{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,6,24]],"date-time":"2026-06-24T20:44:51Z","timestamp":1782333891935,"version":"3.54.5"},"reference-count":42,"publisher":"American Diabetes Association","issue":"5","license":[{"start":{"date-parts":[[2021,8,27]],"date-time":"2021-08-27T00:00:00Z","timestamp":1630022400000},"content-version":"vor","delay-in-days":4572,"URL":"http:\/\/creativecommons.org\/licenses\/by-nc-nd\/3.0\/"}],"content-domain":{"domain":["diabetesjournals.org"],"crossmark-restriction":true},"short-container-title":[],"published-print":{"date-parts":[[2009,5,1]]},"abstract":"<jats:sec>\n                  <jats:title>OBJECTIVE<\/jats:title>\n                  <jats:p>Insulin deficiency in type 1 diabetes and in rodent autoimmune diabetes models is caused by \u03b2-cell\u2013specific killing by autoreactive T-cells. Less is known about \u03b2-cell numbers and phenotype remaining at diabetes onset and the fate of other pancreatic endocrine cellular constituents.<\/jats:p>\n               <\/jats:sec>\n               <jats:sec>\n                  <jats:title>RESEARCH DESIGN AND METHODS<\/jats:title>\n                  <jats:p>We applied multicolor flow cytometry, confocal microscopy, and immunohistochemistry, supported by quantitative RT-PCR, to simultaneously track pancreatic endocrine cell frequencies and phenotypes during a T-cell\u2013mediated \u03b2-cell\u2013destructive process using two independent autoimmune diabetes models, an inducible autoantigen-specific model and the spontaneously diabetic NOD mouse.<\/jats:p>\n               <\/jats:sec>\n               <jats:sec>\n                  <jats:title>RESULTS<\/jats:title>\n                  <jats:p>The proportion of pancreatic insulin-positive \u03b2-cells to glucagon-positive \u03b1-cells was about 4:1 in nondiabetic mice. Islets isolated from newly diabetic mice exhibited the expected severe \u03b2-cell depletion accompanied by phenotypic \u03b2-cell changes (i.e., hypertrophy and degranulation), but they also revealed a substantial loss of \u03b1-cells, which was further confirmed by quantitative immunohistochemisty. While maintaining normal randomly timed serum glucagon levels, newly diabetic mice displayed an impaired glucagon secretory response to non\u2013insulin-induced hypoglycemia.<\/jats:p>\n               <\/jats:sec>\n               <jats:sec>\n                  <jats:title>CONCLUSIONS<\/jats:title>\n                  <jats:p>Systematically applying multicolor flow cytometry and immunohistochemistry to track declining \u03b2-cell numbers in recently diabetic mice revealed an altered endocrine cell composition that is consistent with a prominent and unexpected islet \u03b1-cell loss. These alterations were observed in induced and spontaneous autoimmune diabetes models, became apparent at diabetes onset, and differed markedly within islets compared with sub\u2013islet-sized endocrine cell clusters and among pancreatic lobes. We propose that these changes are adaptive in nature, possibly fueled by worsening glycemia and regenerative processes.<\/jats:p>\n               <\/jats:sec>","DOI":"10.2337\/db08-0616","type":"journal-article","created":{"date-parts":[[2009,2,20]],"date-time":"2009-02-20T01:48:54Z","timestamp":1235094534000},"page":"1175-1184","update-policy":"https:\/\/doi.org\/10.2337\/ada-journal-policies","source":"Crossref","is-referenced-by-count":38,"title":["Dynamic Changes in Pancreatic Endocrine Cell Abundance, Distribution, and Function in Antigen-Induced and Spontaneous Autoimmune Diabetes"],"prefix":"10.2337","volume":"58","author":[{"given":"Klaus","family":"Pechhold","sequence":"first","affiliation":[{"name":"Diabetes Branch, National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Bethesda, Maryland; the"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xiaolong","family":"Zhu","sequence":"additional","affiliation":[{"name":"Diabetes Branch, National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Bethesda, Maryland; the"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Victor S.","family":"Harrison","sequence":"additional","affiliation":[{"name":"Diabetes Branch, National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Bethesda, Maryland; the"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Janet","family":"Lee","sequence":"additional","affiliation":[{"name":"Diabetes Branch, National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Bethesda, Maryland; the"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sagarika","family":"Chakrabarty","sequence":"additional","affiliation":[{"name":"Diabetes Branch, National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Bethesda, Maryland; the"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kerstin","family":"Koczwara","sequence":"additional","affiliation":[{"name":"Diabetes Branch, National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Bethesda, Maryland; the"},{"name":"Institute for Diabetes Research, Research Group for Diabetes at the Helmholtz Center, Munich, Germany; and the"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Oksana","family":"Gavrilova","sequence":"additional","affiliation":[{"name":"Mouse Metabolism Core, National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Bethesda, Maryland."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"David M.","family":"Harlan","sequence":"additional","affiliation":[{"name":"Diabetes Branch, National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Bethesda, Maryland; the"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1167","published-online":{"date-parts":[[2009,2,19]]},"reference":[{"key":"2022031208574246800_B1","doi-asserted-by":"crossref","first-page":"49","DOI":"10.2337\/diab.38.1.49","article-title":"Compensatory growth of pancreatic beta-cells in adult rats after short-term glucose infusion","volume":"38","author":"Bonner-Weir","year":"1989","journal-title":"Diabetes"},{"key":"2022031208574246800_B2","doi-asserted-by":"crossref","first-page":"S32","DOI":"10.2337\/diabetes.54.suppl_2.S32","article-title":"Natural history of beta-cell function in type 1 diabetes","volume":"54","author":"Sherry","year":"2005","journal-title":"Diabetes"},{"key":"2022031208574246800_B3","doi-asserted-by":"crossref","first-page":"394","DOI":"10.1002\/dmrr.463","article-title":"The natural history of insulin content in the pancreas of female and male non-obese diabetic mouse: implications for trials of diabetes prevention in humans","volume":"20","author":"Valorani","year":"2004","journal-title":"Diabetes Metab Res Rev"},{"key":"2022031208574246800_B4","doi-asserted-by":"crossref","first-page":"816","DOI":"10.2337\/diab.44.7.816","article-title":"Very-low-dose streptozotocin induces diabetes in insulin promoter-mB7\u20131 transgenic mice","volume":"44","author":"Harlan","year":"1995","journal-title":"Diabetes"},{"key":"2022031208574246800_B5","doi-asserted-by":"crossref","first-page":"2304","DOI":"10.2337\/diabetes.52.9.2304","article-title":"Increased beta-cell apoptosis prevents adaptive increase in beta-cell mass in mouse model of type 2 diabetes: evidence for role of islet amyloid formation rather than direct action of amyloid","volume":"52","author":"Butler","year":"2003","journal-title":"Diabetes"},{"key":"2022031208574246800_B6","doi-asserted-by":"crossref","first-page":"1341","DOI":"10.2337\/diabetes.49.8.1341","article-title":"Linear correlation between beta-cell mass and body weight throughout the lifespan in Lewis rats: role of beta-cell hyperplasia and hypertrophy","volume":"49","author":"Montanya","year":"2000","journal-title":"Diabetes"},{"key":"2022031208574246800_B7","doi-asserted-by":"crossref","first-page":"939","DOI":"10.2337\/diacare.31.11.939","article-title":"Preparation of rat islet B-cell-enriched fractions by light-scatter flow cytometry","volume":"31","author":"Rabinovitch","year":"1982","journal-title":"Diabetes"},{"key":"2022031208574246800_B8","doi-asserted-by":"crossref","first-page":"177","DOI":"10.1002\/cyto.990030307","article-title":"Flow sorting of mouse pancreatic B cells by forward and orthogonal light scattering","volume":"3","author":"Nielsen","year":"1982","journal-title":"Cytometry"},{"key":"2022031208574246800_B9","doi-asserted-by":"crossref","first-page":"806","DOI":"10.1210\/endo-117-3-806","article-title":"A new in vitro model for the study of pancreatic A and B cells","volume":"117","author":"Pipeleers","year":"1985","journal-title":"Endocrinology"},{"key":"2022031208574246800_B10","doi-asserted-by":"crossref","first-page":"783","DOI":"10.2337\/diab.36.7.783","article-title":"Spontaneous reassociation of dispersed adult rat pancreatic islet cells into aggregates with three-dimensional architecture typical of native islets","volume":"36","author":"Halban","year":"1987","journal-title":"Diabetes"},{"key":"2022031208574246800_B11","doi-asserted-by":"crossref","first-page":"1974","DOI":"10.2337\/diabetes.47.12.1974","article-title":"Sorting human beta-cells consequent to targeted expression of green fluorescent protein","volume":"47","author":"Meyer","year":"1998","journal-title":"Diabetes"},{"key":"2022031208574246800_B12","doi-asserted-by":"crossref","first-page":"197","DOI":"10.1016\/j.cell.2007.12.015","article-title":"Beta cells can be generated from endogenous progenitors in injured adult mouse pancreas","volume":"132","author":"Xu","year":"2008","journal-title":"Cell"},{"key":"2022031208574246800_B13","doi-asserted-by":"crossref","first-page":"615","DOI":"10.1002\/cyto.a.20560","article-title":"A novel method for the detection of viable human pancreatic beta cells by flow cytometry using fluorophores that selectively detect labile zinc, mitochondrial membrane potential and protein thiols","volume":"73","author":"Jayaraman","year":"2008","journal-title":"Cytometry A"},{"key":"2022031208574246800_B14","doi-asserted-by":"crossref","first-page":"5294","DOI":"10.1021\/bi00591a005","article-title":"Isolation of biologically active ribonucleic acid from sources enriched in ribonuclease","volume":"18","author":"Chirgwin","year":"1979","journal-title":"Biochemistry"},{"key":"2022031208574246800_B15","article-title":"Morphology of the endocrine pancreas","volume-title":"Principles and Practice of Endocrinology & Metabolism","author":"Bonner-Weir","year":"2001"},{"key":"2022031208574246800_B16","doi-asserted-by":"crossref","first-page":"6292","DOI":"10.4049\/jimmunol.170.12.6292","article-title":"Fas is detectable on beta cells in accelerated, but not spontaneous, diabetes in nonobese diabetic mice","volume":"170","author":"Darwiche","year":"2003","journal-title":"J Immunol"},{"key":"2022031208574246800_B17","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1016\/S0896-8411(02)00105-1","article-title":"Beta cell-specific CD80 (B7-1) expression disrupts tissue protection from autoantigen-specific CTL-mediated diabetes","volume":"20","author":"Pechhold","year":"2003","journal-title":"J Autoimmun"},{"key":"2022031208574246800_B18","doi-asserted-by":"crossref","first-page":"629","DOI":"10.1038\/346629a0","article-title":"Viral escape by selection of cytotoxic T cell-resistant virus variants in vivo","volume":"346","author":"Pircher","year":"1990","journal-title":"Nature"},{"key":"2022031208574246800_B19","doi-asserted-by":"crossref","first-page":"12","DOI":"10.1053\/meta.2002.29007","article-title":"Differential impairment of glucagon responses to hypoglycemia, neuroglycopenia, arginine, and carbachol in alloxan-diabetic mice","volume":"51","author":"Ahren","year":"2002","journal-title":"Metabolism"},{"key":"2022031208574246800_B20","doi-asserted-by":"crossref","first-page":"1087","DOI":"10.1369\/jhc.5C6684.2005","article-title":"Assessment of human pancreatic islet architecture and composition by laser scanning confocal microscopy","volume":"53","author":"Brissova","year":"2005","journal-title":"J Histochem Cytochem"},{"key":"2022031208574246800_B21","doi-asserted-by":"crossref","first-page":"2334","DOI":"10.1073\/pnas.0510790103","article-title":"The unique cytoarchitecture of human pancreatic islets has implications for islet cell function","volume":"103","author":"Cabrera","year":"2006","journal-title":"Proc Natl Acad Sci U S A"},{"key":"2022031208574246800_B22","doi-asserted-by":"crossref","first-page":"3238","DOI":"10.2337\/db05-1034","article-title":"Effects of autoimmunity and immune therapy on beta-cell turnover in type 1 diabetes","volume":"55","author":"Sherry","year":"2006","journal-title":"Diabetes"},{"key":"2022031208574246800_B23","doi-asserted-by":"crossref","first-page":"1750","DOI":"10.1210\/endo.138.4.5049","article-title":"Differentiation of new insulin-producing cells is induced by injury in adult pancreatic islets","volume":"138","author":"Fernandes","year":"1997","journal-title":"Endocrinology"},{"key":"2022031208574246800_B24","doi-asserted-by":"crossref","first-page":"93","DOI":"10.1677\/joe.0.1650093","article-title":"Islet loss and alpha cell expansion in type 1 diabetes induced by multiple low-dose streptozotocin administration in mice","volume":"165","author":"Li","year":"2000","journal-title":"J Endocrinol"},{"key":"2022031208574246800_B25","doi-asserted-by":"crossref","first-page":"396","DOI":"10.1097\/00006676-199511000-00012","article-title":"Quantitative immunohistochemical changes in the endocrine pancreas of nonobese diabetic (NOD) mice","volume":"11","author":"Gomez Dumm","year":"1995","journal-title":"Pancreas"},{"key":"2022031208574246800_B26","doi-asserted-by":"crossref","first-page":"1230","DOI":"10.1139\/y91-180","article-title":"Insulin secretion and islet endocrine cell content at onset and during the early stages of diabetes in the BB rat: effect of the level of glycemic control","volume":"69","author":"Pederson","year":"1991","journal-title":"Can J Physiol Pharmacol"},{"key":"2022031208574246800_B27","doi-asserted-by":"crossref","first-page":"289","DOI":"10.1007\/s10735-005-7330-4","article-title":"Histopathological changes in insulin, glucagon and somatostatin cells in the islets of NOD mice during cyclophosphamide-accelerated diabetes: a combined immunohistochemical and histochemical study","volume":"36","author":"Reddy","year":"2005","journal-title":"J Mol Histol"},{"key":"2022031208574246800_B28","doi-asserted-by":"crossref","first-page":"1388","DOI":"10.1210\/jcem-72-6-1388","article-title":"Suppression of counterregulatory hormone response to hypoglycemia by insulin per se","volume":"72","author":"Diamond","year":"1991","journal-title":"J Clin Endocrinol Metab"},{"key":"2022031208574246800_B29","doi-asserted-by":"crossref","first-page":"1241","DOI":"10.1084\/jem.185.7.1241","article-title":"Bystander activation of cytotoxic T cells: studies on the mechanism and evaluation of in vivo significance in a transgenic mouse model","volume":"185","author":"Ehl","year":"1997","journal-title":"J Exp Med"},{"key":"2022031208574246800_B30","doi-asserted-by":"crossref","first-page":"305","DOI":"10.1016\/0092-8674(91)90164-T","article-title":"Ablation of \u201ctolerance\u201d and induction of diabetes by virus infection in viral antigen transgenic mice","volume":"65","author":"Ohashi","year":"1991","journal-title":"Cell"},{"key":"2022031208574246800_B31","doi-asserted-by":"crossref","first-page":"643","DOI":"10.2337\/diacare.29.03.06.dc05-1006","article-title":"Patterns of metabolic progression to type 1 diabetes in the Diabetes Prevention Trial-Type 1","volume":"29","author":"Sosenko","year":"2006","journal-title":"Diabetes Care"},{"key":"2022031208574246800_B32","doi-asserted-by":"crossref","first-page":"41","DOI":"10.1038\/nature02520","article-title":"Adult pancreatic beta-cells are formed by self-duplication rather than stem-cell differentiation","volume":"429","author":"Dor","year":"2004","journal-title":"Nature"},{"key":"2022031208574246800_B33","doi-asserted-by":"crossref","first-page":"817","DOI":"10.1016\/j.devcel.2007.04.011","article-title":"Growth and regeneration of adult beta cells does not involve specialized progenitors","volume":"12","author":"Teta","year":"2007","journal-title":"Dev Cell"},{"key":"2022031208574246800_B34","doi-asserted-by":"crossref","first-page":"16","DOI":"10.1111\/j.1399-543X.2004.00075.x","article-title":"The pancreatic ductal epithelium serves as a potential pool of progenitor cells","volume":"5","author":"Bonner-Weir","year":"2004","journal-title":"Pediatr Diabetes"},{"key":"2022031208574246800_B35","doi-asserted-by":"crossref","first-page":"1715","DOI":"10.2337\/diab.42.12.1715","article-title":"A second pathway for regeneration of adult exocrine and endocrine pancreas. A possible recapitulation of embryonic development","volume":"42","author":"Bonner-Weir","year":"1993","journal-title":"Diabetes"},{"key":"2022031208574246800_B36","doi-asserted-by":"crossref","first-page":"171","DOI":"10.1126\/science.182.4108.171","article-title":"Lack of glucagon response to hypoglycemia in diabetes: evidence for an intrinsic pancreatic alpha cell defect","volume":"182","author":"Gerich","year":"1973","journal-title":"Science"},{"key":"2022031208574246800_B37","doi-asserted-by":"crossref","first-page":"2667","DOI":"10.1172\/JCI116883","article-title":"Impaired hormonal responses to hypoglycemia in spontaneously diabetic and recurrently hypoglycemic rats: reversibility and stimulus specificity of the deficits","volume":"92","author":"Powell","year":"1993","journal-title":"J Clin Invest"},{"key":"2022031208574246800_B38","doi-asserted-by":"crossref","first-page":"1422","DOI":"10.1016\/S0026-0495(96)90125-0","article-title":"Time course of the defective alpha-cell response to hypoglycemia in diabetic BB rats","volume":"45","author":"Jacob","year":"1996","journal-title":"Metabolism"},{"key":"2022031208574246800_B39","doi-asserted-by":"crossref","first-page":"544","DOI":"10.1126\/science.1089999","article-title":"Glucagon: role in the hyperglycemia of diabetes mellitus","volume":"187","author":"Dobbs","year":"1975","journal-title":"Science"},{"key":"2022031208574246800_B40","doi-asserted-by":"crossref","first-page":"951","DOI":"10.2337\/diabetes.51.4.951","article-title":"Impaired beta-cell function, incretin effect, and glucagon suppression in patients with type 1 diabetes who have normal fasting glucose","volume":"51","author":"Greenbaum","year":"2002","journal-title":"Diabetes"},{"key":"2022031208574246800_B41","doi-asserted-by":"crossref","first-page":"1706","DOI":"10.1056\/NEJM198406283102605","article-title":"Abnormal glucose counterregulation after subcutaneous insulin in insulin-dependent diabetes mellitus","volume":"310","author":"Bolli","year":"1984","journal-title":"N Engl J Med"},{"key":"2022031208574246800_B42","doi-asserted-by":"crossref","first-page":"235","DOI":"10.1515\/JPEM.1994.7.3.235","article-title":"Impaired counterregulatory hormone responses to hypoglycemia in children and adolescents with new onset IDDM","volume":"7","author":"Hoffman","year":"1994","journal-title":"J Pediatr Endocrinol"}],"container-title":["Diabetes"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/journals.org\/diabetes\/diabetes\/article-pdf\/58\/5\/1175\/392039\/zdb00509001175.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"syndication"},{"URL":"https:\/\/diabetesjournals.org\/diabetes\/article-pdf\/58\/5\/1175\/392039\/zdb00509001175.pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2022,11,2]],"date-time":"2022-11-02T16:16:05Z","timestamp":1667405765000},"score":1,"resource":{"primary":{"URL":"https:\/\/diabetesjournals.org\/diabetes\/article\/58\/5\/1175\/14623\/Dynamic-Changes-in-Pancreatic-Endocrine-Cell"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2009,2,19]]},"references-count":42,"journal-issue":{"issue":"5","published-online":{"date-parts":[[2009,2,19]]},"published-print":{"date-parts":[[2009,5,1]]}},"URL":"https:\/\/doi.org\/10.2337\/db08-0616","relation":{},"ISSN":["0012-1797","1939-327X"],"issn-type":[{"value":"0012-1797","type":"print"},{"value":"1939-327X","type":"electronic"}],"subject":[],"published":{"date-parts":[[2009,2,19]]}}}