Novologue Therapy Improves Mitochondrial Bioenergetics and Modulates Transcriptome Changes in Diabetic Sensory Neurons

Abstract

Diabetic peripheral neuropathy (DPN) is a prevalent diabetic complication with scarce treatment options. Impaired neuronal mitochondrial bioenergetics contributes to the pathophysiologic progression of DPN and may be a focal point for disease management. We have demonstrated that modulating Hsp90 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. We also sought to determine whether KU-596, an analogue of KU-32, offers similar therapeutic potential for treating DPN. Similar to KU-32, KU-596 improved psychosensory and bioenergetic deficits of DPN in a dose-dependent manner. However, the drug could not improve DPN in Hsp70 KO mice. Transcriptomic analysis using RNA sequencing (RNA-Seq) of DRG from diabetic wild type (WT) and Hsp70 KO mice revealed that KU-596 modulated transcription of genes involved in inflammatory pathways independently of Hsp70. In contrast, the effects of KU-596 on genes involved in the production of reactive oxygen species (ROS) are Hsp70-dependent. Our data indicate that modulation of molecular chaperones offers an effective approach towards correcting nerve dysfunction, and that normalization of inflammatory pathways alone by novologue therapy seems to be insufficient to reverse the deficits associated with insensate DPN in our model of type 1 diabetes.