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Antagonism of glucagon effects, by targeting glucagon secretion or disabling the glucagon receptor, is associated with \u03b1\u2010cell hyperplasia. We evaluated the influence of total glucagon withdrawal on islets of Langerhans using prohormone convertase\u20102 knockout mice (<jats:styled-content style=\"fixed-case\">PC<\/jats:styled-content>2\u2010ko), in which \u03b1\u2010cell hyperplasia is present from a young age and persists throughout life, in order to understand whether or not sustained glucagon deficit would lead to islet tumorigenesis. <jats:styled-content style=\"fixed-case\">PC<\/jats:styled-content>2\u2010ko and wild\u2010type (<jats:styled-content style=\"fixed-case\">WT<\/jats:styled-content>) mice were maintained drug\u2010free, and cohorts of these groups sampled at 3, 12 and 18\u00a0months for plasma biochemical and morphological (histological, immunohistochemical, electron microscopical and image analytical) assessments. <jats:styled-content style=\"fixed-case\">WT<\/jats:styled-content> mice showed no islet tumours up to termination of the study, but <jats:styled-content style=\"fixed-case\">PC<\/jats:styled-content>2\u2010ko animals displayed marked changes in islet morphology from \u03b1\u2010cell hypertrophy\/hyperplasia\/atypical hyperplasia, to adenomas and carcinomas, these latter being first encountered at 6\u20138\u00a0months. Islet hyperplasias and tumours primarily consisted of \u03b1\u2010cells associated to varying degrees with other islet endocrine cell types. In addition to substantial increases in islet neoplasia, increased \u03b1\u2010cell neogenesis associated primarily with pancreatic duct(ule)s was present. We conclude that absolute blockade of the glucagon signal results in tumorigenesis and that the <jats:styled-content style=\"fixed-case\">PC<\/jats:styled-content>2\u2010ko mouse represents a valuable model for investigation of islet tumours and pancreatic ductal neogenesis.<\/jats:p>","DOI":"10.1111\/iep.12066","type":"journal-article","created":{"date-parts":[[2014,1,24]],"date-time":"2014-01-24T03:16:27Z","timestamp":1390533387000},"page":"29-48","update-policy":"http:\/\/dx.doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":14,"title":["Islets of Langerhans from prohormone convertase\u20102 knockout mice show \u03b1\u2010cell hyperplasia and tumorigenesis with elevated \u03b1\u2010cell neogenesis"],"prefix":"10.1111","volume":"95","author":[{"given":"Huw B.","family":"Jones","sequence":"first","affiliation":[{"name":"Department of Pathological Sciences AstraZeneca Pharmaceuticals Macclesfield Cheshire UK"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Jaimini","family":"Reens","sequence":"additional","affiliation":[{"name":"Department of Pathological Sciences AstraZeneca Pharmaceuticals Macclesfield Cheshire UK"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Simon R.","family":"Brocklehurst","sequence":"additional","affiliation":[{"name":"Department of Pathological Sciences AstraZeneca Pharmaceuticals Macclesfield Cheshire UK"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Catherine J.","family":"Betts","sequence":"additional","affiliation":[{"name":"Department of Pathological Sciences AstraZeneca Pharmaceuticals Macclesfield Cheshire UK"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Sue","family":"Bickerton","sequence":"additional","affiliation":[{"name":"Department of Pathological Sciences AstraZeneca Pharmaceuticals Macclesfield Cheshire UK"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Alison L.","family":"Bigley","sequence":"additional","affiliation":[{"name":"Department of Pathological Sciences AstraZeneca Pharmaceuticals Macclesfield Cheshire UK"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Richard P.","family":"Jenkins","sequence":"additional","affiliation":[{"name":"Department of Pathological Sciences AstraZeneca Pharmaceuticals Macclesfield Cheshire UK"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Nicky M.","family":"Whalley","sequence":"additional","affiliation":[{"name":"Department of Oncology AstraZeneca Pharmaceuticals Macclesfield Cheshire UK"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Derrick","family":"Morgan","sequence":"additional","affiliation":[{"name":"Department of Pathological Sciences AstraZeneca Pharmaceuticals Macclesfield Cheshire UK"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"David M.","family":"Smith","sequence":"additional","affiliation":[{"name":"AstraZeneca Pharmaceuticals R&amp;D Molndal CVMD Molndal Sweden"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"311","published-online":{"date-parts":[[2014,1,23]]},"reference":[{"key":"e_1_2_6_2_1","doi-asserted-by":"publisher","DOI":"10.1152\/ajpendo.90887.2008"},{"key":"e_1_2_6_3_1","doi-asserted-by":"publisher","DOI":"10.1038\/nbt1115"},{"key":"e_1_2_6_4_1","doi-asserted-by":"publisher","DOI":"10.1007\/BF00400461"},{"key":"e_1_2_6_5_1","doi-asserted-by":"crossref","first-page":"1076","DOI":"10.2337\/diab.45.8.1076","article-title":"Evidence for a major role for glucagon in regulation of plasma glucose in conscious, nondiabetic and alloxan\u2010induced diabetic rabbits","volume":"45","author":"Brand C.L.","year":"1996","journal-title":"Diabetes"},{"key":"e_1_2_6_6_1","volume-title":"International Classification of Rodent Tumors: The Mouse","author":"Capen C.C.","year":"2001"},{"key":"e_1_2_6_7_1","doi-asserted-by":"publisher","DOI":"10.1172\/JCI24196"},{"key":"e_1_2_6_8_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.cell.2009.05.035"},{"key":"e_1_2_6_9_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.semcdb.2010.07.007"},{"key":"e_1_2_6_10_1","doi-asserted-by":"publisher","DOI":"10.1007\/s00125-006-0481-3"},{"key":"e_1_2_6_11_1","doi-asserted-by":"publisher","DOI":"10.1210\/en.2004-1118"},{"key":"e_1_2_6_12_1","first-page":"1617","article-title":"Glucagon receptor antagonists for the treatment of type 2 diabetes: current prospects","volume":"3","author":"Djuric S.W.","year":"2002","journal-title":"Curr. 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