-autonomous mechanisms affecting insulin secretion by using islets isolated from CFTR knockout ferrets. Total insulin content was lower in CF as compared with wild-type (WT) islets. Furthermore, glucose-stimulated insulin secretion (GSIS) was impaired in perifused neonatal CF islets, with reduced first, second, and amplifying phase secretion. Interestingly, CF islets compensated for reduced insulin content under static low-glucose conditions by secreting a larger fraction of islet insulin than WT islets, probably because of elevated SLC2A1 transcripts, increased basal inhibition of adenosine triphosphate-sensitive potassium channels (K-ATP), and elevated basal intracellular Ca2+. Interleukin (IL)-6 secretion by CF islets was higher relative to WT, and IL-6 treatment of WT ferret islets produced a CF-like phenotype with reduced islet insulin content and elevated percentage insulin secretion in low glucose. CF islets exhibited altered expression of INS, CELA3B, and several β-cell maturation and proliferation genes. Pharmacologic inhibition of CFTR reduced GSIS by WT ferret and human islets but similarly reduced insulin secretion and intracellular Ca2+ in CFTR knockout ferret islets, indicating that the mechanism of action is not through CFTR. Single-molecule fluorescent in situ hybridization, on isolated ferret and human islets and ferret pancreas, demonstrated that CFTR RNA colocalized within KRT7+ ductal cells but not endocrine cells. These results suggest that CFTR affects β-cell function via a paracrine mechanism involving proinflammatory factors secreted from islet-associated exocrine-derived cell types.
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Affiliation(s)
- Xingshen Sun
- Anatomy and Cell Biology, University of Iowa, Iowa City, Iowa 52242
| | - Yaling Yi
- Anatomy and Cell Biology, University of Iowa, Iowa City, Iowa 52242
| | - Weiliang Xie
- Anatomy and Cell Biology, University of Iowa, Iowa City, Iowa 52242
| | - Bo Liang
- Anatomy and Cell Biology, University of Iowa, Iowa City, Iowa 52242
| | | | - Nan He
- Anatomy and Cell Biology, University of Iowa, Iowa City, Iowa 52242
| | - Xiaoming Liu
- Anatomy and Cell Biology, University of Iowa, Iowa City, Iowa 52242
| | - Meihui Luo
- Anatomy and Cell Biology, University of Iowa, Iowa City, Iowa 52242
| | - Yu Yang
- Anatomy and Cell Biology, University of Iowa, Iowa City, Iowa 52242
| | - Katie Larson Ode
- Department of Pediatrics, University of Iowa, Iowa City, Iowa 52242
- Fraternal Order of Eagles Diabetes Research Center, University of Iowa, Iowa City, Iowa 52242
| | - Aliye Uc
- Department of Pediatrics, University of Iowa, Iowa City, Iowa 52242
| | - Andrew W. Norris
- Department of Pediatrics, University of Iowa, Iowa City, Iowa 52242
- Fraternal Order of Eagles Diabetes Research Center, University of Iowa, Iowa City, Iowa 52242
| | - John F. Engelhardt
- Anatomy and Cell Biology, University of Iowa, Iowa City, Iowa 52242
- Fraternal Order of Eagles Diabetes Research Center, University of Iowa, Iowa City, Iowa 52242
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23
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Kessler L, Abély M. Atteinte pancréatique exocrine et endocrine dans la mucoviscidose. Arch Pediatr 2016; 23:12S21-12S32. [DOI: 10.1016/s0929-693x(17)30059-3] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/25/2022]
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24
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Litvin M, Nwachukwu S. Cystic Fibrosis Related Diabetes: a Unique Challenge in Diabetes Care. MISSOURI MEDICINE 2016; 113:384-389. [PMID: 30228505 PMCID: PMC6139848] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Subscribe] [Scholar Register] [Indexed: 06/08/2023]
Abstract
Cystic Fibrosis (CF) is a common autosomal recessive disease that affects multiple organs due to a defect in the gene encoding the cystic fibrosis transmembrane conductance regulator (CFTR). This transporter is present in various organs and tissues, including the airway epithelium, sinuses, pancreas, intestine, biliary tree, the vas deferens, and the sweat ducts, making CF a multi-system disease1. As CF patients are living longer, pancreatic function declines and diabetes emerges, further complicating the nutritional status and care of these patients.
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Affiliation(s)
- Marina Litvin
- Marina Litvin, MD, is an Assistant Professor, Division of Endocrinology, Metabolism, and Lipid Research, department of Medicine, Washington University School of Medicine, St. Louis
| | - Schola Nwachukwu
- Schola Nwachukwu, MD, is a Clinical Fellow, Division of Endocrinology, Metabolism, and Lipid Research, department of Medicine, Washington University School of Medicine, St. Louis
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25
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Abstract
Cystic fibrosis is frequently complicated by endocrine disorders. Diabetes can be expected to affect most with CF and pancreatic insufficiency and varies widely in age of onset, but early identification and treatment improve morbidity and mortality. Short stature can be exacerbated by relative delay of puberty and by use of inhaled corticosteroids. Bone disease in CF causes fragility fractures and should be assessed by monitoring bone mineral density and optimizing vitamin D status. Detecting and managing endocrine complications in CF can reduce morbidity and mortality in CF. These complications can be expected to become more common as the CF population ages.
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Affiliation(s)
- Scott M. Blackman
- Division of Pediatric Endocrinology, Department of Pediatrics, Johns Hopkins University and Johns Hopkins Hospital, Baltimore, MD
| | - Vin Tangpricha
- Division of Endocrinology, Metabolism and Lipids, Department of Medicine, Emory University School of Medicine and the Atlanta VA Medical Center, Atlanta, GA
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26
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Konrad K, Kapellen T, Lilienthal E, Prinz N, Bauer M, Thon A, Rietschel E, Wiemann D, Holl RW. Does β-Cell Autoimmunity Play a Role in Cystic Fibrosis-Related Diabetes? Analysis Based on the German/Austrian Diabetes Patienten Verlaufsdokumentation Registry. Diabetes Care 2016; 39:1338-44. [PMID: 27271187 DOI: 10.2337/dc16-0020] [Citation(s) in RCA: 15] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/05/2016] [Accepted: 05/03/2016] [Indexed: 02/03/2023]
Abstract
OBJECTIVE Research on β-cell autoimmunity in cystic fibrosis (CF)-related diabetes (CFRD) is still rare. We aimed to analyze the frequency of β-cell autoimmunity and the influence on age at diabetes onset, insulin requirement, type of insulin therapy, and hypoglycemic or ketoacidotic events in patients with CFRD compared with antibody-negative patients with CFRD in the Diabetes Patienten Verlaufsdokumentation (DPV) registry. RESEARCH DESIGN AND METHODS We analyzed data of 837 patients with CFRD in the German/Austrian DPV database by multivariable mixed-regression modeling. RESULTS In our cohort, 8.5% of patients with CFRD (n = 72) were found to be β-cell antibody positive. There was a female preponderance in this patient group: 65.3 vs. 57.6%. Diabetes onset (median [interquartile range]) was earlier (14.00 [10.15-15.90] vs. 16.10 [13.50-21.20] years; P < 0.005), and insulin dose/kg body weight was higher (0.95 [0.61-1.15] vs. 0.67 [0.33-1.04] IU/kg; P < 0.05). There were also differences in the type of insulin treatment. Insulin pump therapy was used significantly more often in patients with CFRD with β-cell autoimmunity (18.2 vs. 6.4%; P < 0.05). The differences for multiple daily injections (ICT) and conventional therapy (CT) were not significant (ICT: 67.7 vs. 79.0%; CT: 15.2 vs. 14.6). Oral antidiabetic agents were rarely used in both groups. Rate of severe hypoglycemia with coma and rate of ketoacidosis were higher in antibody-positive patients (hypoglycemia with coma: 8.0 vs. 1.4, P < 0.05; ketoacidosis: 9.3 vs. 0.9, P < 0.05). CONCLUSIONS Presence of β-cell autoantibodies in our cohort of patients with CFRD (8.5%) appeared to be greater than in the general population and was associated with female sex, earlier onset of diabetes, and higher insulin requirement. Insulin pump therapy was used significantly more often in patients with β-cell antibodies. Severe hypoglycemia and ketoacidosis were significantly more frequent in CFRD with β-cell autoimmunity compared with β-cell antibody-negative patients with CFRD.
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Affiliation(s)
- Katja Konrad
- Department of Pediatric and Adolescent Medicine, University of Cologne, Cologne, Germany Department of Pediatric and Adolescent Medicine, Elisabeth-Hospital Essen, Essen, Germany
| | - Thomas Kapellen
- Department of Pediatrics, University of Leipzig, Leipzig, Germany
| | | | - Nicole Prinz
- Institute of Epidemiology and Medical Biometry, University of Ulm, Ulm, Germany
| | - Maria Bauer
- Department of Pediatric and Adolescent Medicine, University of Linz, Linz, Austria
| | - Angelika Thon
- Department of Pediatrics, Hannover Medical School, Hannover, Germany
| | - Ernst Rietschel
- Department of Pediatric and Adolescent Medicine, University of Cologne, Cologne, Germany
| | - Dagobert Wiemann
- Department of Pediatrics, University of Magdeburg, Magdeburg, Germany
| | - Reinhard W Holl
- Institute of Epidemiology and Medical Biometry, University of Ulm, Ulm, Germany German Center for Diabetes Research, München-Neuherberg, Germany
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27
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Prentice B, Hameed S, Verge CF, Ooi CY, Jaffe A, Widger J. Diagnosing cystic fibrosis-related diabetes: current methods and challenges. Expert Rev Respir Med 2016; 10:799-811. [DOI: 10.1080/17476348.2016.1190646] [Citation(s) in RCA: 12] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/31/2022]
Affiliation(s)
- Bernadette Prentice
- Department of Respiratory Medicine, Sydney Children’s Hospital, Randwick, Australia
- School of Women’s and Children’s Health, The University of New South Wales, Randwick, Australia
| | - Shihab Hameed
- School of Women’s and Children’s Health, The University of New South Wales, Randwick, Australia
- Department of Endocrinology, Sydney Children’s Hospital, Randwick, Australia
| | - Charles F. Verge
- School of Women’s and Children’s Health, The University of New South Wales, Randwick, Australia
- Department of Endocrinology, Sydney Children’s Hospital, Randwick, Australia
| | - Chee Y. Ooi
- School of Women’s and Children’s Health, The University of New South Wales, Randwick, Australia
- Department of Gastroenterology, Sydney Children’s Hospital, Randwick, Australia
| | - Adam Jaffe
- Department of Respiratory Medicine, Sydney Children’s Hospital, Randwick, Australia
- School of Women’s and Children’s Health, The University of New South Wales, Randwick, Australia
| | - John Widger
- Department of Respiratory Medicine, Sydney Children’s Hospital, Randwick, Australia
- School of Women’s and Children’s Health, The University of New South Wales, Randwick, Australia
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28
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Coriati A, Ziai S, Lavoie A, Berthiaume Y, Rabasa-Lhoret R. The 1-h oral glucose tolerance test glucose and insulin values are associated with markers of clinical deterioration in cystic fibrosis. Acta Diabetol 2016. [PMID: 26215312 DOI: 10.1007/s00592-015-0791-3] [Citation(s) in RCA: 23] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 11/28/2022]
Abstract
AIMS Cystic fibrosis (CF) is associated with the emergence of CF-related diabetes (CFRD). CFRD is associated with increased risk of accelerated weight and/or lung function loss (clinical degradation). Data in the CF pediatric population reported an association between higher 60-min oral glucose tolerance test (OGTT) plasma glucose values and reduced lung function. Our objective was to evaluate the relationship between the 60-min OGTT insulin and glucose values and markers of clinical degradation in adult patients with CF. METHODS This study was based on an ongoing observational cohort of CF adult patients (≥18 years). All patients underwent a 2-h OGTT with 30-min interval sample measurements. Plasma insulin and glucose levels were measured. Adult patients (N = 240) were categorized based on the 60-min OGTT median values of glucose (G60, 11.0 mmol/L) and/or insulin (I60, 43.4 μU/mL). RESULTS A negative association was observed between the 60-min OGTT glucose value and pulmonary function (FEV1; P = 0.001), whereas 60-min OGTT insulin values were positively associated with BMI (P = 0.004). Patients with high G60 values displayed lower FEV1 than patients with low G60 values (P = 0.025). Patients with higher I60 values demonstrated higher values of both FEV1 (P = 0.022) and BMI (P = 0.003) than patients with low I60 values. More importantly, when adjusting for BMI, the difference in FEV1 between both groups no longer existed (P = 0.166). CONCLUSIONS Both insulin and glucose values at 60-min OGTT are associated with indicators of clinical degradation in adult patients with CF. Future prospective analyses are essential in establishing the clinical utility of these indicators.
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Affiliation(s)
- Adèle Coriati
- Institut de recherches cliniques de Montréal, 110 avenue des Pins Ouest, Montréal, QC, H2W 1R7, Canada.
- Department of Nutrition, Université de Montréal, Montréal, QC, H3T 1A8, Canada.
| | - Sophie Ziai
- Institut de recherches cliniques de Montréal, 110 avenue des Pins Ouest, Montréal, QC, H2W 1R7, Canada
- Department of Nutrition, Université de Montréal, Montréal, QC, H3T 1A8, Canada
| | - Annick Lavoie
- Cystic Fibrosis Clinic of the Centre hospitalier de l'Université de Montréal, Montréal, QC, H2W 1T8, Canada
| | - Yves Berthiaume
- Institut de recherches cliniques de Montréal, 110 avenue des Pins Ouest, Montréal, QC, H2W 1R7, Canada
- Cystic Fibrosis Clinic of the Centre hospitalier de l'Université de Montréal, Montréal, QC, H2W 1T8, Canada
- Department of Medicine, Université de Montréal, Montréal, QC, H3T 1J4, Canada
| | - Rémi Rabasa-Lhoret
- Institut de recherches cliniques de Montréal, 110 avenue des Pins Ouest, Montréal, QC, H2W 1R7, Canada
- Department of Nutrition, Université de Montréal, Montréal, QC, H3T 1A8, Canada
- Cystic Fibrosis Clinic of the Centre hospitalier de l'Université de Montréal, Montréal, QC, H2W 1T8, Canada
- Department of Medicine, Université de Montréal, Montréal, QC, H3T 1J4, Canada
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29
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Nyabam S, Wang Z, Thibault T, Oluseyi A, Basar R, Marshall L, Griffin M. A novel regulatory role for tissue transglutaminase in epithelial-mesenchymal transition in cystic fibrosis. BIOCHIMICA ET BIOPHYSICA ACTA-MOLECULAR CELL RESEARCH 2016; 1863:2234-44. [PMID: 27234323 DOI: 10.1016/j.bbamcr.2016.05.012] [Citation(s) in RCA: 21] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Received: 12/05/2015] [Revised: 05/15/2016] [Accepted: 05/17/2016] [Indexed: 01/23/2023]
Abstract
Cystic fibrosis (CF) is a genetic disorder caused by mutation of the cystic fibrosis transmembrane conductance regulator (CFTR) for which there is no overall effective treatment. Recent work indicates tissue transglutaminase (TG2) plays a pivotal intracellular role in proteostasis in CF epithelia and that the pan TG inhibitor cysteamine improves CFTR stability. Here we show TG2 has another role in CF pathology linked with TGFβ1 activation and signalling, induction of epithelial-mesenchymal transition (EMT), CFTR stability and induction of matrix deposition. We show that increased TG2 expression in normal and CF bronchial epithelial cells increases TGFβ1 levels, promoting EMT progression, and impairs tight junctions as measured by Transepithelial Electric Resistance (TEER) which can be reversed by selective inhibition of TG2 with an observed increase in CFTR stability. Our data indicate that selective inhibition of TG2 provides a potential therapeutic avenue for reducing fibrosis and increasing CFTR stability in CF.
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Affiliation(s)
- Samuel Nyabam
- School of Life and Health Sciences, Aston University, Aston Triangle, Birmingham B4 7ET, United Kingdom
| | - Zhuo Wang
- School of Life and Health Sciences, Aston University, Aston Triangle, Birmingham B4 7ET, United Kingdom.
| | - Thomas Thibault
- School of Life and Health Sciences, Aston University, Aston Triangle, Birmingham B4 7ET, United Kingdom
| | - Ayinde Oluseyi
- School of Life and Health Sciences, Aston University, Aston Triangle, Birmingham B4 7ET, United Kingdom
| | - Rameeza Basar
- School of Life and Health Sciences, Aston University, Aston Triangle, Birmingham B4 7ET, United Kingdom
| | - Lindsay Marshall
- School of Life and Health Sciences, Aston University, Aston Triangle, Birmingham B4 7ET, United Kingdom
| | - Martin Griffin
- School of Life and Health Sciences, Aston University, Aston Triangle, Birmingham B4 7ET, United Kingdom.
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30
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Gibson-Corley KN, Meyerholz DK, Engelhardt JF. Pancreatic pathophysiology in cystic fibrosis. J Pathol 2015; 238:311-20. [PMID: 26365583 DOI: 10.1002/path.4634] [Citation(s) in RCA: 85] [Impact Index Per Article: 8.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/30/2015] [Revised: 09/04/2015] [Accepted: 09/08/2015] [Indexed: 12/28/2022]
Abstract
The pancreas is one of the earliest, and most commonly affected, organs in patients with cystic fibrosis (CF). Studying the pathogenesis of pancreatic disease is limited in CF patients, due to its early clinical onset, co-morbidities and lack of tissue samples from the early phases of disease. In recent years, several new CF animal models have been developed that have advanced our understanding of both CF exocrine and endocrine pancreatic disease. Additionally, these models have helped us to better define the influence of pancreatic lesions on CF disease progression in other organs, such as the gastrointestinal tract and lung.
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Affiliation(s)
| | - David K Meyerholz
- Department of Pathology, Carver College of Medicine, University of Iowa, Iowa City, IA 52242, USA
| | - John F Engelhardt
- Department of Anatomy and Cell Biology, Carver College of Medicine, University of Iowa, Iowa City, IA 52242, USA
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31
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Franzese A, Mozzillo E, Fattorusso V, Raia V, Valerio G. Screening of glucose metabolism derangements in pediatric cystic fibrosis patients: how, when, why. Acta Diabetol 2015; 52:633-8. [PMID: 25863781 DOI: 10.1007/s00592-015-0743-y] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/08/2014] [Accepted: 03/14/2015] [Indexed: 10/23/2022]
Abstract
Diabetes mellitus is the most common comorbidity in cystic fibrosis (CF), occurring in a variable number of children and adolescents. Glucose metabolism derangements (GMDs) are responsible for a negative impact on the general health status of CF patients. Screening of GMDs is important since the youngest age and should be performed by means of OGTT, including its intermediate times, that could detect other non-traditional GMDs. Insulin treatment, administered before overt diabetes, could be beneficial in reducing the number of pulmonary infections, in improving both pulmonary function and nutritional status. Early screening of GMDs in pediatric age can exert an important preventing role regarding all aspects of health status of patients with CF.
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Affiliation(s)
- Adriana Franzese
- Department of Medical and Translational Medical Sciences, Section of Pediatrics, University of Naples "Federico II", Via S. Pansini 5, 80131, Naples, Italy,
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