{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2025,11,1]],"date-time":"2025-11-01T02:28:43Z","timestamp":1761964123542},"reference-count":0,"publisher":"American Diabetes Association","issue":"7","content-domain":{"domain":["diabetesjournals.org"],"crossmark-restriction":true},"short-container-title":[],"published-print":{"date-parts":[[1999,7,1]]},"abstract":"<jats:p>Relative hypersecretion of proinsulin is a feature of type 2 diabetes. We investigated to what extent this feature can be induced in human pancreatic islets by elevated glucose or fatty acids, two major abnormalities of the diabetic state. A 48-h culture period with 27 mmol\/l glucose increased the intraislet proinsulin-to-insulin (PI\/I) ratio 5.0-fold, owing to preferential decrease of insulin. The PI\/I ratio in culture medium was enhanced 1.9-fold versus islets cultured with 5.5 mmol\/l glucose. This effect of elevated glucose persisted after normalization of glucose levels: during 60-min postculture incubations at a basal glucose concentration (3.3 mmol\/l), the PI\/I ratio of secretion increased 4.9-fold. The ratio was also increased (14-fold) after renewed postculture stimulation with 16.7 mmol\/l glucose. Diazoxide was added to culture medium to block glucose-induced insulin secretion and thus investigate the importance of overstimulation. In cultures at 27 mmol\/l glucose, the presence of diazoxide decreased the PI\/I ratio of islet contents by 76%, the accumulated secretion to culture medium by 70%, and the release at 3.3 or 16.7 mmol\/l glucose during postculture incubations by 85 and 86%, respectively. None of these PI\/I-decreasing effects of diazoxide were reproduced during or after coculture with 5.5 mmol\/l glucose. Culture with 0.2 mmol\/l palmitate and 5.5 mmol\/l glucose decreased islet contents of proinsulin and insulin and increased the secreted products in culture media without affecting PI\/I ratios. During postculture conditions, however, prior palmitate culture enhanced the PI\/I ratio of release at 3.3 mmol\/l glucose (from 2.2 +\/- 0.4 to 5.4 +\/- 0.9%, P &amp;lt; 0.05). Culture with palmitate together with 27 mmol\/l glucose decreased islet contents of proinsulin and insulin and further enhanced intraislet PI\/I ratios (from 9.3 +\/- 1.1 to 13.4 +\/- 2.5%, P &amp;lt; 0.05). However, palmitate failed to affect PI\/I ratios in culture medium. In contrast, in postculture incubations at 3.3 mmol\/l glucose, prior palmitate culture further elevated the PI\/I ratio of secretion (from 10.8 +\/- 1.2 after previous 27 mmol\/l glucose alone to 13.9 +\/- 2.8% after palmitate and glucose, P &amp;lt; 0.05). We conclude that 1) long-term exposure of human islets to elevated glucose leads to preferential secretion of proinsulin, and this effect persists also after glucose normalization; 2) the glucose effect appears secondary to depletion of mature insulin granules; and 3) elevated fatty acids influence PI\/I ratios of secretion by mechanisms that are, in part, incongruous with an over-stimulation effect.<\/jats:p>","DOI":"10.2337\/diabetes.48.7.1409","type":"journal-article","created":{"date-parts":[[2007,3,6]],"date-time":"2007-03-06T19:04:22Z","timestamp":1173207862000},"page":"1409-1414","update-policy":"http:\/\/dx.doi.org\/10.2337\/ada-journal-policies","source":"Crossref","is-referenced-by-count":29,"title":["Enhancing effects of long-term elevated glucose and palmitate on stored and secreted proinsulin-to-insulin ratios in human pancreatic islets."],"prefix":"10.2337","volume":"48","author":[{"given":"A","family":"Bj\u00f6rklund","sequence":"first","affiliation":[{"name":"Department of Molecular Medicine, Karolinska Hospital, Karolinska Institute, Stockholm, Sweden. anneli.bjorklund@molmed.ki.se"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"V","family":"Grill","sequence":"additional","affiliation":[{"name":"Department of Molecular Medicine, Karolinska Hospital, Karolinska Institute, Stockholm, Sweden. anneli.bjorklund@molmed.ki.se"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"1167","container-title":["Diabetes"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/journals.org\/diabetes\/diabetes\/article-pdf\/48\/7\/1409\/364700\/10389846.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"syndication"},{"URL":"https:\/\/diabetesjournals.org\/diabetes\/article-pdf\/48\/7\/1409\/364700\/10389846.pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2022,11,2]],"date-time":"2022-11-02T16:48:27Z","timestamp":1667407707000},"score":1,"resource":{"primary":{"URL":"https:\/\/diabetesjournals.org\/diabetes\/article\/48\/7\/1409\/10521\/Enhancing-effects-of-long-term-elevated-glucose"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[1999,7,1]]},"references-count":0,"journal-issue":{"issue":"7","published-print":{"date-parts":[[1999,7,1]]}},"URL":"https:\/\/doi.org\/10.2337\/diabetes.48.7.1409","relation":{},"ISSN":["0012-1797","1939-327X"],"issn-type":[{"value":"0012-1797","type":"print"},{"value":"1939-327X","type":"electronic"}],"subject":[],"published":{"date-parts":[[1999,7,1]]}}}