title: Heat shock protein 70 is necessary to improve mitochondrial bioenergetics and reverse diabetic sensory neuropathy following KU-32 therapy.
abstract: Impaired neuronal mitochondrial bioenergetics contributes to the pathophysiologic progression of diabetic peripheral neuropathy (DPN) and may be a focal point for disease management. We have demonstrated that modulating heat shock protein (Hsp) 90 and Hsp70 with the small-molecule drug KU-32 ameliorates psychosensory, electrophysiologic, morphologic, and bioenergetic deficits of DPN in animal models of type 1 diabetes. The current study used mouse models of type 1 and type 2 diabetes to determine the relationship of changes in sensory neuron mitochondrial bioenergetics to the onset of and recovery from DPN. The onset of DPN showed a tight temporal correlation with a decrease in mitochondrial bioenergetics in a genetic model of type 2 diabetes. In contrast, sensory hypoalgesia developed 10 weeks before the occurrence of significant declines in sensory neuron mitochondrial bioenergetics in the type 1 model. KU-32 therapy improved mitochondrial bioenergetics in both the type 1 and type 2 models, and this tightly correlated with a decrease in DPN. Mechanistically, improved mitochondrial function following KU-32 therapy required Hsp70, since the drug was ineffective in diabetic Hsp70 knockout mice. Our data indicate that changes in mitochondrial bioenergetics may rapidly contribute to nerve dysfunction in type 2 diabetes, but not type 1 diabetes, and that modulating Hsp70 offers an effective approach toward correcting sensory neuron bioenergetic deficits and DPN in both type 1 and type 2 diabetes.
authors.affiliation: Department of Pharmacology and Toxicology (J.M., K.L.F., P.P. M.J.U., R.T.D.) and Department of Medicinal Chemistry (H.Z., B.S.J.B.), The University of Kansas, Lawrence, Kansas.
authors.forename: Jiacheng
authors.initials: J
authors.lastname: Ma
authors.forename: Kevin L
authors.initials: KL
authors.lastname: Farmer
authors.forename: Pan
authors.initials: P
authors.lastname: Pan
authors.forename: Michael J
authors.initials: MJ
authors.lastname: Urban
authors.forename: Huiping
authors.initials: H
authors.lastname: Zhao
authors.forename: Brian S J
authors.initials: BS
authors.lastname: Blagg
authors.forename: Rick T
authors.initials: RT
authors.lastname: Dobrowsky
mesh_terms: D000818:Animals; D002478:Cells, Cultured; D003922:Diabetes Mellitus, Type 1 / Q000150:complications / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D003924:Diabetes Mellitus, Type 2 / Q000150:complications / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D003929:Diabetic Neuropathies / Q000517:prevention & control*; D004305:Dose-Response Relationship, Drug; D005260:Female; D005727:Ganglia, Spinal / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D018840:HSP70 Heat-Shock Proteins / Q000235:genetics / Q000378:metabolism*; D007004:Hypoglycemic Agents / Q000008:administration & dosage / Q000097:blood / Q000493:pharmacokinetics / Q000627:therapeutic use*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008822:Mice, Transgenic; D008928:Mitochondria / Q000187:drug effects* / Q000201:enzymology / Q000378:metabolism; D063154:Mitochondrial Dynamics / Q000187:drug effects; D009443:Neuritis / Q000517:prevention & control; D009474:Neurons / Q000187:drug effects / Q000201:enzymology / Q000378:metabolism; D018696:Neuroprotective Agents / Q000008:administration & dosage / Q000097:blood / Q000493:pharmacokinetics / Q000627:therapeutic use; D009675:Novobiocin / Q000008:administration & dosage / Q000031:analogs & derivatives* / Q000097:blood / Q000493:pharmacokinetics / Q000627:therapeutic use; D010085:Oxidative Phosphorylation / Q000187:drug effects*; D011984:Sensory Receptor Cells / Q000187:drug effects / Q000378:metabolism
chemical_list: D018840:HSP70 Heat-Shock Proteins; D007004:Hypoglycemic Agents; C581040:KU-32 compound; D018696:Neuroprotective Agents; D009675:Novobiocin