{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,11,1]],"date-time":"2026-11-01T22:33:19Z","timestamp":1793572399209,"version":"4.5.0"},"reference-count":149,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2023,11,23]],"date-time":"2023-11-23T00:00:00Z","timestamp":1700697600000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":["frontiersin.org"],"crossmark-restriction":true},"short-container-title":["Front. Endocrinol."],"abstract":"<jats:p>\n                    Cystic fibrosis (CF) is a multi-organ disease caused by loss-of-function mutations in\n                    <jats:italic>CFTR<\/jats:italic>\n                    (which encodes the CF transmembrane conductance regulator ion channel). Cystic fibrosis related diabetes (CFRD) occurs in 40-50% of adults with CF and is associated with significantly increased morbidity and mortality. CFRD arises from insufficient insulin release from \u03b2 cells in the pancreatic islet, but the mechanisms underlying the loss of \u03b2 cell function remain understudied. Widespread pathological changes in the CF pancreas provide clues to these mechanisms. The exocrine pancreas is the epicenter of pancreas pathology in CF, with ductal pathology being the initiating event. Loss of CFTR function results in ductal plugging and subsequent obliteration. This in turn leads to destruction of acinar cells, fibrosis and fatty replacement. Despite this adverse environment, islets remain relatively well preserved. However, islet composition and arrangement are abnormal, including a modest decrease in \u03b2 cells and an increase in \u03b1, \u03b4 and \u03b3 cell abundance. The small amount of available data suggest that substantial loss of pancreatic\/islet microvasculature, autonomic nerve fibers and intra-islet macrophages occur. Conversely, T-cell infiltration is increased and, in CFRD, islet amyloid deposition is a frequent occurrence. Together, these pathological changes clearly demonstrate that CF is a disease of the pancreas\/islet microenvironment. Any or all of these changes are likely to have a dramatic effect on the \u03b2 cell, which relies on positive signals from all of these neighboring cell types for its normal function and survival. A thorough characterization of the CF pancreas microenvironment is needed to develop better therapies to treat, and ultimately prevent CFRD.\n                  <\/jats:p>","DOI":"10.3389\/fendo.2023.1269139","type":"journal-article","created":{"date-parts":[[2023,11,23]],"date-time":"2023-11-23T11:32:43Z","timestamp":1700739163000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":31,"title":["Pancreas and islet morphology in cystic fibrosis: clues to the etiology of cystic fibrosis-related diabetes"],"prefix":"10.3389","volume":"14","author":[{"given":"Sarah S.","family":"Malik","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Diksha","family":"Padmanabhan","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Rebecca L.","family":"Hull-Meichle","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1965","published-online":{"date-parts":[[2023,11,23]]},"reference":[{"key":"B1","doi-asserted-by":"publisher","DOI":"10.1016\/S0140-6736(16)00576-6","article-title":"Cystic fibrosis","volume":"388","author":"Elborn","year":"2016","journal-title":"Lancet"},{"key":"B2","doi-asserted-by":"publisher","first-page":"575","DOI":"10.1002\/humu.10041","article-title":"Cystic fibrosis: a worldwide analysis of CFTR mutations\u2013correlation with incidence data and application to screening","volume":"19","author":"Bobadilla","year":"2002","journal-title":"Hum Mutat"},{"key":"B3","unstructured":"Cystic Fibrosis Foundation Patient Registry Annual Data Report2021"},{"key":"B4","doi-asserted-by":"publisher","DOI":"10.1016\/0092-8674(93)90353-R","article-title":"Molecular mechanisms of CFTR chloride channel dysfunction in cystic fibrosis","volume":"73","author":"Welsh","year":"1993","journal-title":"Cell"},{"key":"B5","doi-asserted-by":"publisher","DOI":"10.2337\/dc09-0586","article-title":"Cystic fibrosis-related diabetes: current trends in prevalence, incidence, and mortality","volume":"32","author":"Moran","year":"2009","journal-title":"Diabetes Care"},{"key":"B6","doi-asserted-by":"publisher","DOI":"10.1016\/j.jcf.2019.03.007","article-title":"The impact of cystic fibrosis-related diabetes on health-related quality of life","volume":"18","author":"Kwong","year":"2019","journal-title":"J Cyst Fibros"},{"key":"B7","doi-asserted-by":"publisher","DOI":"10.1016\/j.jpeds.2004.12.039","article-title":"Epidemiology of cystic fibrosis-related diabetes","volume":"146","author":"Marshall","year":"2005","journal-title":"J Pediatr"},{"key":"B8","doi-asserted-by":"publisher","first-page":"194","DOI":"10.1164\/rccm.201403-0576OC","article-title":"Diabetes-related mortality in adults with cystic fibrosis","volume":"191","author":"Lewis","year":"2015","journal-title":"Role genotype Sex Am J Respir Crit Care Med"},{"key":"B9","doi-asserted-by":"publisher","DOI":"10.1016\/j.jcf.2019.10.009","article-title":"Cystic fibrosis related diabetes in Europe: Prevalence, risk factors and outcome","volume":"19","author":"Olesen","year":"2020","journal-title":"J Cyst Fibros"},{"key":"B10","doi-asserted-by":"publisher","DOI":"10.1016\/S0022-3476(05)80032-0","article-title":"Pancreatic endocrine function in cystic fibrosis","volume":"118","author":"Moran","year":"1991","journal-title":"J Pediatr"},{"key":"B11","doi-asserted-by":"publisher","DOI":"10.1016\/j.jcf.2014.06.004","article-title":"Disposition index identifies defective beta-cell function in cystic fibrosis subjects with normal glucose tolerance","volume":"14","author":"Merjaneh","year":"2015","journal-title":"J Cyst Fibros"},{"key":"B12","doi-asserted-by":"publisher","DOI":"10.1164\/rccm.201512-2518OC","article-title":"Abnormal glucose tolerance in infants and young children with cystic fibrosis","volume":"194","author":"Yi","year":"2016","journal-title":"Am J Respir Crit Care Med"},{"key":"B13","doi-asserted-by":"publisher","DOI":"10.2337\/db16-0394","article-title":"Reduced beta-cell secretory capacity in pancreatic-insufficient, but not pancreatic-sufficient, cystic fibrosis despite normal glucose tolerance","volume":"66","author":"Sheikh","year":"2017","journal-title":"Diabetes"},{"key":"B14","doi-asserted-by":"publisher","DOI":"10.1111\/pedi.12700","article-title":"Beta-cell secretory defects are present in pancreatic insufficient cystic fibrosis with 1-hour oral glucose tolerance test glucose \u2265155 mg\/dL","volume":"19","author":"Nyirjesy","year":"2018","journal-title":"Pediatr Diabetes"},{"key":"B15","doi-asserted-by":"publisher","DOI":"10.1111\/dme.14121","article-title":"Loss of incretin effect contributes to postprandial hyperglycaemia in cystic fibrosis-related diabetes","volume":"36","author":"Frost","year":"2019","journal-title":"Diabetes Med"},{"key":"B16","doi-asserted-by":"publisher","DOI":"10.2337\/db22-0399","article-title":"Effects of GLP-1 and GIP on islet function in glucose-intolerant, pancreatic-insufficient cystic fibrosis","volume":"71","author":"Nyirjesy","year":"2022","journal-title":"Diabetes"},{"key":"B17","doi-asserted-by":"publisher","DOI":"10.1172\/JCI115358","article-title":"Localization of the cystic fibrosis transmembrane conductance regulator in pancreas","volume":"88","author":"Marino","year":"1991","journal-title":"J Clin Invest"},{"key":"B18","doi-asserted-by":"publisher","first-page":"a009746","DOI":"10.1101\/cshperspect.a009746","article-title":"The cystic fibrosis of exocrine pancreas","volume":"3","author":"Wilschanski","year":"2013","journal-title":"Cold Spring Harb Perspect Med"},{"key":"B19","doi-asserted-by":"publisher","DOI":"10.3389\/fped.2022.914790","article-title":"The exocrine pancreas in cystic fibrosis in the era of CFTR modulation: A mini review","volume":"10","author":"McKay","year":"2022","journal-title":"Front Pediatr"},{"key":"B20","doi-asserted-by":"publisher","first-page":"294","DOI":"10.5858\/arpa.2022-0202-RA","article-title":"Acute and chronic alcoholic pancreatitis, including paraduodenal pancreatitis","volume":"147","author":"Kloppel","year":"2023","journal-title":"Arch Pathol Lab Med"},{"key":"B21","doi-asserted-by":"publisher","DOI":"10.3389\/fphys.2012.00344","article-title":"Pancreatic stellate cells: a starring role in normal and diseased pancreas","volume":"3","author":"Apte","year":"2012","journal-title":"Front Physiol"},{"key":"B22","doi-asserted-by":"publisher","DOI":"10.1016\/j.cgh.2009.07.038","article-title":"Roles of pancreatic stellate cells in pancreatic inflammation and fibrosis","volume":"7","author":"Masamune","year":"2009","journal-title":"Clin Gastroenterol Hepatol"},{"key":"B23","first-page":"697","article-title":"Quantitative evaluation of the development of the exocrine pancreas in cystic fibrosis and control infants","volume":"95","author":"Imrie","year":"1979","journal-title":"Am J Pathol"},{"key":"B24","doi-asserted-by":"publisher","first-page":"17231","DOI":"10.1038\/s41598-017-17404-z","article-title":"Structural abnormalities in islets from very young children with cystic fibrosis may contribute to cystic fibrosis-related diabetes","volume":"7","author":"Bogdani","year":"2017","journal-title":"Sci Rep"},{"key":"B25","doi-asserted-by":"publisher","first-page":"e096","DOI":"10.1097\/PG9.0000000000000096","article-title":"Acute pancreatitis in a previously exocrine pancreatic insufficient cystic fibrosis patient who had improved pancreatic function after being treated with lumacaftor\/ivacaftor","volume":"2","author":"Redman","year":"2021","journal-title":"JPGN Rep"},{"key":"B26","doi-asserted-by":"publisher","DOI":"10.1111\/j.1464-5491.2009.02738.x","article-title":"Mechanisms of glucose intolerance in cystic fibrosis","volume":"26","author":"Mohan","year":"2009","journal-title":"Diabetes Med"},{"key":"B27","doi-asserted-by":"publisher","DOI":"10.1530\/JOE-18-0570","article-title":"Defective exocytosis and processing of insulin in a cystic fibrosis mouse model","volume":"241","author":"Edlund","year":"2019","journal-title":"J Endocrinol"},{"key":"B28","article-title":"Islets of Langerhans in adolescents and adults with cystic fibrosis. A quantitative study","volume":"110","author":"Abdul-Karim","year":"1986","journal-title":"Arch Pathol Lab Med"},{"key":"B29","doi-asserted-by":"publisher","DOI":"10.1210\/jcem.81.3.8772610","article-title":"Diabetes mellitus in cystic fibrosis is characterized by islet amyloidosis","volume":"81","author":"Couce","year":"1996","journal-title":"J Clin Endocrinol Metab"},{"key":"B30","doi-asserted-by":"publisher","DOI":"10.1172\/jci.insight.98240","article-title":"Cystic fibrosis-related diabetes is caused by islet loss and inflammation","volume":"3","author":"Hart","year":"2018","journal-title":"JCI Insight"},{"key":"B31","doi-asserted-by":"publisher","DOI":"10.1007\/BF00718598","article-title":"Cystic fibrosis associated islet changes may provide a basis for diabetes. An immunocytochemical and morphometrical study","volume":"414","author":"Lohr","year":"1989","journal-title":"Virchows Arch A Pathol Anat Histopathol"},{"key":"B32","doi-asserted-by":"publisher","DOI":"10.2337\/dc17-1387","article-title":"Islet interleukin-1beta immunoreactivity is an early feature of cystic fibrosis that may contribute to beta-cell failure","volume":"41","author":"Hull","year":"2018","journal-title":"Diabetes Care"},{"key":"B33","doi-asserted-by":"publisher","DOI":"10.1016\/S0046-8177(84)80191-4","article-title":"Endocrine pancreas in cystic fibrosis: an immunohistochemical study","volume":"15","author":"Iannucci","year":"1984","journal-title":"Hum Pathol"},{"key":"B34","doi-asserted-by":"publisher","first-page":"25","DOI":"10.3109\/15513818609025923","article-title":"Pancreatic islets in older patients with cystic fibrosis with and without diabetes mellitus: morphometric and immunocytologic studies","volume":"6","author":"Soejima","year":"1986","journal-title":"Pediatr Pathol"},{"key":"B35","doi-asserted-by":"publisher","DOI":"10.1111\/dom.12727","article-title":"Pancreatic beta-cell identity in diabetes","author":"Remedi","year":"2016","journal-title":"Diabetes Obes Metab"},{"key":"B36","doi-asserted-by":"publisher","DOI":"10.1074\/jbc.274.20.14112","article-title":"Chronic hyperglycemia triggers loss of pancreatic beta cell differentiation in an animal model of diabetes","volume":"274","author":"Jonas","year":"1999","journal-title":"J Biol Chem"},{"key":"B37","doi-asserted-by":"publisher","DOI":"10.1210\/endrev\/bnab010","article-title":"The human islet: mini-organ with mega-impact","volume":"42","author":"Walker","year":"2021","journal-title":"Endocr Rev"},{"key":"B38","doi-asserted-by":"publisher","DOI":"10.1210\/js.2018-00143","article-title":"An increase in chromogranin A-positive, hormone-negative endocrine cells in pancreas in cystic fibrosis","volume":"2","author":"Cory","year":"2018","journal-title":"J Endocr Soc"},{"key":"B39","doi-asserted-by":"publisher","DOI":"10.1177\/193229681000400607","article-title":"The physiology of glucagon","volume":"4","author":"Taborsky","year":"2010","journal-title":"J Diabetes Sci Technol"},{"key":"B40","doi-asserted-by":"publisher","DOI":"10.1007\/s00125-023-05947-y","article-title":"100 years of glucagon and 100 more","volume":"66","author":"Wewer Albrechtsen","year":"2023","journal-title":"Diabetologia"},{"key":"B41","doi-asserted-by":"publisher","DOI":"10.1007\/s00125-020-05096-6","article-title":"Impaired counterregulatory responses to hypoglycaemia following oral glucose in adults with cystic fibrosis","volume":"63","author":"Aitken","year":"2020","journal-title":"Diabetologia"},{"key":"B42","doi-asserted-by":"publisher","DOI":"10.3390\/biology10020074","article-title":"delta-cells: the neighborhood watch in the islet community","volume":"10","author":"Gao","year":"2021","journal-title":"Biol (Basel)"},{"key":"B43","doi-asserted-by":"publisher","DOI":"10.1136\/adc.68.1.123","article-title":"Preservation of somatostatin secretion in cystic fibrosis patients with diabetes","volume":"68","author":"Meacham","year":"1993","journal-title":"Arch Dis Child"},{"key":"B44","doi-asserted-by":"publisher","DOI":"10.1097\/MCO.0b013e328365b9be","article-title":"Ghrelin: much more than a hunger hormone","volume":"16","author":"Pradhan","year":"2013","journal-title":"Curr Opin Clin Nutr Metab Care"},{"key":"B45","doi-asserted-by":"publisher","DOI":"10.5114\/aoms.2012.28599","article-title":"Plasma ghrelin levels in children with cystic fibrosis and healthy children","volume":"9","author":"Monajemzadeh","year":"2013","journal-title":"Arch Med Sci"},{"key":"B46","doi-asserted-by":"publisher","DOI":"10.1101\/gad.235499.113","article-title":"The diabetes gene Hhex maintains delta-cell differentiation and islet function","volume":"28","author":"Zhang","year":"2014","journal-title":"Genes Dev"},{"key":"B47","doi-asserted-by":"publisher","DOI":"10.1210\/er.2009-0035","article-title":"The role of blood vessels, endothelial cells, and vascular pericytes in insulin secretion and peripheral insulin action","volume":"31","author":"Richards","year":"2010","journal-title":"Endocr Rev"},{"key":"B48","doi-asserted-by":"publisher","first-page":"3","DOI":"10.2337\/db13-0617","article-title":"The beta-cell\/EC axis: how do islet cells talk to each other","volume":"63","author":"Peiris","year":"2014","journal-title":"Diabetes"},{"key":"B49","doi-asserted-by":"publisher","DOI":"10.1007\/s00125-017-4272-9","article-title":"The islet endothelial cell: a novel contributor to beta cell secretory dysfunction in diabetes","volume":"60","author":"Hogan","year":"2017","journal-title":"Diabetologia"},{"key":"B50","doi-asserted-by":"publisher","first-page":"799","DOI":"10.1002\/cphy.c160050","article-title":"Pancreatic blood flow with special emphasis on blood perfusion of the islets of Langerhans","volume":"9","author":"Jansson","year":"2019","journal-title":"Compr Physiol"},{"key":"B51","doi-asserted-by":"publisher","DOI":"10.1210\/en.2005-0997","article-title":"Islet endothelial cells and pancreatic beta-cell proliferation: studies in vitro and during pregnancy in adult rats","volume":"147","author":"Johansson","year":"2006","journal-title":"Endocrinology"},{"key":"B52","doi-asserted-by":"publisher","first-page":"397","DOI":"10.1016\/j.devcel.2006.01.015","article-title":"The vascular basement membrane: a niche for insulin gene expression and Beta cell proliferation","volume":"10","author":"Nikolova","year":"2006","journal-title":"Dev Cell"},{"key":"B53","doi-asserted-by":"publisher","DOI":"10.1007\/s00125-009-1485-6","article-title":"Endothelial cell signalling supports pancreatic beta cell function in the rat","volume":"52","author":"Johansson","year":"2009","journal-title":"Diabetologia"},{"key":"B54","doi-asserted-by":"publisher","DOI":"10.1016\/j.devcel.2016.10.003","article-title":"Neurotrophin signaling Is required for glucose-induced insulin secretion","volume":"39","author":"Houtz","year":"2016","journal-title":"Dev Cell"},{"key":"B55","doi-asserted-by":"publisher","first-page":"293","DOI":"10.1210\/en.2016-1393","article-title":"Markers of islet endothelial dysfunction occur in male B6.BKS(D)-Leprdb\/J mice and may contribute to reduced insulin release","volume":"158","author":"Hogan","year":"2017","journal-title":"Endocrinology"},{"key":"B56","doi-asserted-by":"publisher","DOI":"10.2337\/db17-0697","article-title":"Pancreatic pericytes support beta-cell function in a Tcf7l2-dependent manner","volume":"67","author":"Sakhneny","year":"2018","journal-title":"Diabetes"},{"key":"B57","doi-asserted-by":"publisher","first-page":"2378","DOI":"10.1038\/s41598-021-81774-8","article-title":"Pericytes contribute to the islet basement membranes to promote beta-cell gene expression","volume":"11","author":"Sakhneny","year":"2021","journal-title":"Sci Rep"},{"key":"B58","doi-asserted-by":"publisher","DOI":"10.1369\/0022155415573324","article-title":"Human islets have fewer blood vessels than mouse islets and the density of islet vascular structures is increased in type 2 diabetes","volume":"63","author":"Brissova","year":"2015","journal-title":"J Histochem Cytochem"},{"key":"B59","doi-asserted-by":"publisher","DOI":"10.1369\/0022155418778546","article-title":"Islet microvasculature alterations with loss of beta-cells in patients with type 1 diabetes","author":"Canzano","year":"2018","journal-title":"J Histochem Cytochem"},{"key":"B60","doi-asserted-by":"publisher","DOI":"10.1371\/journal.pone.0006963","article-title":"Islet endothelial activation and oxidative stress gene expression is reduced by IL-1Ra treatment in the type 2 diabetic GK rat","volume":"4","author":"Lacraz","year":"2009","journal-title":"PloS One"},{"key":"B61","doi-asserted-by":"publisher","DOI":"10.1007\/s00125-022-05756-9","article-title":"Islet amyloid polypeptide aggregation exerts cytotoxic and proinflammatory effects on the islet vasculature in mice","volume":"65","author":"Castillo","year":"2022","journal-title":"Diabetologia"},{"key":"B62","doi-asserted-by":"publisher","first-page":"13-OR","DOI":"10.2337\/db22-13-OR","article-title":"13-OR: Cystic fibrosis donors exhibit striking decrease in pancreatic islet and exocrine capillaries","volume":"71","author":"Castillo","year":"2022","journal-title":"Diabetes"},{"key":"B63","doi-asserted-by":"publisher","first-page":"630","DOI":"10.1016\/j.cmet.2018.02.016","article-title":"The pericyte of the pancreatic islet regulates capillary diameter and local blood flow","volume":"27","author":"Almaca","year":"2018","journal-title":"Cell Metab"},{"key":"B64","doi-asserted-by":"publisher","first-page":"27","DOI":"10.1007\/978-3-030-11093-2_2","article-title":"Pancreatic pericytes in glucose homeostasis and diabetes","volume":"1122","author":"Landsman","year":"2019","journal-title":"Adv Exp Med Biol"},{"key":"B65","doi-asserted-by":"publisher","DOI":"10.1007\/s00125-020-05168-7","article-title":"Islet pericytes convert into profibrotic myofibroblasts in a mouse model of islet vascular fibrosis","volume":"63","author":"Mateus Goncalves","year":"2020","journal-title":"Diabetologia"},{"key":"B66","doi-asserted-by":"publisher","first-page":"393","DOI":"10.1007\/s001250051322","article-title":"Autonomic regulation of islet hormone secretion\u2013implications for health and disease","volume":"43","author":"Ahren","year":"2000","journal-title":"Diabetologia"},{"key":"B67","doi-asserted-by":"publisher","DOI":"10.1007\/s00125-022-05691-9","article-title":"Unravelling innervation of pancreatic islets","volume":"65","author":"Hampton","year":"2022","journal-title":"Diabetologia"},{"key":"B68","doi-asserted-by":"publisher","DOI":"10.1042\/CS20140059","article-title":"Glycaemic regulation and insulin secretion are abnormal in cystic fibrosis pigs despite sparing of islet cell mass","volume":"128","author":"Uc","year":"2015","journal-title":"Clin Sci (Lond)"},{"key":"B69","doi-asserted-by":"publisher","first-page":"14","DOI":"10.1172\/JCI88877","article-title":"Islet inflammation in type 2 diabetes and physiology","volume":"127","author":"Eguchi","year":"2017","journal-title":"J Clin Invest"},{"key":"B70","doi-asserted-by":"publisher","DOI":"10.2337\/db07-1577","article-title":"Critical roles for macrophages in islet angiogenesis and maintenance during pancreatic degeneration","volume":"57","author":"Tessem","year":"2008","journal-title":"Diabetes"},{"key":"B71","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.1321347111","article-title":"M2 macrophages promote beta-cell proliferation by up-regulation of SMAD7","volume":"111","author":"Xiao","year":"2014","journal-title":"Proc Natl Acad Sci USA"},{"key":"B72","doi-asserted-by":"publisher","first-page":"498","DOI":"10.1016\/j.cmet.2014.02.001","article-title":"Islet microenvironment, modulated by vascular endothelial growth factor-A signaling, promotes beta cell regeneration","volume":"19","author":"Brissova","year":"2014","journal-title":"Cell Metab"},{"key":"B73","doi-asserted-by":"publisher","DOI":"10.1172\/jci.insight.93834","article-title":"A CCR2+ myeloid cell niche required for pancreatic beta cell growth","volume":"2","author":"Mussar","year":"2017","journal-title":"JCI Insight"},{"key":"B74","doi-asserted-by":"publisher","DOI":"10.1152\/ajpendo.00248.2019","article-title":"Islet macrophages are associated with islet vascular remodeling and compensatory hyperinsulinemia during diabetes","volume":"317","author":"Chittezhath","year":"2019","journal-title":"Am J Physiol Endocrinol Metab"},{"key":"B75","doi-asserted-by":"publisher","first-page":"100775","DOI":"10.1016\/j.isci.2019.100775","article-title":"Islet macrophages shift to a reparative state following pancreatic beta-cell death and are a major source of islet insulin-like growth factor-1","volume":"23","author":"Nackiewicz","year":"2020","journal-title":"iScience"},{"key":"B76","doi-asserted-by":"publisher","DOI":"10.1210\/jc.2004-0405","article-title":"Islet amyloid: a critical entity in the pathogenesis of type 2 diabetes","volume":"89","author":"Hull","year":"2004","journal-title":"J Clin Endocrinol Metab"},{"key":"B77","article-title":"Hyalinization of the islets of Langerhans in nondiabetic individuals","volume":"35","author":"Bell","year":"1959","journal-title":"Am J Pathol"},{"key":"B78","doi-asserted-by":"publisher","first-page":"87","DOI":"10.1186\/1741-7015-12-87","article-title":"CFTR and Anoctamin 1 (ANO1) contribute to cAMP amplified exocytosis and insulin secretion in human and murine pancreatic beta-cells","volume":"12","author":"Edlund","year":"2014","journal-title":"BMC Med"},{"key":"B79","doi-asserted-by":"publisher","first-page":"4420","DOI":"10.1038\/ncomms5420","article-title":"Glucose-induced electrical activities and insulin secretion in pancreatic islet beta-cells are modulated by CFTR","volume":"5","author":"Guo","year":"2014","journal-title":"Nat Commun"},{"key":"B80","doi-asserted-by":"publisher","DOI":"10.1152\/ajpendo.00333.2015","article-title":"CFTR silencing in pancreatic beta-cells reveals a functional impact on glucose-stimulated insulin secretion and oxidative stress response","volume":"310","author":"Ntimbane","year":"2016","journal-title":"Am J Physiol Endocrinol Metab"},{"key":"B81","doi-asserted-by":"publisher","first-page":"197","DOI":"10.1007\/s12020-007-9026-x","article-title":"Expression and localization of cystic fibrosis transmembrane conductance regulator in the rat endocrine pancreas","volume":"32","author":"Boom","year":"2007","journal-title":"Endocrine"},{"key":"B82","doi-asserted-by":"publisher","DOI":"10.1210\/en.2017-00187","article-title":"CFTR influences beta cell function and insulin secretion through non-cell autonomous exocrine-derived factors","volume":"158","author":"Sun","year":"2017","journal-title":"Endocrinology"},{"key":"B83","doi-asserted-by":"crossref","first-page":"1260419","DOI":"10.1126\/science.1260419","article-title":"Proteomics. Tissue-based map of the human proteome","volume":"347","author":"Uhlen","year":"2015","journal-title":"Science"},{"key":"B84","doi-asserted-by":"publisher","DOI":"10.1210\/clinem\/dgz209","article-title":"In situ analysis reveals that CFTR is expressed in only a small minority of beta-cells in normal adult human pancreas","volume":"105","author":"White","year":"2019","journal-title":"J Clin Endocrinol Metab"},{"key":"B85","doi-asserted-by":"publisher","DOI":"10.1530\/JOE-18-0468","article-title":"Survival in a bad neighborhood: pancreatic islets in cystic fibrosis","volume":"241","author":"Norris","year":"2019","journal-title":"J Endocrinol"},{"key":"B86","doi-asserted-by":"publisher","DOI":"10.1369\/jhc.5R6640.2005","article-title":"Association between endocrine pancreas and ductal system. More than an epiphenomenon of endocrine differentiation and development","volume":"53","author":"Bertelli","year":"2005","journal-title":"J Histochem Cytochem"},{"key":"B87","doi-asserted-by":"publisher","DOI":"10.1210\/en.2015-1175","article-title":"Intraislet pancreatic ducts can give rise to insulin-positive cells","volume":"157","author":"El-Gohary","year":"2016","journal-title":"Endocrinology"},{"key":"B88","doi-asserted-by":"publisher","DOI":"10.1210\/en.2017-03076","article-title":"Three-dimensional analysis of the human pancreas","volume":"159","author":"Fowler","year":"2018","journal-title":"Endocrinology"},{"key":"B89","doi-asserted-by":"publisher","DOI":"10.3892\/ijmm.12.6.851","article-title":"Effects of cryopreservation and coculture with pancreatic ductal epithelial cells on insulin secretion from human pancreatic islets","volume":"12","author":"Gatto","year":"2003","journal-title":"Int J Mol Med"},{"key":"B90","doi-asserted-by":"publisher","DOI":"10.1007\/s00125-008-1247-x","article-title":"Sustained insulin secretory response in human islets co-cultured with pancreatic duct-derived epithelial cells within a rotational cell culture system","volume":"52","author":"Murray","year":"2009","journal-title":"Diabetologia"},{"key":"B91","doi-asserted-by":"publisher","DOI":"10.2337\/diabetes.53.12.3107","article-title":"Islet graft assessment in the Edmonton Protocol: implications for predicting long-term clinical outcome","volume":"53","author":"Street","year":"2004","journal-title":"Diabetes"},{"key":"B92","doi-asserted-by":"publisher","DOI":"10.5661\/bger-28-101","article-title":"The potential benefit of non-purified islets preparations for islet transplantation","volume":"28","author":"Webb","year":"2012","journal-title":"Biotechnol Genet Eng Rev"},{"key":"B93","doi-asserted-by":"publisher","DOI":"10.1111\/ajt.14514","article-title":"Purity of islet preparations and 5-year metabolic outcome of allogenic islet transplantation","volume":"18","author":"Benomar","year":"2018","journal-title":"Am J Transplant"},{"key":"B94","doi-asserted-by":"publisher","DOI":"10.1371\/journal.pone.0220064","article-title":"Pancreatic ductal cells may have a negative effect on human islet transplantation","volume":"14","author":"Marin-Canas","year":"2019","journal-title":"PloS One"},{"key":"B95","doi-asserted-by":"publisher","first-page":"3124","DOI":"10.1038\/s41467-019-11178-w","article-title":"Patient-derived pancreas-on-a-chip to model cystic fibrosis-related disorders","volume":"10","author":"Shik Mun","year":"2019","journal-title":"Nat Commun"},{"key":"B96","doi-asserted-by":"publisher","DOI":"10.1038\/labinvest.2008.87","article-title":"Characterization of pancreatic ductal cells in human islet preparations","volume":"88","author":"Ichii","year":"2008","journal-title":"Lab Invest"},{"key":"B97","doi-asserted-by":"publisher","DOI":"10.1001\/archsurg.140.8.735","article-title":"Improved human pancreatic islet isolation for a prospective cohort study of islet transplantation vs best medical therapy in type 1 diabetes mellitus","volume":"140","author":"Warnock","year":"2005","journal-title":"Arch Surg"},{"key":"B98","doi-asserted-by":"publisher","first-page":"593","DOI":"10.1016\/j.cmet.2016.08.020","article-title":"Single-cell transcriptome profiling of human pancreatic islets in health and type 2 diabetes","volume":"24","author":"Segerstolpe","year":"2016","journal-title":"Cell Metab"},{"key":"B99","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.0608141103","article-title":"Correlation between beta cell mass and glycemic control in type 1 diabetic recipients of islet cell graft","volume":"103","author":"Keymeulen","year":"2006","journal-title":"Proc Natl Acad Sci USA"},{"key":"B100","doi-asserted-by":"publisher","DOI":"10.1124\/jpet.109.162032","article-title":"Cystic fibrosis transmembrane regulator inhibitors CFTR(inh)-172 and GlyH-101 target mitochondrial functions, independently of chloride channel inhibition","volume":"333","author":"Kelly","year":"2010","journal-title":"J Pharmacol Exp Ther"},{"key":"B101","doi-asserted-by":"publisher","DOI":"10.1111\/bph.12726","article-title":"Revisiting CFTR inhibition: a comparative study of CFTRinh -172 and GlyH-101 inhibitors","volume":"171","author":"Melis","year":"2014","journal-title":"Br J Pharmacol"},{"key":"B102","doi-asserted-by":"publisher","DOI":"10.3389\/fphar.2017.00328","article-title":"Comparative effects of chloride channel inhibitors on LRRC8\/VRAC-mediated chloride conductance","volume":"8","author":"Friard","year":"2017","journal-title":"Front Pharmacol"},{"key":"B103","doi-asserted-by":"publisher","DOI":"10.1136\/gutjnl-2016-312423","article-title":"Human pluripotent stem cell-derived acinar\/ductal organoids generate human pancreas upon orthotopic transplantation and allow disease modelling","volume":"66","author":"Hohwieler","year":"2017","journal-title":"Gut"},{"key":"B104","doi-asserted-by":"publisher","DOI":"10.1016\/j.jcf.2021.04.010","article-title":"Lack of CFTR alters the ferret pancreatic ductal epithelial secretome and cellular proteome: Implications for exocrine\/endocrine signaling","volume":"21","author":"Rotti","year":"2022","journal-title":"J Cyst Fibros"},{"key":"B105","doi-asserted-by":"publisher","first-page":"18","DOI":"10.1186\/1471-2172-12-18","article-title":"Toll-like receptor 4 (TLR4) expression in human and murine pancreatic beta-cells affects cell viability and insulin homeostasis","volume":"12","author":"Garay-Malpartida","year":"2011","journal-title":"BMC Immunol"},{"key":"B106","doi-asserted-by":"publisher","DOI":"10.1371\/journal.pone.0036200","article-title":"Lipopolysaccharides impair insulin gene expression in isolated islets of Langerhans via Toll-Like Receptor-4 and NF-kappaB signalling","volume":"7","author":"Amyot","year":"2012","journal-title":"PloS One"},{"key":"B107","doi-asserted-by":"publisher","DOI":"10.1371\/journal.pone.0143589","article-title":"Can CD44 be a mediator of cell destruction? The challenge of type 1 diabetes","volume":"10","author":"Assayag-Asherie","year":"2015","journal-title":"PloS One"},{"key":"B108","doi-asserted-by":"publisher","DOI":"10.1172\/jci.insight.89590","article-title":"Beta cell-specific increased expression of calpastatin prevents diabetes induced by islet amyloid polypeptide toxicity","volume":"1","author":"Gurlo","year":"2016","journal-title":"JCI Insight"},{"key":"B109","doi-asserted-by":"publisher","DOI":"10.1021\/acs.jproteome.9b00441","article-title":"Multiorgan systems study reveals Igfbp7 as a suppressor of gluconeogenesis after gastric bypass surgery","volume":"19","author":"Arima","year":"2020","journal-title":"J Proteome Res"},{"key":"B110","doi-asserted-by":"publisher","first-page":"58","DOI":"10.1016\/0021-9681(58)90185-1","article-title":"Cystic fibrosis of the pancreas","volume":"7","author":"Andersen","year":"1958","journal-title":"J Chronic Dis"},{"key":"B111","doi-asserted-by":"publisher","first-page":"199","DOI":"10.1111\/j.1365-2362.1972.tb00645.x","article-title":"The role of insulin in the regulation of alpha-amylase synthesis in the rat pancreas","volume":"2","author":"S\u00f6ling","year":"1972","journal-title":"Eur J Clin Invest"},{"key":"B112","doi-asserted-by":"publisher","DOI":"10.1055\/s-0028-1093717","article-title":"Regulation of exocrine pancreatic secretory process by insulin in vivo","volume":"7","author":"Adler","year":"1975","journal-title":"Horm Metab Res"},{"key":"B113","doi-asserted-by":"publisher","DOI":"10.1016\/S0140-6736(69)90171-8","article-title":"Why are the islets of langerhans","volume":"2","author":"Henderson","year":"1969","journal-title":"Lancet"},{"key":"B114","doi-asserted-by":"publisher","DOI":"10.1371\/journal.pone.0095110","article-title":"Distinct cell clusters touching islet cells induce islet cell replication in association with over-expression of Regenerating Gene (REG) protein in fulminant type 1 diabetes","volume":"9","author":"Aida","year":"2014","journal-title":"PloS One"},{"key":"B115","doi-asserted-by":"publisher","DOI":"10.1016\/j.bbrc.2018.06.103","article-title":"Crucial role of Reg I from acinar-like cell cluster touching with islets (ATLANTIS) on mitogenesis of beta cells in EMC virus-induced diabetic mice","volume":"503","author":"Aida","year":"2018","journal-title":"Biochem Biophys Res Commun"},{"key":"B116","doi-asserted-by":"publisher","first-page":"108043","DOI":"10.1016\/j.celrep.2020.108043","article-title":"Zonation of pancreatic acinar cells in diabetic mice","volume":"32","author":"Egozi","year":"2020","journal-title":"Cell Rep"},{"key":"B117","doi-asserted-by":"publisher","DOI":"10.1016\/j.ajpath.2017.08.017","article-title":"Human pancreatic acinar cells: proteomic characterization, physiologic responses, and organellar disorders in ex vivo pancreatitis","volume":"187","author":"Lugea","year":"2017","journal-title":"Am J Pathol"},{"key":"B118","doi-asserted-by":"publisher","first-page":"76","DOI":"10.1038\/s42255-021-00516-2","article-title":"Abnormal exocrine-endocrine cell cross-talk promotes beta-cell dysfunction and loss in MODY8","volume":"4","author":"Kahraman","year":"2022","journal-title":"Nat Metab"},{"key":"B119","doi-asserted-by":"publisher","first-page":"90","DOI":"10.1038\/s41598-017-00098-8","article-title":"CFTR is involved in the regulation of glucagon secretion in human and rodent alpha cells","volume":"7","author":"Edlund","year":"2017","journal-title":"Sci Rep"},{"key":"B120","doi-asserted-by":"publisher","DOI":"10.3389\/fphys.2017.00835","article-title":"Abnormal CFTR affects glucagon production by islet alpha cells in cystic fibrosis and polycystic ovarian syndrome","volume":"8","author":"Huang","year":"2017","journal-title":"Front Physiol"},{"key":"B121","doi-asserted-by":"publisher","DOI":"10.2337\/db23-1753-P","article-title":"Islet GLP-1R protein expression is reduced in humans with cystic fibrosis\u2013related diabetes","volume":"72","author":"Vemireddy","year":"2023","journal-title":"Diabetes"},{"key":"B122","doi-asserted-by":"publisher","DOI":"10.1016\/j.bbagen.2014.11.005","article-title":"Pancreatic polypeptide regulates glucagon release through PPYR1 receptors expressed in mouse and human alpha-cells","volume":"1850","author":"Aragon","year":"2015","journal-title":"Biochim Biophys Acta"},{"key":"B123","doi-asserted-by":"publisher","DOI":"10.3389\/fcell.2021.694276","article-title":"Activation of pancreatic stellate cells is beneficial for exocrine but not endocrine cell differentiation in the developing human pancreas","volume":"9","author":"Li","year":"2021","journal-title":"Front Cell Dev Biol"},{"key":"B124","doi-asserted-by":"publisher","DOI":"10.1016\/j.bbrc.2013.02.095","article-title":"Pancreatic stellate cells reduce insulin expression and induce apoptosis in pancreatic beta-cells","volume":"433","author":"Kikuta","year":"2013","journal-title":"Biochem Biophys Res Commun"},{"key":"B125","doi-asserted-by":"publisher","DOI":"10.3109\/03009734.2015.1032453","article-title":"Activated pancreatic stellate cells can impair pancreatic islet function in mice","volume":"120","author":"Zang","year":"2015","journal-title":"Ups J Med Sci"},{"key":"B126","doi-asserted-by":"publisher","DOI":"10.4093\/dmj.2019.0181","article-title":"Hypoxia Increases beta-Cell Death by Activating Pancreatic Stellate Cells within the Islet","volume":"44","author":"Kim","year":"2020","journal-title":"Diabetes Metab J"},{"key":"B127","doi-asserted-by":"publisher","first-page":"165612","DOI":"10.1155\/2014\/165612","article-title":"High glucose aggravates the detrimental effects of pancreatic stellate cells on Beta-cell function","volume":"2014","author":"Zha","year":"2014","journal-title":"Int J Endocrinol"},{"key":"B128","doi-asserted-by":"publisher","DOI":"10.1016\/j.bbrc.2017.02.082","article-title":"A role of pancreatic stellate cells in islet fibrosis and beta-cell dysfunction in type 2 diabetes mellitus","volume":"485","author":"Lee","year":"2017","journal-title":"Biochem Biophys Res Commun"},{"key":"B129","doi-asserted-by":"publisher","DOI":"10.1097\/MPA.0b013e318214efaf","article-title":"Analysis of the human pancreatic stellate cell secreted proteome","volume":"40","author":"Wehr","year":"2011","journal-title":"Pancreas"},{"key":"B130","doi-asserted-by":"publisher","first-page":"596","DOI":"10.1186\/s12885-019-5803-1","article-title":"Secretion of fibronectin by human pancreatic stellate cells promotes chemoresistance to gemcitabine in pancreatic cancer cells","volume":"19","author":"Amrutkar","year":"2019","journal-title":"BMC Cancer"},{"key":"B131","doi-asserted-by":"publisher","DOI":"10.3390\/cells8010023","article-title":"Commonly used pancreatic stellate cell cultures differ phenotypically and in their interactions with pancreatic cancer cells","volume":"8","author":"Lenggenhager","year":"2019","journal-title":"Cells"},{"key":"B132","doi-asserted-by":"publisher","first-page":"5303","DOI":"10.1038\/s41598-019-41740-x","article-title":"Impact of the secretome of activated pancreatic stellate cells on growth and differentiation of pancreatic tumour cells","volume":"9","author":"Marzoq","year":"2019","journal-title":"Sci Rep"},{"key":"B133","doi-asserted-by":"publisher","DOI":"10.3390\/cells9010227","article-title":"Establishment and characterization of paired primary cultures of human pancreatic cancer cells and stellate cells derived from the same tumor","volume":"9","author":"Amrutkar","year":"2020","journal-title":"Cells"},{"key":"B134","article-title":"NADPH oxidase 1 in chronic pancreatitis-activated pancreatic stellate cells facilitates the progression of pancreatic cancer","volume":"13","author":"Chakraborty","year":"2023","journal-title":"Am J Cancer Res"},{"key":"B135","doi-asserted-by":"publisher","first-page":"897","DOI":"10.1038\/ni.1935","article-title":"Activation of the NLRP3 inflammasome by islet amyloid polypeptide provides a mechanism for enhanced IL-1beta in type 2 diabetes","volume":"11","author":"Masters","year":"2010","journal-title":"Nat Immunol"},{"key":"B136","doi-asserted-by":"publisher","DOI":"10.4049\/jimmunol.1002854","article-title":"IL-1 blockade attenuates islet amyloid polypeptide-induced proinflammatory cytokine release and pancreatic islet graft dysfunction","volume":"187","author":"Westwell-Roper","year":"2011","journal-title":"J Immunol"},{"key":"B137","doi-asserted-by":"publisher","first-page":"68","DOI":"10.1016\/j.jcf.2019.05.015","article-title":"Disease progression in patients with cystic fibrosis treated with ivacaftor: Data from national US and UK registries","volume":"19","author":"Volkova","year":"2020","journal-title":"J Cyst Fibros"},{"key":"B138","doi-asserted-by":"publisher","first-page":"1991","DOI":"10.1056\/NEJMoa0909825","article-title":"Effect of VX-770 in persons with cystic fibrosis and the G551D-CFTR mutation","volume":"363","author":"Accurso","year":"2010","journal-title":"N Engl J Med"},{"key":"B139","doi-asserted-by":"publisher","DOI":"10.1056\/NEJMoa1908639","article-title":"Elexacaftor-tezacaftor-ivacaftor for cystic fibrosis with a single Phe508del allele","volume":"381","author":"Middleton","year":"2019","journal-title":"N Engl J Med"},{"key":"B140","doi-asserted-by":"publisher","DOI":"10.1164\/rccm.201906-1227OC","article-title":"Real-life safety and effectiveness of lumacaftor-ivacaftor in patients with cystic fibrosis","volume":"201","author":"Burgel","year":"2020","journal-title":"Am J Respir Crit Care Med"},{"key":"B141","doi-asserted-by":"publisher","first-page":"100286","DOI":"10.1016\/j.jcte.2021.100286","article-title":"The role of modulators in cystic fibrosis related diabetes","volume":"27","author":"Merjaneh","year":"2022","journal-title":"J Clin Transl Endocrinol"},{"key":"B142","doi-asserted-by":"publisher","DOI":"10.1111\/j.1399-5448.2009.00632.x","article-title":"Oral glucose tolerance testing in children with cystic fibrosis","volume":"11","author":"Ode","year":"2010","journal-title":"Pediatr Diabetes"},{"key":"B143","doi-asserted-by":"publisher","DOI":"10.1016\/S2213-2600(15)00545-7","article-title":"Safety, pharmacokinetics, and pharmacodynamics of ivacaftor in patients aged 2-5 years with cystic fibrosis and a CFTR gating mutation (KIWI): an open-label, single-arm study","volume":"4","author":"Davies","year":"2016","journal-title":"Lancet Respir Med"},{"key":"B144","doi-asserted-by":"publisher","DOI":"10.1016\/j.jcf.2019.03.009","article-title":"An open-label extension study of ivacaftor in children with CF and a CFTR gating mutation initiating treatment at age 2-5years (KLIMB)","volume":"18","author":"Rosenfeld","year":"2019","journal-title":"J Cyst Fibros"},{"key":"B145","doi-asserted-by":"publisher","DOI":"10.1164\/rccm.202008-3177OC","article-title":"Ivacaftor in infants aged 4 to <12 months with cystic fibrosis and a gating mutation. Results of a two-part phase 3 clinical trial","volume":"203","author":"Davies","year":"2021","journal-title":"Am J Respir Crit Care Med"},{"key":"B146","doi-asserted-by":"publisher","DOI":"10.1111\/pedi.12026","article-title":"Insulin secretion improves in cystic fibrosis following ivacaftor correction of CFTR: a small pilot study","volume":"14","author":"Bellin","year":"2013","journal-title":"Pediatr Diabetes"},{"key":"B147","doi-asserted-by":"publisher","DOI":"10.1164\/rccm.201806-1018OC","article-title":"Islet hormone and incretin secretion in cystic fibrosis after four months of ivacaftor therapy","volume":"199","author":"Kelly","year":"2019","journal-title":"Am J Respir Crit Care Med"},{"key":"B148","doi-asserted-by":"publisher","first-page":"100276","DOI":"10.1016\/j.jcte.2021.100276","article-title":"Obesity in cystic fibrosis","volume":"26","author":"Kutney","year":"2021","journal-title":"J Clin Transl Endocrinol"},{"key":"B149","doi-asserted-by":"publisher","DOI":"10.1210\/clinem\/dgaa167","article-title":"Semaglutide in cystic fibrosis-related diabetes","volume":"105","author":"Gnanapragasam","year":"2020","journal-title":"J Clin Endocrinol Metab"}],"container-title":["Frontiers in Endocrinology"],"original-title":[],"link":[{"URL":"https:\/\/www.frontiersin.org\/articles\/10.3389\/fendo.2023.1269139\/full","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2023,11,23]],"date-time":"2023-11-23T11:32:48Z","timestamp":1700739168000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.frontiersin.org\/articles\/10.3389\/fendo.2023.1269139\/full"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2023,11,23]]},"references-count":149,"alternative-id":["10.3389\/fendo.2023.1269139"],"URL":"https:\/\/doi.org\/10.3389\/fendo.2023.1269139","relation":{},"ISSN":["1664-2392"],"issn-type":[{"value":"1664-2392","type":"electronic"}],"subject":[],"published":{"date-parts":[[2023,11,23]]},"article-number":"1269139"}}