Dataset Information

Efficacy and safety of aldose reductase inhibitor for the treatment of diabetic cardiovascular autonomic neuropathy: systematic review and meta-analysis.

ABSTRACT:

Background

Aldose reductase inhibitors (ARIs) can block the metabolism of the polyol pathway, and have been used to slow or reverse the progression of diabetic cardiovascular autonomic neuropathy (DCAN). The purpose of this study was to review the effectiveness and safety of ARIs in the treatment of DCAN as determined by five cardiac autonomic neuropathy function tests.

Methods

CENTRAL, MEDLINE, EMBASE, Scopus databases (inception to May 2012) were searched to identify randomized controlled trials (RCTs) and non-randomized controlled trials (non-RCTs) investigating ARIs for the treatment of DCAN with an English-language restriction. The data were analyzed using RevMan 5.0, and the heterogeneity between the trials was evaluated using the Cochrane's Q-test as well as the I² test. The type of model (random or fixed) used for analysis was based on heterogeneity. Weighted mean differences (WMD) with 95% confidence intervals (CI) were computed for the five cardiac automatic neuropathy function tests to evaluate the effects.

Results

Ten articles met the prerequisites for this review. Analysis of the results showed that ARIs significantly improved function in at least three of the five automatic neuropathy tests, including the resting heart rate variation coefficients (WMD?=?0.25, 95%CI 0.02 to 0.48, P?=?0.040); the 30?15 ratio (WMD?=?0.06, 95%CI 0.01 to 0.10, P?=?0.010) and the postural systolic blood pressure change (WMD?=?-5.94, 95%CI -7.31 to -4.57, P?=?0.001). The expiration/inspiration ratio showed a marginally significant benefit (WMD?=?0.05, 95%CI 0.00 to 0.09, P?=?0.040). Glycaemic control was not significantly affected by ARIs. Adverse effects of ARIs except for Tolerestat were minimal.

Conclusions

Based on these results, we conclude that ARIs could ameliorate cardiac automatic neuropathy especially mild or asymptomatic DCAN but need further investigation.

SUBMITTER: Hu X

PROVIDER: S-EPMC3922720 | biostudies-literature | 2014

REPOSITORIES: biostudies-literature

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Publications

Efficacy and safety of aldose reductase inhibitor for the treatment of diabetic cardiovascular autonomic neuropathy: systematic review and meta-analysis.

Hu Xin X Li Shengbing S Yang Gangyi G Liu Hua H Boden Guenther G Li Ling L

PloS one 20140212 2

<h4>Background</h4>Aldose reductase inhibitors (ARIs) can block the metabolism of the polyol pathway, and have been used to slow or reverse the progression of diabetic cardiovascular autonomic neuropathy (DCAN). The purpose of this study was to review the effectiveness and safety of ARIs in the treatment of DCAN as determined by five cardiac autonomic neuropathy function tests.<h4>Methods</h4>CENTRAL, MEDLINE, EMBASE, Scopus databases (inception to May 2012) were searched to identify randomized ...[more]

PMID: 24533052

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Project description:Long-term metabolic aberrations contribute to the development of diabetic neuropathy but the precise mechanism or mechanisms remains elusive. We have previously shown that aldose reductase-deficient mice exhibit delayed onset and progression of neuropathy following induction of diabetes, suggesting a role both for downstream metabolites of this enzyme and also for other unrelated pathways. In this study, we have utilized comprehensive metabolomics analyses to identify potential neurotoxic metabolites in nerve of diabetic mice and explored the mechanism of peripheral nerve injury. Aldose reductase knockout and control C57Bl/6J mice were made diabetic by injection of streptozotocin and followed for 8-16 weeks. Diabetic aldose reductase knockout mice exhibited delayed onset of nerve conduction slowing compared to diabetic wild-type mice. The sciatic nerves from aldose reductase knockout mice exposed to 12 weeks of diabetes were used for metabolomics analysis and compared with analyses of nerves from age-matched diabetic wild-type mice as well as non-diabetic aldose reductase knockout and wild-type mice. Neurotoxicity of candidate metabolites was evaluated using cultured Schwann cells and dorsal root ganglion neurons, and further confirmed in vivo. Metabolomics analysis identified elevated glucosamine levels in both diabetic aldose reductase knockout and diabetic wild mice. Exposure to glucosamine reduced survival of cultured Schwann cells and neurons accompanied by increased expression of cleaved caspase 3, CCAT-enhancer-binding homologous protein and mitochondrial hexokinase-I, along with ATP depletion. These changes were suppressed by siRNA to hexokinase-I or the ATP donor, inosine, but not by the antioxidant N-acetylcysteine or the endoplasmic reticulum-stress inhibitor 4-phenylbutyrate. The O-GlcNAcylation enhancer, O-(2-acetamido-2-deoxy-d-glucopyranosylidene) amino N-phenylcarbamate, did not augment glucosamine neurotoxicity. Single dose glucosamine injection into mice caused a reduction of sciatic nerve Na, K-ATPase activity, ATP content and augmented expression of hexokinase-I, which were suppressed by pretreatment with inosine but not with 4-phenylbutyrate. Mice implanted with a subcutaneous pump to infuse glucosamine for 12 weeks developed nerve conduction slowing and intraepidermal nerve fibre loss, recapitulating prominent indices of diabetic neuropathy. While acute glucosamine neurotoxicity is unlikely to contribute substantially to the slowly developing neuropathy phenotype in humans, sustained energy deprivation induced by glucosamine may well contribute to the pathogenesis of diabetic neuropathy. Our data thus identifies a novel pathway for diabetic neuropathy that may offer a potential new therapeutic target.

Dataset Information

Efficacy and safety of aldose reductase inhibitor for the treatment of diabetic cardiovascular autonomic neuropathy: systematic review and meta-analysis.

Background

Methods

Results

Conclusions

Publications

Efficacy and safety of aldose reductase inhibitor for the treatment of diabetic cardiovascular autonomic neuropathy: systematic review and meta-analysis.

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