{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,4]],"date-time":"2026-10-04T19:30:24Z","timestamp":1791142224102,"version":"4.1.0"},"reference-count":23,"publisher":"National Academy of Sciences","issue":"10","content-domain":{"domain":["www.pnas.org"],"crossmark-restriction":true},"short-container-title":["Proc. Natl. Acad. Sci. U.S.A."],"published-print":{"date-parts":[[1997,5,13]]},"abstract":"<jats:p>\n                    Two mouse insulin genes,\n                    <jats:italic>Ins1<\/jats:italic>\n                    and\n                    <jats:italic>Ins2<\/jats:italic>\n                    , were disrupted and\n                    <jats:italic>lacZ<\/jats:italic>\n                    was inserted at the\n                    <jats:italic>Ins2<\/jats:italic>\n                    locus by gene targeting. Double nullizygous insulin-deficient pups were growth-retarded. They did not show any glycosuria at birth but soon after suckling developed diabetes mellitus with ketoacidosis and liver steatosis and died within 48 h. Interestingly, insulin deficiency did not preclude pancreas organogenesis and the appearance of the various cell types of the endocrine pancreas. The presence of\n                    <jats:italic>lacZ<\/jats:italic>\n                    expressing \u03b2 cells and glucagon-positive \u03b1 cells was demonstrated by cytochemistry and immunocytochemistry. Reverse transcription-coupled PCR analysis showed that somatostatin and pancreatic polypeptide mRNAs were present, although at reduced levels, accounting for the presence also of \u03b4 and pancreatic polypeptide cells, respectively. Morphometric analysis revealed enlarged islets of Langherans in the pancreas from insulin-deficient pups, suggesting that insulin might function as a negative regulator of islet cell growth. Whether insulin controls the growth of specific islet cell types and the molecular basis for this action remain to be elucidated.\n                  <\/jats:p>","DOI":"10.1073\/pnas.94.10.5137","type":"journal-article","created":{"date-parts":[[2002,7,26]],"date-time":"2002-07-26T10:35:50Z","timestamp":1027679750000},"page":"5137-5140","update-policy":"https:\/\/doi.org\/10.1073\/pnas.cm10313","source":"Crossref","is-referenced-by-count":225,"title":["Phenotypic alterations in insulin-deficient\u2009mutant\u2009mice"],"prefix":"10.1073","volume":"94","author":[{"given":"Bertrand","family":"Duvilli\u00e9","sequence":"first","affiliation":[{"name":"Institut Cochin de G\u00e9n\u00e9tique Mol\u00e9culaire, Institut National de la Sant\u00e9 et de la Recherche M\u00e9dicale U257, 24 rue du Faubourg Saint Jacques,  75014 Paris, France"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Nathalie","family":"Cordonnier","sequence":"additional","affiliation":[{"name":"Institut Cochin de G\u00e9n\u00e9tique Mol\u00e9culaire, Institut National de la Sant\u00e9 et de la Recherche M\u00e9dicale U257, 24 rue du Faubourg Saint Jacques,  75014 Paris, France"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Louise","family":"Deltour","sequence":"additional","affiliation":[{"name":"Institut Cochin de G\u00e9n\u00e9tique Mol\u00e9culaire, Institut National de la Sant\u00e9 et de la Recherche M\u00e9dicale U257, 24 rue du Faubourg Saint Jacques,  75014 Paris, France"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Fran\u00e7oise","family":"Dandoy-Dron","sequence":"additional","affiliation":[{"name":"Institut Cochin de G\u00e9n\u00e9tique Mol\u00e9culaire, Institut National de la Sant\u00e9 et de la Recherche M\u00e9dicale U257, 24 rue du Faubourg Saint Jacques,  75014 Paris, France"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jean-Michel","family":"Itier","sequence":"additional","affiliation":[{"name":"Institut Cochin de G\u00e9n\u00e9tique Mol\u00e9culaire, Institut National de la Sant\u00e9 et de la Recherche M\u00e9dicale U257, 24 rue du Faubourg Saint Jacques,  75014 Paris, France"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Eliane","family":"Monthioux","sequence":"additional","affiliation":[{"name":"Institut Cochin de G\u00e9n\u00e9tique Mol\u00e9culaire, Institut National de la Sant\u00e9 et de la Recherche M\u00e9dicale U257, 24 rue du Faubourg Saint Jacques,  75014 Paris, France"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jacques","family":"Jami","sequence":"additional","affiliation":[{"name":"Institut Cochin de G\u00e9n\u00e9tique Mol\u00e9culaire, Institut National de la Sant\u00e9 et de la Recherche M\u00e9dicale U257, 24 rue du Faubourg Saint Jacques,  75014 Paris, France"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Rajiv L.","family":"Joshi","sequence":"additional","affiliation":[{"name":"Institut Cochin de G\u00e9n\u00e9tique Mol\u00e9culaire, Institut National de la Sant\u00e9 et de la Recherche M\u00e9dicale U257, 24 rue du Faubourg Saint Jacques,  75014 Paris, France"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Danielle","family":"Bucchini","sequence":"additional","affiliation":[{"name":"Institut Cochin de G\u00e9n\u00e9tique Mol\u00e9culaire, Institut National de la Sant\u00e9 et de la Recherche M\u00e9dicale U257, 24 rue du Faubourg Saint Jacques,  75014 Paris, France"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"341","published-online":{"date-parts":[[1997,5,13]]},"reference":[{"key":"e_1_3_3_1_2","doi-asserted-by":"publisher","DOI":"10.1159\/000217832"},{"key":"e_1_3_3_2_2","doi-asserted-by":"publisher","DOI":"10.1242\/dev.121.6.1569"},{"key":"e_1_3_3_3_2","doi-asserted-by":"publisher","DOI":"10.1111\/j.1432-1033.1996.435rr.x"},{"key":"e_1_3_3_4_2","doi-asserted-by":"publisher","DOI":"10.1002\/j.1460-2075.1993.tb06109.x"},{"key":"e_1_3_3_5_2","doi-asserted-by":"publisher","DOI":"10.1242\/dev.121.1.11"},{"key":"e_1_3_3_6_2","doi-asserted-by":"publisher","DOI":"10.1038\/371606a0"},{"key":"e_1_3_3_7_2","doi-asserted-by":"publisher","DOI":"10.1242\/dev.122.3.983"},{"key":"e_1_3_3_8_2","doi-asserted-by":"publisher","DOI":"10.1038\/385257a0"},{"key":"e_1_3_3_9_2","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.91.26.12999"},{"key":"e_1_3_3_10_2","volume-title":"Molecular Cloning: A Laboratory Manual","author":"Sambrook J","year":"1989","unstructured":"J Sambrook, E F Fritsch, T Maniatis Molecular Cloning: A Laboratory Manual (Cold Spring Harbor Lab. 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