Diabetic neuropathy (DN) is a widespread disabling disorder comprising peripheral nerves’ damage.DNdevelops on a background of hyperglycemia and an entangled metabolic imbalance, mainly oxidative stress. The majority of related pathways like polyol, advanced glycation end products, poly-ADP-ribose polymerase, hexosamine, and protein kinase c all originated from initial oxidative stress. To date, no absolute cure for DN has been defined; although some drugs are conventionally used, much more can be found if all pathophysiological links with oxidative stress would be taken into account. In this paper, although current therapies for DN have been reviewed, we have mainly focused on the links between DN and oxidative stress and therapies on the horizon, such as inhibitors of protein kinase C, aldose reductase, and advanced glycation. With reference to oxidative stress and the related pathways, the following new drugs are under study such as taurine, acetyl-L-carnitine, alpha lipoic acid, protein kinase C inhibitor (ruboxistaurin), aldose reductase inhibitors (fidarestat, epalrestat, ranirestat), advanced glycation end product inhibitors (benfotiamine, aspirin, aminoguanidine), the hexosamine pathway inhibitor (benfotiamine), inhibitor of poly ADPribose polymerase (nicotinamide), and angiotensin-converting enzyme inhibitor (trandolapril).Thedevelopment ofmodern drugs to treat DN is a real challenge and needs intensive long-term comparative trials.

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Abstract

Diabetic neuropathy presents a major public health problem. It is defined by the symptoms and signs of peripheral nerve dysfunction in diabetic patients, in whom other causes of neuropathy have been excluded. Pathogenetic mechanisms that have been implicated in diabetic neuropathy are: a) increased flux through the polyol pathway, leading to accumulation of sorbitol, a reduction in myo-inositol, and an associated reduced Na+-K+-ATPase activity, and b) endoneurial microvascular damage and hypoxia due to nitric oxide inactivation by increased oxygen free radical activity. Alpha-lipoic acid seems to delay or reverse peripheral diabetic neuropathy through its multiple antioxidant properties. Treatment with alpha-lipoic acid increases reduced glutathione, an important endogenous antioxidant. In clinical trials, 600 mg alpha-lipoic acid has been shown to improve neuropathic deficits. This review focuses on the relationship of alphalipoic acid and auto-oxidative glycosylation. It discusses the impact of alpha-lipoic acid on hyperglycemia-induced oxidative stress, and examines the role of alpha-lipoic acid in preventing glycation process and nerve hypoxia.

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1. Introduction

Diabetes affects more than 300 million individuals in the world with significant morbidity and mortality worldwide [1]. In the United States, it has been estimated that the incidence is about 1 million new cases per year [2]. People with diabetes are at high risk of microvascular complications including diabetic retinopathy, diabetic nephropathy, and diabetic neuropathy, which have bad impact on quality of life and are associated with increasedmortality [3–5]. Risk factors for the development of diabetic microvascular complications include glycaemic control, age, diabetes duration, and smoking. Additional risk factors are age at onset of diabetes and genetic factors [4, 6]. In parallel to the increase in the prevalence of diabetes mellitus, there has been a resurgence of vitamin D deficiency worldwide [7, 8]. Immigrants to Europe fromtheMiddle East and Asia carry a high risk for vitamin D deficiency [7]. VitaminDhas traditionally been associated with calcemic activities, namely, calcium and phosphorus homeostasis and bone. However, recent evidence fromvarious lines of research suggested nontraditional roles of vitamin D in human health including cancer, autoimmune, infectious, respiratory, and cardiovascular diseases [9–18]. Hypovitaminosis D has recently emerged as one of the factors contributing to the development of both type 1 and type 2 diabetes mellitus [19–25]. The first report between hypovitaminosis D and glucose intolerance dates back to over 20 years ago when Pietschmann et al. showed that serum 25 (OH) vitamin
D (25-OHD) levels were lower in patients with DM2 as compared to nondiabetic controls [26]. Since then, several cross-sectional and case-control studies have shown an association between serum 25-OHD level and DM2 [19–25]. The third National Health and Nutrition Examination Survey (NHANES) data showed a negative relationship between fasting blood glucose and 25-OHD concentrations in healthy white postmenopausal women, and in Mexican American men and women but no similar effect was observed in non-Hispanic black population, suggesting this effect might differ by ethnicity [21].While there is accumulating evidence that hypovitaminosis D is associated with higher prevalence DM2, data on the effect of vitamin D deficiency on diabetes control and complications, namely, microvascular complications are scarce. Suzuki et al. showed in a cohort of 581 Japanese diabetic subjects that serum25-OHDlevels were significantly lower in subjectswithdiabetic retinopathy comparedtothose without diabetic retinopathy and in those withmicrovascular complications compared to those without microvascular complications [27]. Inukai et al. showed that serum 25- OHDlevels were decreased inDM2 patients with retinopathy and/or proteinuria when compared with DM2 patients who had no microangiopathy [28]. Both in vitro and in vivo studies showed that vitaminD is a neurotrophic substance but its role in diabetic neuropathic pain is uncertain [29]. Lee and Chen showed that vitamin D supplementation over 3months improved neuropathic symptoms by 50% in diabetic patients whose vitamin D was deficient at baseline [30]. In this study we assessed the relationship between serum 25-OHD levels and diabetes control and microvascular diabetic complications in patients with type 2 diabetes mellitus presenting to a tertiary care center in Beirut.

To evaluate the effects and safety of 300–600 mg a-lipoic acid (ALA) given i.v. for diabetic
peripheral neuropathy (DPN).

1.1. Subjects.

All patients with type DM2 presenting to the diabetes clinic at our tertiary care center during the study period extending from November to February were invited to participate. 136 patients with balanced representation with regard to socioeconomic status were enrolled in the study. In addition, 74 healthy patients visiting the clinic during the same period for nondiabetes medical issues served as controls.

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Objective:

To evaluate the effects and safety of 300–600 mg a-lipoic acid (ALA) given i.v. for diabetic
peripheral neuropathy (DPN).

Methods:

We searched the databases of Medline, Embase, and Cochrane central register of Controlled Trials and Chinese biological medicine for clinical trials of ALA in the treatment of DPN. Data were extracted to examine methodological quality and describe characteristics of studies. The primary outcomes were efficacy, median motor nerve conduction velocity (MNCV), median sensory nerve conduction velocity (SNCV), peroneal MNCV, and peroneal SNCV. Secondary outcomes were adverse events.

Results:

Fifteen randomized controlled trials met the inclusion criteria. The treatment group involved the administration ofALA300–600 mgi.v. per day. And the control group used the same interventions except for ALA. Compared with the control group, nerve conduction velocities increased significantly in the treatment group. The weighted mean differences in nerve conduction velocities were 4.63 (95% confidence interval 3.58–5.67) formedian MNCV, 3.17 (1.75–4.59) for median SNCV, 4.25 (2.78–5.72) for peroneal MNCV, and 3.65 (1.50–5.80) for peroneal SNCV in favor of the treatment group. The odds ratio in terms of efficacy was 4.03 (2.73–5.94) for ALA. Furthermore, no serious adverse events were observed during the treatment period.

Conclusions:

The results of this meta-analysis provide evidence that treatment with ALA (300–600 mg/day i.v. for 2–4 weeks) is safe and that the treatment can significantly improve both nerve conduction velocity and positive neuropathic symptoms. However, the evidence may not be strong because most of the studies included in this meta-analysis have poor methodological quality.

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Alpha-lipoic acid (LA) has become a common ingredient in multivitamin formulas, anti-aging supplements, and even pet food. It is well-defined as a therapy for preventing diabetic polyneuropathies, and scavenges free radicals, chelates metals, and restores intracellular glutathione levels which otherwise decline with age. How do the biochemical properties of LA relate to its biological effects? Herein, we review the molecular mechanisms of LA discovered using cell and animal models, and the effects of LA on human subjects. Though LA has long been touted as an antioxidant, it has also been shown to improve glucose and ascorbate handling, increase eNOS activity, activate Phase II detoxification via the transcription factor Nrf2, and lower expression of MMP-9 and VCAM-1 through repression of NF-kappa-B. LA and its reduced form, dihydrolipoic
acid, may use their chemical properties as a redox couple to alter protein conformations by forming mixed disulfides. Beneficial effects are achieved with low micromolar levels of LA, suggesting that some of its therapeutic potential extends beyond the strict definition of an antioxidant. Current trials are investigating whether these beneficial properties of LA make it an appropriate treatment not just for diabetes, but also for the prevention of vascular disease, hypertension, and inflammation.

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Background:

Neuropathic pain is difficult to treat. We identified those studies in the literature in which the effectiveness of alpha lipoic acid as a treatment for neuropathic pain was evaluated.

Methods:

Systematic literature review. The databases MEDLINE and EMBASE were searched using the keywords “lipoic acid”, “thioctic acid”, “diabet*”, and the medical subject headings (MeSH ) “thioctic acid” and “diabetes mellitus”. Randomised placebo-controlled trials (RCTs) and meta-analyses were selected and assessed for their methodological quality.

Results:

Five RCTs and one meta-analysis were found. The Total Symptom Score (TSS ) was used as the primary outcome measure. A significant improvement in the TSS was reported in four of the RCTs. An oral or intravenous alpha lipoic dose of at least 600 mg per day resulted in a 50% reduction in the TSS . However, compared with the control group, the TSS reduction in most groups was less than 30%, which is the threshold presumed to be clinically relevant. Four RCTs were of good quality (level of evidence 1b), one RCT had methodological limitations (level 2b), and the methodological quality of the meta-analysis was insufficient for the purposes of this review.

Conclusion:

Based on the currently available evidence, when given intravenously at a dosage of 600 mg once daily over a period of three weeks, alpha lipoic acid leads to a significant and clinically relevant reduction in neuropathic pain (grade of recommendation A). It is unclear if the significant improvements seen after three to five weeks of oral administration at a dosage of ≥600 mg daily are clinically relevant.

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