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Targeting the Diabetic Chaperome to Improve Peripheral Neuropathy.

ABSTRACT: The chaperome constitutes a broad family of molecular chaperones and co-chaperones that facilitate the folding, refolding, and degradation of the proteome. Heat shock protein 90 (Hsp90) promotes the folding of numerous oncoproteins to aid survival of malignant phenotypes, and small molecule inhibitors of the Hsp90 chaperone complex offer a viable approach to treat certain cancers. One therapeutic attribute of this approach is the selectivity of these molecules to target high affinity oncogenic Hsp90 complexes present in tumor cells, which are absent in nontransformed cells. This selectivity has given rise to the idea that disease may contribute to forming a stress chaperome that is functionally distinct in its ability to interact with small molecule Hsp90 modulators. Consistent with this premise, modulating Hsp90 improves clinically relevant endpoints of diabetic peripheral neuropathy but has little impact in nondiabetic nerve. The concept of targeting the "diabetic chaperome" to treat diabetes and its complications is discussed.

SUBMITTER: Dobrowsky RT

PROVIDER: S-EPMC4929790 | biostudies-literature | 2016 Aug

REPOSITORIES: biostudies-literature

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Targeting the Diabetic Chaperome to Improve Peripheral Neuropathy.

Dobrowsky Rick T RT

Current diabetes reports 20160801 8

The chaperome constitutes a broad family of molecular chaperones and co-chaperones that facilitate the folding, refolding, and degradation of the proteome. Heat shock protein 90 (Hsp90) promotes the folding of numerous oncoproteins to aid survival of malignant phenotypes, and small molecule inhibitors of the Hsp90 chaperone complex offer a viable approach to treat certain cancers. One therapeutic attribute of this approach is the selectivity of these molecules to target high affinity oncogenic H ...[more]

PMID: 27318486

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Project description:BackgroundDiabetic peripheral neuropathy (DPN) is a common complication of diabetes mellitus and can lead to serious complications. Therapeutic strategies for pain control are available but there are few approaches that influence neurological deficits such as numbness.AimTo investigate the effectiveness of acupuncture on improving neurological deficits in patients suffering from type 2 DPN.MethodsThe acupuncture in DPN (ACUDPN) study was a two-armed, randomized, controlled, parallel group, open, multicenter clinical trial. Patients were randomized in a 1:1 ratio into two groups: The acupuncture group received 12 acupuncture treatments over 8 wk, and the control group was on a waiting list during the first 16 wk, before it received the same treatment as the other group. Both groups received routine care. Outcome parameters were evaluated after 8, 16 and 24 wk and included neurological scores, such as an 11-point numeric rating scale (NRS) 11 for hypesthesia, neuropathic pain symptom inventory (NPSI), neuropathy deficit score (NDS), neuropathy symptom score (NSS); nerve conduction studies (NCS) were assessed with a handheld point-of-care device.ResultsSixty-two participants were included. The NRS for numbness showed a difference of 2.3 (P < 0.001) in favor of the acupuncture group, the effect persisted until week 16 with a difference of 2.2 (P < 0.001) between groups and 1.8 points at week 24 compared to baseline. The NPSI was improved in the acupuncture group by 12.6 points (P < 0.001) at week 8, the NSS score at week 8 with a difference of 1.3 (P < 0.001); the NDS and the TNSc score improved for the acupuncture group in week 8, with a difference of 2.0 points (P < 0.001) compared to the control group. Effects were persistent in week 16 with a difference of 1.8 points (P < 0.05). The NCS showed no meaningful changes. In both groups only minor side effects were reported.ConclusionStudy results suggest that acupuncture may be beneficial in type 2 diabetic DPN and seems to lead to a reduction in neurological deficits. No serious adverse events were recorded and the adherence to treatment was high. Confirmatory randomized sham-controlled clinical studies with adequate patient numbers are needed to confirm the results.

Project description:BackgroundDecreased lean muscle mass in the lower extremity in diabetic peripheral neuropathy (DPN) is thought to contribute to altered joint loading, immobility, and disability. However, the mechanism behind this loss is unknown and could derive from a reduction in size of myofibers (atrophy), destruction of myofibers (degeneration), or both. Degenerative changes require participation of muscle stem (satellite) cells to regenerate lost myofibers and restore lean mass. Determining the degenerative state and residual regenerative capacity of DPN muscle will inform the utility of regeneration-targeted therapeutic strategies.MethodsBiopsies were acquired from 2 muscles in 12 individuals with and without diabetic neuropathy undergoing below-knee amputation surgery. Biopsies were subdivided for histological analysis, transcriptional profiling, and satellite cell isolation and culture.ResultsHistological analysis revealed evidence of ongoing degeneration and regeneration in DPN muscles. Transcriptional profiling supports these findings, indicating significant upregulation of regeneration-related pathways. However, regeneration appeared to be limited in samples exhibiting the most severe structural pathology as only extremely small, immature regenerated myofibers were found. Immunostaining for satellite cells revealed a significant decrease in their relative frequency only in the subset with severe pathology. Similarly, a reduction in fusion in cultured satellite cells in this group suggests impairment in regenerative capacity in severe DPN pathology.ConclusionDPN muscle exhibited features of degeneration with attempted regeneration. In the most severely pathological muscle samples, regeneration appeared to be stymied and our data suggest that this may be partly due to intrinsic dysfunction of the satellite cell pool in addition to extrinsic structural pathology (eg, nerve damage).Clinical relevanceRestoration of DPN muscle function for improved mobility and physical activity is a goal of surgical and rehabilitation clinicians. Identifying myofiber degeneration and compromised regeneration as contributors to dysfunction suggests that adjuvant cell-based therapies may improve clinical outcomes.

Dataset Information

Targeting the Diabetic Chaperome to Improve Peripheral Neuropathy.

Publications

Targeting the Diabetic Chaperome to Improve Peripheral Neuropathy.

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