title: Insulin-regulated aminopeptidase inhibitors do not alter glucose handling in normal and diabetic rats.
abstract: Insulin-regulated aminopeptidase (IRAP) co-localizes with the glucose transporter 4 (GLUT4) in GLUT4 storage vesicles (GSV) in insulin-responsive cells. In response to insulin, IRAP is the only transmembrane enzyme known to translocate together with GLUT4 to the plasma membrane in adipocytes and muscle cells. Although the intracellular region of IRAP is associated with GLUT4 vesicle trafficking, the role of the aminopeptidase activity in insulin-responsive cells has not been elucidated. The aim of this study was to investigate whether the inhibition of the aminopeptidase activity of IRAP facilitates glucose uptake in insulin-responsive cells. In bothin vitroandin vivostudies, inhibition of IRAP aminopeptidase activity with the specific inhibitor, HFI-419, did not modulate glucose uptake. IRAP inhibition in the L6GLUT4myc cell line did not alter glucose uptake in both basal and insulin-stimulated state. In keeping with these results, HFI419 did not affect peripheral, whole-body glucose handling after an oral glucose challenge, neither in normal rats nor in the streptozotocin (STZ)-induced experimental rat model of diabetes mellitus (DM). Therefore, acute inhibition of IRAP aminopeptidase activity does not affect glucose homeostasis.
authors.affiliation: College of Health and BiomedicineVictoria University St Albans, Victoria, Australia.
authors.forename: Anthony L
authors.initials: AL
authors.lastname: Albiston
authors.affiliation: College of Health and BiomedicineVictoria University St Albans, Victoria, Australia.
authors.forename: Mauricio
authors.initials: M
authors.lastname: Cacador
authors.affiliation: College of Health and BiomedicineVictoria University St Albans, Victoria, Australia.
authors.forename: Puspha
authors.initials: P
authors.lastname: Sinnayah
authors.affiliation: Department of PhysiologyBiomedicine Discovery Institute, Monash University, Clayton, Victoria, Australia.
authors.forename: Peta
authors.initials: P
authors.lastname: Burns
authors.affiliation: Department of PhysiologyBiomedicine Discovery Institute, Monash University, Clayton, Victoria, Australia siew.chai@monash.edu.
authors.forename: Siew Yeen
authors.initials: SY
authors.lastname: Chai
mesh_terms: D000818:Animals; D001692:Biological Transport; D002454:Cell Differentiation; D002460:Cell Line; D010122:Cystinyl Aminopeptidase / Q000037:antagonists & inhibitors / Q000235:genetics* / Q000378:metabolism; D003847:Deoxyglucose / Q000494:pharmacology; D003921:Diabetes Mellitus, Experimental / Q000139:chemically induced / Q000201:enzymology* / Q000235:genetics / Q000473:pathology; D005786:Gene Expression Regulation; D005947:Glucose / Q000378:metabolism*; D051275:Glucose Transporter Type 4 / Q000235:genetics* / Q000378:metabolism; D007328:Insulin / Q000378:metabolism / Q000494:pharmacology*; D008297:Male; D032446:Myoblasts / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D011480:Protease Inhibitors / Q000494:pharmacology; D051381:Rats; D017207:Rats, Sprague-Dawley; D015398:Signal Transduction; D013311:Streptozocin
chemical_list: D051275:Glucose Transporter Type 4; D007328:Insulin; D011480:Protease Inhibitors; C495694:Slc2a4 protein, rat; D013311:Streptozocin; D003847:Deoxyglucose; D010122:Cystinyl Aminopeptidase; C105964:leucyl-cystinyl aminopeptidase; D005947:Glucose
keywords: GLUT4; IRAP; aminopeptidase; diabetes; glucose