title: The effects of repeated exposure to sub-toxic doses of plecomacrolide antibiotics on the endocrine pancreas.
abstract: The plecomacrolide vacuolar ATPase inhibitors bafilomycin and concanamycin contaminate tuberous vegetables and damage pancreatic islets in mice. The consequences of repeated exposure of adult mice to sub-toxic doses of bafilomycin A1 or concanamycin A was examined by injection of the plecomacrolides on each of five consecutive days. There was a significant reduction in islet size in female C57BL/6j mice (p<0.004 and p<0.0001 respectively). There were no significant differences in fasted insulin levels and beta cell mass between treated and control groups but oral glucose tolerance worsened with increasing age in BALB/c female mice injected with concanamycin A. Streptozotocin reduced glucose tolerance and islet number but not islet size in all strains and sexes. Chronic exposure of C57BL/6j mice to concanamycin A for 16 weeks caused a significant reduction in islet size in both sexes and a significant increase in the spleen weight of female mice (p<0.001). We conclude that repeated exposure to small quantities of vacuolar proton-translocating ATPase inhibitory plecomacrolides reduces islet size and can lead to glucose intolerance, possibly due to impaired maintenance of pancreatic islets. This may lead to earlier progression to beta cell failure and insulin deficiency in those at risk of diabetes.
authors.affiliation: Department of Biochemistry and Molecular Biology, Monash University, Wellington Road, Clayton, Vic. 3800, Australia.
authors.forename: Kalindi D
authors.initials: KD
authors.lastname: Hettiarachchi
authors.forename: Paul Z
authors.initials: PZ
authors.lastname: Zimmet
authors.forename: Mark A
authors.initials: MA
authors.lastname: Myers
mesh_terms: D000818:Animals; D000900:Anti-Bacterial Agents / Q000633:toxicity*; D001786:Blood Glucose / Q000187:drug effects; D001835:Body Weight / Q000187:drug effects; D004791:Enzyme Inhibitors / Q000633:toxicity*; D005260:Female; D005951:Glucose Tolerance Test; D007328:Insulin / Q000097:blood; D007515:Islets of Langerhans / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology; D018942:Macrolides / Q000633:toxicity*; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D009929:Organ Size / Q000187:drug effects; D006180:Proton-Translocating ATPases / Q000037:antagonists & inhibitors*; D013154:Spleen / Q000187:drug effects / Q000473:pathology; D013311:Streptozocin / Q000633:toxicity
chemical_list: D000900:Anti-Bacterial Agents; D001786:Blood Glucose; D004791:Enzyme Inhibitors; D007328:Insulin; D018942:Macrolides; D013311:Streptozocin; C036978:concanamycin A; C040929:bafilomycin A1; D006180:Proton-Translocating ATPases