{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,30]],"date-time":"2026-10-30T06:59:07Z","timestamp":1793343547882,"version":"4.5.0"},"reference-count":39,"publisher":"American Diabetes Association","issue":"9","content-domain":{"domain":["diabetesjournals.org"],"crossmark-restriction":true},"short-container-title":[],"published-print":{"date-parts":[[2003,9,1]]},"abstract":"<jats:p>Amylin (islet amyloid polypeptide) is the chief component of the islet amyloid found in type 2 diabetes, and amylin fibril precursors may be cytotoxic to pancreatic \u03b2-cells. Little is known about the prevention of amylin aggregation. We investigated the role of insulin-degrading enzyme (IDE) in amylin degradation, amyloid deposition, and cytotoxicity in RIN-m5F insulinoma cells. Human 125I-labeled amylin degradation was inhibited by 46 and 65% with the addition of 100 nmol\/l human amylin or insulin, respectively. 125I-labeled insulin degradation was inhibited with 100 nmol\/l human amylin, rat amylin, and insulin (by 50, 50, and 73%, respectively). The IDE inhibitor bacitracin inhibited amylin degradation by 78% and insulin degradation by 100%. Amyloid staining by Congo red fluorescence was detectable at 100 nmol\/l amylin and was pronounced at 1,000 nmol\/l amylin treatment for 48 h. Bacitracin treatment markedly increased staining at all amylin concentrations. Bacitracin with amylin caused a dramatic decrease in cell viability compared with amylin alone (68 and 25%, respectively, at 10 nmol\/l amylin). In summary, RIN-m5F cells degraded both amylin and insulin through a common proteolytic pathway. IDE inhibition by bacitracin impaired amylin degradation, increased amyloid formation, and increased amylin-induced cytotoxicity, suggesting a role for IDE in amylin clearance and the prevention of amylin aggregation.<\/jats:p>","DOI":"10.2337\/diabetes.52.9.2315","type":"journal-article","created":{"date-parts":[[2007,3,6]],"date-time":"2007-03-06T19:04:22Z","timestamp":1173207862000},"page":"2315-2320","update-policy":"https:\/\/doi.org\/10.2337\/ada-journal-policies","source":"Crossref","is-referenced-by-count":102,"title":["An Insulin-Degrading Enzyme Inhibitor Decreases Amylin Degradation, Increases Amylin-Induced Cytotoxicity, and Increases Amyloid Formation in Insulinoma Cell Cultures"],"prefix":"10.2337","volume":"52","author":[{"given":"Robert G.","family":"Bennett","sequence":"first","affiliation":[{"name":"Department of Internal Medicine, University of Nebraska Medical Center, Omaha, Nebraska"},{"name":"Department of Medical Research, Veterans Affairs Medical Center, Omaha, Nebraska"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Frederick G.","family":"Hamel","sequence":"additional","affiliation":[{"name":"Department of Internal Medicine, University of Nebraska Medical Center, Omaha, Nebraska"},{"name":"Department of Medical Research, Veterans Affairs Medical Center, Omaha, Nebraska"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"William C.","family":"Duckworth","sequence":"additional","affiliation":[{"name":"Endocrinology Section, Carl T. Hayden VA Medical Center, Phoenix, Arizona"},{"name":"Molecular and Cellular Biology Program, Arizona State University, Tempe, Arizona"},{"name":"Department of Medicine, University of Arizona, Tucson, Arizona"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1167","reference":[{"key":"2022031207321044000_R1","doi-asserted-by":"crossref","unstructured":"Kahn SE, Andrikopoulos S, Verchere CB: Islet amyloid: a long-recognized but underappreciated pathological feature of type 2 diabetes.Diabetes\u200848:241\u2013253,1999","DOI":"10.2337\/diabetes.48.2.241"},{"key":"2022031207321044000_R2","doi-asserted-by":"crossref","unstructured":"Kahn SE, D\u2019Alessio DA, Schwartz MW, Fujimoto WY, Ensinck JW, Taborsky GJ Jr, Porte D Jr: Evidence of cosecretion of islet amyloid polypeptide and insulin by beta-cells.Diabetes\u200839:634\u2013638,1990","DOI":"10.2337\/diabetes.39.5.634"},{"key":"2022031207321044000_R3","doi-asserted-by":"crossref","unstructured":"Janson J, Ashley RH, Harrison D, McIntyre S, Butler PC: The mechanism of islet amyloid polypeptide toxicity is membrane disruption by intermediate-sized toxic amyloid particles.Diabetes\u200848:491\u2013498,1999","DOI":"10.2337\/diabetes.48.3.491"},{"key":"2022031207321044000_R4","doi-asserted-by":"crossref","unstructured":"Janson J, Soeller WC, Roche PC, Nelson RT, Torchia AJ, Kreutter DK, Butler PC: Spontaneous diabetes mellitus in transgenic mice expressing human islet amyloid polypeptide.Proc Natl Acad Sci U S A\u200893:7283\u20137288,1996","DOI":"10.1073\/pnas.93.14.7283"},{"key":"2022031207321044000_R5","doi-asserted-by":"crossref","unstructured":"Verchere CB, D\u2019Alessio DA, Wang S, Andrikopoulos S, Kahn SE: Transgenic overproduction of islet amyloid polypeptide (amylin) is not sufficient for islet amyloid formation.Horm Metab Res\u200829:311\u2013316,1997","DOI":"10.1055\/s-2007-979042"},{"key":"2022031207321044000_R6","doi-asserted-by":"crossref","unstructured":"Hoppener JW, Verbeek JS, de Koning EJ, Oosterwijk C, van Hulst KL, Visser-Vernooy HJ, Hofhuis FM, van Gaalen S, Berends MJ, Hackeng WH, et al: Chronic overproduction of islet amyloid polypeptide\/amylin in transgenic mice: lysosomal localization of human islet amyloid polypeptide and lack of marked hyperglycaemia or hyperinsulinaemia.Diabetologia\u200836:1258\u20131265,1993","DOI":"10.1007\/BF00400803"},{"key":"2022031207321044000_R7","doi-asserted-by":"crossref","unstructured":"Fox N, Schrementi J, Nishi M, Ohagi S, Chan SJ, Heisserman JA, Westermark GT, Leckstrom A, Westermark P, Steiner DF: Human islet amyloid polypeptide transgenic mice as a model of non- insulin-dependent diabetes mellitus (NIDDM).FEBS Lett\u2008323:40\u201344,1993","DOI":"10.1016\/0014-5793(93)81444-5"},{"key":"2022031207321044000_R8","doi-asserted-by":"crossref","unstructured":"Couce M, Kane LA, O\u2019Brien TD, Charlesworth J, Soeller W, McNeish J, Kreutter D, Roche P, Butler PC: Treatment with growth hormone and dexamethasone in mice transgenic for human islet amyloid polypeptide causes islet amyloidosis and beta-cell dysfunction.Diabetes\u200845:1094\u20131101,1996","DOI":"10.2337\/diabetes.45.8.1094"},{"key":"2022031207321044000_R9","doi-asserted-by":"crossref","unstructured":"Verchere CB, D\u2019Alessio DA, Palmiter RD, Weir GC, Bonner-Weir S, Baskin DG, Kahn SE: Islet amyloid formation associated with hyperglycemia in transgenic mice with pancreatic beta cell expression of human islet amyloid polypeptide.Proc Natl Acad Sci U S A\u200893:3492\u20133496,1996","DOI":"10.1073\/pnas.93.8.3492"},{"key":"2022031207321044000_R10","doi-asserted-by":"crossref","unstructured":"Hoppener JW, Oosterwijk C, Nieuwenhuis MG, Posthuma G, Thijssen JH, Vroom TM, Ahren B, Lips CJ: Extensive islet amyloid formation is induced by development of type II diabetes mellitus and contributes to its progression: pathogenesis of diabetes in a mouse model.Diabetologia\u200842:427\u2013434,1999","DOI":"10.1007\/s001250051175"},{"key":"2022031207321044000_R11","doi-asserted-by":"crossref","unstructured":"Duckworth WC, Bennett RG, Hamel FG: Insulin degradation: progress and potential.Endocr Rev\u200819:608\u2013624,1998","DOI":"10.1210\/edrv.19.5.0349"},{"key":"2022031207321044000_R12","doi-asserted-by":"crossref","unstructured":"Kurochkin IV: Insulin-degrading enzyme: embarking on amyloid destruction.Trends Biochem Sci\u200826:421\u2013425,2001","DOI":"10.1016\/S0968-0004(01)01876-X"},{"key":"2022031207321044000_R13","doi-asserted-by":"crossref","unstructured":"Bennett RG, Duckworth WC, Hamel FG: Degradation of amylin by insulin-degrading enzyme.J Biol Chem\u2008275:36621\u201336625,2000","DOI":"10.1074\/jbc.M006170200"},{"key":"2022031207321044000_R14","doi-asserted-by":"crossref","unstructured":"Vekrellis K, Ye Z, Qiu WQ, Walsh D, Hartley D, Chesneau V, Rosner MR, Selkoe DJ: Neurons regulate extracellular levels of amyloid beta-protein via proteolysis by insulin-degrading enzyme.J Neurosci\u200820:1657\u20131665,2000","DOI":"10.1523\/JNEUROSCI.20-05-01657.2000"},{"key":"2022031207321044000_R15","doi-asserted-by":"crossref","unstructured":"Shii K, Roth RA: Inhibition of insulin degradation by hepatoma cells after microinjection of monoclonal antibodies to a specific cytosolic protease.Proc Natl Acad Sci U S A\u200883:4147\u20134151,1986","DOI":"10.1073\/pnas.83.12.4147"},{"key":"2022031207321044000_R16","doi-asserted-by":"crossref","unstructured":"Bhathena SJ, Oie HK, Gazdar AF, Voyles NR, Wilkins SD, Recant L: Insulin, glucagon, and somatostatin receptors on cultured cells and clones from rat islet cell tumor.Diabetes\u200831:521\u2013531,1982","DOI":"10.2337\/diab.31.6.521"},{"key":"2022031207321044000_R17","doi-asserted-by":"crossref","unstructured":"Peavy DE, Edmondson JW, Duckworth WC: Selective effects of inhibitors of hormone processing on insulin action in isolated hepatocytes.Endocrinology\u2008114:753\u2013760,1984","DOI":"10.1210\/endo-114-3-753"},{"key":"2022031207321044000_R18","doi-asserted-by":"crossref","unstructured":"Churukian CJ: Improved Puchtler\u2019s Congo red method for demonstrating amyloid.J Histotechnol\u200823:139\u2013141,2000","DOI":"10.1179\/his.2000.23.2.139"},{"key":"2022031207321044000_R19","doi-asserted-by":"crossref","unstructured":"Hansen MB, Nielsen SE, Berg K: Re-examination and further development of a precise and rapid dye method for measuring cell growth\/cell kill.J Immunol Methods\u2008119:203\u2013210,1989","DOI":"10.1016\/0022-1759(89)90397-9"},{"key":"2022031207321044000_R20","doi-asserted-by":"crossref","unstructured":"Westermark P, Li ZC, Westermark GT, Leckstrom A, Steiner DF: Effects of beta cell granule components on human islet amyloid polypeptide fibril formation.FEBS Lett\u2008379:203\u2013206,1996","DOI":"10.1016\/0014-5793(95)01512-4"},{"key":"2022031207321044000_R21","doi-asserted-by":"crossref","unstructured":"Puchtler H, Sweat F, Levine M: On the binding of Congo red by amyloid.J Histochem Cytochem\u200810:355\u2013364,1962","DOI":"10.1177\/10.3.355"},{"key":"2022031207321044000_R22","doi-asserted-by":"crossref","unstructured":"Howard CF: Longitudinal studies on the development of diabetes in individual Macaca nigra.Diabetologia\u200829:301\u2013306,1986","DOI":"10.1007\/BF00452067"},{"key":"2022031207321044000_R23","doi-asserted-by":"crossref","unstructured":"Kahn SE, Verchere CB, Andrikopoulos S, Asberry PJ, Leonetti DL, Wahl PW, Boyko EJ, Schwartz RS, Newell-Morris L, Fujimoto WY: Reduced amylin release is a characteristic of impaired glucose tolerance and type 2 diabetes in Japanese Americans.Diabetes\u200847:640\u2013645,1998","DOI":"10.2337\/diabetes.47.4.640"},{"key":"2022031207321044000_R24","doi-asserted-by":"crossref","unstructured":"Westermark P: Amyloid and polypeptide hormones. What is their relationship?Amyloid\u20081:47\u201360,1994","DOI":"10.3109\/13506129409148624"},{"key":"2022031207321044000_R25","doi-asserted-by":"crossref","unstructured":"D\u2019Alessio DA, Verchere CB, Kahn SE, Hoagland V, Baskin DG, Palmiter RD, Ensinck JW: Pancreatic expression and secretion of human islet amyloid polypeptide in a transgenic mouse.Diabetes\u200843:1457\u20131461,1994","DOI":"10.2337\/diabetes.43.12.1457"},{"key":"2022031207321044000_R26","doi-asserted-by":"crossref","unstructured":"Becker AB, Roth RA: Insulysin and pitrilysin: insulin-degrading enzymes of mammals and bacteria.Meth Enzymol\u2008248:693\u2013703,1995","DOI":"10.1016\/0076-6879(95)48046-3"},{"key":"2022031207321044000_R27","doi-asserted-by":"crossref","unstructured":"Sipe JD: Amyloidosis.Annu Rev Biochem\u200861:947\u2013975,1992","DOI":"10.1146\/annurev.bi.61.070192.004503"},{"key":"2022031207321044000_R28","doi-asserted-by":"crossref","unstructured":"Kurochkin IV: Amyloidogenic determinant as a substrate recognition motif of insulin-degrading enzyme.FEBS Lett\u2008427:153\u2013156,1998","DOI":"10.1016\/S0014-5793(98)00422-0"},{"key":"2022031207321044000_R29","doi-asserted-by":"crossref","unstructured":"Goto S, Kurochkin IV: Alzheimer\u2019s\u2019s \u03b2-amyloid peptide interacts with and is degraded by insulin degrading enzyme.FEBS Lett\u2008345:33\u201337,1994","DOI":"10.1016\/0014-5793(94)00387-4"},{"key":"2022031207321044000_R30","doi-asserted-by":"crossref","unstructured":"Qiu WQ, Walsh DM, Ye Z, Vekrellis K, Zhang J, Podlisny MB, Rosner MR, Safavi A, Hersh LB, Selkoe DJ: Insulin-degrading enzyme regulates extracellular levels of amyloid beta-protein by degradation.J Biol Chem\u2008273:32730\u201332738,1998","DOI":"10.1074\/jbc.273.49.32730"},{"key":"2022031207321044000_R31","doi-asserted-by":"crossref","unstructured":"Wiltshire S, Hattersley AT, Hitman GA, Walker M, Levy JC, Sampson M, O\u2019Rahilly S, Frayling TM, Bell JI, Lathrop GM, Bennett A, Dhillon R, Fletcher C, Groves CJ, Jones E, Prestwich P, Simecek N, Rao PV, Wishart M, Bottazzo GF, Foxon R, Howell S, Smedley D, Cardon LR, Menzel S, McCarthy MI: A genomewide scan for loci predisposing to type 2 diabetes in a U.K. population (the Diabetes UK Warren 2 Repository): analysis of 573 pedigrees provides independent replication of a susceptibility locus on chromosome 1q.Am J Hum Genet\u200869:553\u2013569,2001","DOI":"10.1086\/323249"},{"key":"2022031207321044000_R32","doi-asserted-by":"crossref","unstructured":"Bertram L, Blacker D, Mullin K, Keeney D, Jones J, Basu S, Yhu S, McInnis MG, Go RC, Vekrellis K, Selkoe DJ, Saunders AJ, Tanzi RE: Evidence for genetic linkage of Alzheimer\u2019s\u2019s disease to chromosome 10q.Science\u2008290:2302\u20132303,2000","DOI":"10.1126\/science.290.5500.2302"},{"key":"2022031207321044000_R33","doi-asserted-by":"crossref","unstructured":"Myers A, Holmans P, Marshall H, Kwon J, Meyer D, Ramic D, Shears S, Booth J, DeVrieze FW, Crook R, Hamshere M, Abraham R, Tunstall N, Rice F, Carty S, Lillystone S, Kehoe P, Rudrasingham V, Jones L, Lovestone S, Perez-Tur J, Williams J, Owen MJ, Hardy J, Goate AM: Susceptibility locus for Alzheimer\u2019s\u2019s disease on chromosome 10.Science\u2008290:2304\u20132305,2000","DOI":"10.1126\/science.290.5500.2304"},{"key":"2022031207321044000_R34","doi-asserted-by":"crossref","unstructured":"Ertekin-Taner N, Graff-Radford N, Younkin LH, Eckman C, Baker M, Adamson J, Ronald J, Blangero J, Hutton M, Younkin SG: Linkage of plasma Abeta42 to a quantitative locus on chromosome 10 in late-onset Alzheimer\u2019s\u2019s disease pedigrees.Science\u2008290:2303\u20132304,2000","DOI":"10.1126\/science.290.5500.2303"},{"key":"2022031207321044000_R35","doi-asserted-by":"crossref","unstructured":"Fakhrai-Rad H, Nikoshkov A, Kamel A, Fernstrom M, Zierath JR, Norgren S, Luthman H, Galli J: Insulin-degrading enzyme identified as a candidate diabetes susceptibility gene in GK rats.Hum Mol Genet\u20089:2149\u20132158,2000","DOI":"10.1093\/hmg\/9.14.2149"},{"key":"2022031207321044000_R36","doi-asserted-by":"crossref","unstructured":"Farris W, Mansourian S, Chang Y, Lindsley L, Eckman EA, Frosch MP, Eckman CB, Tanzi RE, Selkoe DJ, Guenette S: Insulin-degrading enzyme regulates the levels of insulin, amyloid beta-protein, and the beta-amyloid precursor protein intracellular domain in vivo.Proc Natl Acad Sci U S A\u2008100:4162\u20134167,2003","DOI":"10.1073\/pnas.0230450100"},{"key":"2022031207321044000_R37","doi-asserted-by":"crossref","unstructured":"Bhathena SJ, Timmers KI, Oie HK, Voyles NR, Recant L: Cytosolic insulin-degrading activity in islet-derived tumor cell lines and in normal rat islets.Diabetes\u200834:121\u2013128,1985","DOI":"10.2337\/diabetes.34.2.121"},{"key":"2022031207321044000_R38","unstructured":"Oehler G, Bleyl H, Matthes KJ: Hyperinsulinemia in hepatic steatosis.Int J Obe Relat Metab Disord\u20086 (Suppl. 1):137\u2013144,1982"},{"key":"2022031207321044000_R39","doi-asserted-by":"crossref","unstructured":"Hamel FG, Upward JL, Bennett RG: In vitro inhibition of insulin-degrading enzyme by long chain fatty acids and their coenzyme A thioesters.Endocrinology\u2008144:2404\u20132408,2003","DOI":"10.1210\/en.2002-0007"}],"container-title":["Diabetes"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/journals.org\/diabetes\/diabetes\/article-pdf\/52\/9\/2315\/650170\/db0903002315.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"syndication"},{"URL":"https:\/\/diabetesjournals.org\/diabetes\/article-pdf\/52\/9\/2315\/650170\/db0903002315.pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2022,11,2]],"date-time":"2022-11-02T16:19:05Z","timestamp":1667405945000},"score":1,"resource":{"primary":{"URL":"https:\/\/diabetesjournals.org\/diabetes\/article\/52\/9\/2315\/11511\/An-Insulin-Degrading-Enzyme-Inhibitor-Decreases"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2003,9,1]]},"references-count":39,"journal-issue":{"issue":"9","published-print":{"date-parts":[[2003,9,1]]}},"URL":"https:\/\/doi.org\/10.2337\/diabetes.52.9.2315","relation":{},"ISSN":["0012-1797","1939-327X"],"issn-type":[{"value":"0012-1797","type":"print"},{"value":"1939-327X","type":"electronic"}],"subject":[],"published":{"date-parts":[[2003,9,1]]}}}