{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,23]],"date-time":"2026-10-23T12:36:21Z","timestamp":1792758981852,"version":"4.5.0"},"reference-count":41,"publisher":"American Diabetes Association","issue":"9","license":[{"start":{"date-parts":[[2021,8,26]],"date-time":"2021-08-26T00:00:00Z","timestamp":1629936000000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/www.diabetesjournals.org\/content\/license"}],"content-domain":{"domain":["diabetesjournals.org"],"crossmark-restriction":true},"short-container-title":[],"published-print":{"date-parts":[[2021,9,1]]},"abstract":"<jats:sec>\n                  <jats:title>OBJECTIVE<\/jats:title>\n                  <jats:p>Endogenous insulin clearance (EIC) is physiologically reduced at increasing insulin secretion rate (ISR). Computing EIC at the prevailing ISR does not distinguish the effects of hypersecretion from those of other mechanisms of glucose homeostasis. We aimed to measure EIC in standardized ISR conditions (i.e., at fixed ISR levels) and to analyze its associations with relevant physiologic factors.<\/jats:p>\n               <\/jats:sec>\n               <jats:sec>\n                  <jats:title>RESEARCH DESIGN AND METHODS<\/jats:title>\n                  <jats:p>We estimated standardized EIC (EICISR) by mathematical modeling in nine different studies with insulin and glucose infusions (N = 2,067). EICISR association with various traits was analyzed by stepwise multivariable regression in studies with both euglycemic clamp and oral glucose tolerance test (OGTT) (N = 1,410). We also tested whether oral glucose ingestion, as opposed to intravenous infusion, has an independent effect on EIC (N = 1,555).<\/jats:p>\n               <\/jats:sec>\n               <jats:sec>\n                  <jats:title>RESULTS<\/jats:title>\n                  <jats:p>Insulin sensitivity (as M\/I from the euglycemic clamp) is the strongest determinant of EICISR, approximately four times more influential than insulin resistance\u2013related hypersecretion. EICISR independently associates positively with M\/I, fasting and mean OGTT glucose or type 2 diabetes, and \u03b2-cell glucose sensitivity and negatively with African American or Hispanic race, female sex, and female age. With oral glucose ingestion, an ISR-independent \u223c10% EIC reduction is necessary to explain the observed insulin concentration profiles.<\/jats:p>\n               <\/jats:sec>\n               <jats:sec>\n                  <jats:title>CONCLUSIONS<\/jats:title>\n                  <jats:p>Based on EICISR, we posit the existence of two adaptive processes involving insulin clearance: the first reduces EICISR with insulin resistance (not with higher BMI per se) and is more relevant than the concomitant hypersecretion; the second reduces EICISR with \u03b2-cell dysfunction. These processes are dysregulated in type 2 diabetes. Finally, oral glucose ingestion per se reduces insulin clearance.<\/jats:p>\n               <\/jats:sec>","DOI":"10.2337\/dc21-0545","type":"journal-article","created":{"date-parts":[[2021,8,6]],"date-time":"2021-08-06T18:15:14Z","timestamp":1628273714000},"page":"2115-2123","update-policy":"https:\/\/doi.org\/10.2337\/ada-journal-policies","source":"Crossref","is-referenced-by-count":29,"title":["New Insights on the Interactions Between Insulin Clearance and the Main Glucose Homeostasis Mechanisms"],"prefix":"10.2337","volume":"44","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-8251-1730","authenticated-orcid":false,"given":"Roberto","family":"Bizzotto","sequence":"first","affiliation":[{"name":"CNR Institute of Neuroscience, Padua, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-7633-1346","authenticated-orcid":false,"given":"Domenico","family":"Tric\u00f2","sequence":"additional","affiliation":[{"name":"Department of Surgical, Medical and Molecular Pathology and Critical Care Medicine, University of Pisa, Pisa, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Andrea","family":"Natali","sequence":"additional","affiliation":[{"name":"Department of Clinical and Experimental Medicine, University of Pisa, Pisa, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-2594-1651","authenticated-orcid":false,"given":"Amalia","family":"Gastaldelli","sequence":"additional","affiliation":[{"name":"CNR Institute of Clinical Physiology, Padua, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Elza","family":"Muscelli","sequence":"additional","affiliation":[{"name":"Department of Clinical and Experimental Medicine, University of Pisa, Pisa, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-8581-6273","authenticated-orcid":false,"given":"Ralph A.","family":"De Fronzo","sequence":"additional","affiliation":[{"name":"Department of Medicine, University of Texas Health Science Center at San Antonio, San Antonio, TX"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-1528-9324","authenticated-orcid":false,"given":"Silva","family":"Arslanian","sequence":"additional","affiliation":[{"name":"Center for Pediatric Research in Obesity and Metabolism, UPMC Children\u2019s Hospital of Pittsburgh, University of Pittsburgh, Pittsburgh, PA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-1384-1584","authenticated-orcid":false,"given":"Ele","family":"Ferrannini","sequence":"additional","affiliation":[{"name":"CNR Institute of Clinical Physiology, Padua, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-1436-5591","authenticated-orcid":false,"given":"Andrea","family":"Mari","sequence":"additional","affiliation":[{"name":"CNR Institute of Neuroscience, Padua, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1167","published-online":{"date-parts":[[2021,8,26]]},"reference":[{"key":"2022031309571839100_B1","doi-asserted-by":"crossref","first-page":"365","DOI":"10.1002\/dmr.5610030202","article-title":"The kinetics of insulin in man. 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