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.
Publication types
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Research Support, N.I.H., Extramural
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Research Support, Non-U.S. Gov't
MeSH terms
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Animals
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Cells, Cultured
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Diabetes Mellitus, Type 1 / complications
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Diabetes Mellitus, Type 1 / drug therapy*
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Diabetes Mellitus, Type 1 / metabolism
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Diabetes Mellitus, Type 1 / pathology
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Diabetes Mellitus, Type 2 / complications
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Diabetes Mellitus, Type 2 / drug therapy*
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Diabetes Mellitus, Type 2 / metabolism
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Diabetes Mellitus, Type 2 / pathology
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Diabetic Neuropathies / prevention & control*
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Dose-Response Relationship, Drug
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Female
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Ganglia, Spinal / drug effects
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Ganglia, Spinal / metabolism
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Ganglia, Spinal / pathology
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HSP70 Heat-Shock Proteins / genetics
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HSP70 Heat-Shock Proteins / metabolism*
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Hypoglycemic Agents / administration & dosage
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Hypoglycemic Agents / blood
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Hypoglycemic Agents / pharmacokinetics
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Hypoglycemic Agents / therapeutic use*
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Male
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Mice
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Mice, Inbred C57BL
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Mice, Knockout
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Mice, Transgenic
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Mitochondria / drug effects*
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Mitochondria / enzymology
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Mitochondria / metabolism
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Mitochondrial Dynamics / drug effects
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Neuritis / prevention & control
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Neurons / drug effects
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Neurons / enzymology
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Neurons / metabolism
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Neuroprotective Agents / administration & dosage
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Neuroprotective Agents / blood
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Neuroprotective Agents / pharmacokinetics
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Neuroprotective Agents / therapeutic use
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Novobiocin / administration & dosage
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Novobiocin / analogs & derivatives*
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Novobiocin / blood
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Novobiocin / pharmacokinetics
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Novobiocin / therapeutic use
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Oxidative Phosphorylation / drug effects*
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Sensory Receptor Cells / drug effects
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Sensory Receptor Cells / metabolism
Substances
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HSP70 Heat-Shock Proteins
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Hypoglycemic Agents
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KU-32 compound
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Neuroprotective Agents
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Novobiocin