title: KU-32, a novel drug for diabetic neuropathy, is safe for human islets and improves in vitro insulin secretion and viability.
abstract: KU-32 is a novel, novobiocin-based Hsp90 inhibitor that protects against neuronal glucotoxicity and reverses multiple clinical indices of diabetic peripheral neuropathy in a rodent model. However, any drug with potential for treating diabetic complications must also have no adverse effects on the function of pancreatic islets. Thus, the goal of the current study was to assess the effect of KU-32 on the in vitro viability and function of human islets. Treating human islets with KU-32 for 24 hours showed no toxicity as assessed using the alamarBlue assay. Confocal microscopy confirmed that with a minimum of 2-day exposure, KU-32 improved cellular viability by blocking apoptosis. Functionally, isolated human islets released more glucose-stimulated insulin when preincubated in KU-32. However, diabetic BKS-db/db mice, a model for type 2 diabetes, administered KU-32 for 10 weeks did not show any significant changes in blood glucose and insulin levels, despite having greater insulin staining/beta cell in the pancreas compared to untreated BKS db/db mice. In summary, KU-32 did not harm isolated human islets and may even be protective. However, the effect does not appear significant enough to alter the in vivo metabolic parameters of diabetic mice.
authors.affiliation: Department of Pharmacology and Toxicology, University of Kansas, 5064 Malott Hall, Lawrence, KS 66045, USA.
authors.forename: Kevin
authors.initials: K
authors.lastname: Farmer
authors.forename: S Janette
authors.initials: SJ
authors.lastname: Williams
authors.forename: Lesya
authors.initials: L
authors.lastname: Novikova
authors.forename: Karthik
authors.initials: K
authors.lastname: Ramachandran
authors.forename: Sonia
authors.initials: S
authors.lastname: Rawal
authors.forename: Brian S J
authors.initials: BS
authors.lastname: Blagg
authors.forename: Rick
authors.initials: R
authors.lastname: Dobrowsky
authors.forename: Lisa
authors.initials: L
authors.lastname: Stehno-Bittel
mesh_terms: D000328:Adult; D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D001786:Blood Glucose / Q000187:drug effects / Q000378:metabolism; D002470:Cell Survival / Q000187:drug effects; D003924:Diabetes Mellitus, Type 2 / Q000097:blood / Q000150:complications / Q000188:drug therapy* / Q000473:pathology; D003929:Diabetic Neuropathies / Q000097:blood / Q000188:drug therapy* / Q000473:pathology; D004195:Disease Models, Animal; D004305:Dose-Response Relationship, Drug; D005260:Female; D018841:HSP90 Heat-Shock Proteins / Q000037:antagonists & inhibitors / Q000378:metabolism; D006801:Humans; D007328:Insulin / Q000097:blood / Q000378:metabolism*; D000078790:Insulin Secretion; D007515:Islets of Langerhans / Q000187:drug effects* / Q000378:metabolism; D008297:Male; D051379:Mice; D018613:Microscopy, Confocal; D008875:Middle Aged; D018696:Neuroprotective Agents / Q000494:pharmacology*; D009675:Novobiocin / Q000031:analogs & derivatives* / Q000494:pharmacology / Q000633:toxicity; D013997:Time Factors; D046509:Tissue Culture Techniques
chemical_list: D001786:Blood Glucose; D018841:HSP90 Heat-Shock Proteins; D007328:Insulin; C581040:KU-32 compound; D018696:Neuroprotective Agents; D009675:Novobiocin