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Abstract

This study was designed to investigate the effects of combined administration of lipoic acid and pyridoxine on albuminuria, oxidative stress, blood pressure, serum advanced glycation end-products, nitric oxide (NO), and endothelin-1 in patients with diabetic nephropathy. Thirty-four patients were randomly assigned to either a supplement group or a placebo group. The patients in the supplement group received 800 mg lipoic acid and 80 mg pyridoxine daily for 12 weeks, whereas the placebo group received corresponding placebos. Urinary albumin, serum malondialdehyde (MDA), and systolic blood pressure decreased significantly in the supplement group compared to the placebo group (p < 0.05). Serum NO increased in the supplement group compared to the placebo group (p < 0.05). Serum pentosidine and carboxymethyl lysine decreased significantly in the supplement group at the end of week 12 compared to baseline (p < 0.05). No statistically significant differences were observed between the two groups in mean changes of serum endothelin-1, glucose, and diastolic blood pressure. The present study indicates that combined administration of lipoic acid and pyridoxine improves albuminuria in patients with diabetic nephropathy by reducing oxidative stress, advanced glycation end-products, and systolic blood pressure. The reduction in microalbuminuria may be of benefit in retarding the progression of diabetic nephropathy.

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... During this period, a total of 4191 related kinds of literature were searched, excluding duplicate publications, reviews, systematic reviews, meta-analyses, and non-RCTs, leaving 554 RCTs. Due to incomplete data in some pieces of literature, non-double-blind, and placebocontrolled trials, 19 studies [89,90,[92][93][94][95][96][97][98][99][100][101][102][103][104][105][106][107][108] finally met the inclusion criteria. The filtering process is shown in Table 2. ...
... Fourteen studies provided information on generating randomized sequences [90, 92-94, 96, 98, 100-106, 108]. Fourteen studies improved assignment hiding methods [89, 92, 94, 96-98, 100-103, 105-108], and eighteen randomized controlled trials were double-blind [89,90,[92][93][94][95][96][97][98][99][100][101][102][103][104][105][106][107] and one trial was triple-blind [108]. All studies had low attrition bias [89,90,[92][93][94][95][96][97][98][99][100][101][102][103][104][105][106][107][108]. ...
... Fourteen studies improved assignment hiding methods [89, 92, 94, 96-98, 100-103, 105-108], and eighteen randomized controlled trials were double-blind [89,90,[92][93][94][95][96][97][98][99][100][101][102][103][104][105][106][107] and one trial was triple-blind [108]. All studies had low attrition bias [89,90,[92][93][94][95][96][97][98][99][100][101][102][103][104][105][106][107][108]. The reporting bias was low in one study and unclear in the remaining subjects [90]. ...
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Diabetic kidney disease (DKD) is more prevalent with an increase in diabetes mellitus. Oxidative stress is a major factor in the occurrence and progression of DKD. Defending against oxidative stress and restoring antioxidant defense might be key to preventing and treating DKD. The purpose of this article is to provide an explanation of how oxidative stress affects DKD, conduct a systematic review and meta-analysis on DKD, and examine the effect of antioxidants on the disease. An analysis of 19 randomized controlled trials showed that the use of antioxidants could reduce UAE (albumin excretion rate) in patients with DKD (SMD: − 0.31; 95% CI [− 0.47, − 0.14], I ² = 0%), UACR (urine albumin/creatinine ratio) (SMD: − 0.60; 95% CI [− 1.15, − 0.06], I ² = 89%), glycosylated hemoglobin (hbA1c) (MD: − 0.61; 95% CI [− 1.00, − 0.21], I ² = 93%) and MDA (malonaldehyde) (SMD:-1.05; 95% CI [− 1.87, − 0.23], I ² = 94%), suggesting that antioxidants seemed to have therapeutic effects in patients with DKD, especially in reducing proteinuria and hbA1c. The purpose of this study is to provide new targets and ideas for drug research and clinical treatment of DKD.
... Supplementary Table 2 contains a summary of the excluded articles based on full-text assessment with reasons for exclusion. Table 2 summarizes the general characteristics of 16 studies [15,[35][36][37][38][39][40][41][42][43][44][45][46][47][48][49] with 1035 participants included in this dose-response meta-analysis. In brief, the included RCTs had parallel designs and were published from March 1997 to October 2020. ...
... In brief, the included RCTs had parallel designs and were published from March 1997 to October 2020. Of the 16 included studies, eight studies were conducted in Asia [36, 40-43, 45, 48, 50], five were conducted in Europe [15,35,39,47,51], while three were conducted in the US [37,44,46]. All trials included adult patients with type 2 diabetes. ...
... Pooling the results of 10 trials with 669 participants [15, 35-37, 39, 40, 44, 46, 47, 50] showed a significant effect for each 500 mg/d increase in ALA supplementation in reducing TG levels (MD: -19.18 mg/dL; 95% CI -38.19 to -0.17, p=0.05) (Supplementary Figure 10). The association with ALA was driven by six studies [36,37,39,40,44,46] and did not persist when these studies were excluded (Supplementary Table 18). Subgroup analysis did not show credible differences between groups Supplementary Table 19. ...
Article
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Objective: To examine the dose-dependent influence of oral ALA supplementation on cardiometabolic risk factors in type 2 diabetes (T2D) patients. Design: We followed instructions outlined in the Cochrane Handbook for Systematic Reviews of Interventions and the Grading of Recommendations, Assessment, Development, and Evaluation Handbook to conduct our systematic review. The protocol of the study was registered in PROSPERO (CRD42021260587). Method: We searched PubMed, Scopus, and Web of Science to May 2021 for trials of oral ALA supplementation in adults with T2D. The primary outcomes were HbA1c, weight loss, and low-density lipoprotein cholesterol (LDL-C). Secondary outcomes included fasting plasma glucose (FPG), triglyceride, C-reactive protein, and blood pressure. We conducted a random-effects dose-response meta-analysis to calculate the mean difference (MD) and 95%CI for each 500 mg/d oral ALA supplementation. Non-linear dose-response meta-analyses were also conducted. Results: We included 16 trials with 1035 patients. Each 500 mg/d increase in oral ALA supplementation significantly reduced HbA1c, body weight, CRP, FPG, and TG. Dose-response meta-analyses indicated a linear decrement in body weight at ALA supplementation of more than 600 mg/d (mean difference 600 mg/d: -0.30 kg, 95%CI: -0.04, -0.57). A relatively J-shaped effect was seen for HbA1c (mean difference: -0.32%, 95%CI: -0.45, -0.18). Levels of FPG and LDL decreased up to 600 mg/d ALA intake. The point estimates of the certainty of evidence were below minimal clinically important difference thresholds for all outcomes. Conclusion: Despite significant improvements, the effects of oral ALA supplementation on cardiometabolic risk factors in T2D patients were not clinically important.
... Ergür et al. conducted a study in which ALA was administered orally in rats at a dosage of 100 mg/kg, and reported a significant reduction of secondary hypertension [8]. However, the findings of human trials are controversial [12][13][14]. In a recent study by Mohammadi et al., the daily supplementation of ALA with a dose of 600 mg on subjects with cardiovascular risk factors and chronic spinal cord injury revealed the systolic and diastolic blood pressure lowering effects [12]. ...
... More studies were excluded because of the following reasons: inappropriate reporting data on SBP or DBP, supplementation of ALA in less than two weeks, improper study design such as non-randomized trial, and lack of control group. Finally, ten studies were included in the meta-analysis [12][13][14][15][16][20][21][22][23][24]. ...
... Supplementation duration was between 8 weeks to 20 weeks, and the dose of supplementation varied from 300 to 1800 mg/d. Of the ten included trials, five recruited Type 2 Diabetic patients [13][14][15][16]20], one trial was performed in chronic spinal cord injury patients [12], one trial included subjects with stroke [24], two studies elected participants with obesity [16,23], the patients with metabolic syndrome and coronary artery disease were used in one study [22] and one more trial was conducted in patients with rheumatoid arthritis [21]. The mean age of subjects varied between 11.5 to 62.3 years. ...
Article
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Background: The aim of the present meta-Analysis was to detect the effect of a-lipoic acid (ALA) supplementation on systolic and diastolic blood pressure (BP). Material and methods: The related records were selected from several electronic databases from the earliest date 1980 until October 2019. The heterogeneities were assessed by I2 test (I2 50%) and c2 test on Cochrane s Q statistic. Standardized mean difference (SMD) and their 95% confidence intervals (CIs) were considered for net change in systolic blood pressure (SBP) and diastolic blood pressure (DBP). Subgroup analyses were also conducted by baseline BP, health status, doses of supplementation, study duration and supplement utilization. Results: As a result, a total of 10 studies with 612 subjects were included in the final analysis. Alpha-lipoic acid supplementation significantly reduced SBP (SMD =0.50, 95% CI:0.84,0.16, p = 0.004) and DBP (SMD =0.40, 95% CI:0.71,0.09, p = 0.01), compared to the controls, with the reduction of 6.1 mm Hg and 3.6 mm Hg of the mean SBP and DBP, respectively. Heterogeneities were explored in both SBP and DBP. Moreover, a statistically significant reduction in BP was detected in elevated BP and hypertensive patients as compared with the normotensive subjects. Conclusion: ALA supplementation could be considered as a BP-lowering agent, especially in subjects with higher blood pressure.
... [2,3] Besides the antioxidant properties of ALA, nitric oxide synthesis can be increased by ALA, which may improve endothelial function. [4] Several animal [5][6][7] and human [8][9][10] studies investigated the effect of ALA on blood pressure (BP) and some introduced it as a potential BP regulator. In addition, evidence suggests that ALA can reduce blood glucose by increasing glucose transporter-4 (GLUT-4) transportation to muscle and fat cell membranes and increasing glucose uptake. ...
... It is suggested to work by elevating nitric oxide production in endothelial cells, increasing reduced GSH levels in tissues, and affecting GSH peroxidase activity. [2,4,21] Several animal [5][6][7] and human [8][9][10]22,23] studies have supported our finding even though none of them has evaluated the effect of ALA consumption on BP in patients experienced stroke. Consistent with this trial Mohammadi et al. [8] examined the effect of 12-weeks supplementation with 600 mg ALA on BP in men with chronic spinal cord injury and reported a significant reduction in SBP and DBP within ALA group and between two groups. ...
... [10] In another clinical trial, a significant reduction in SBP and no change in DBP were observed following 12 weeks administration of combined ALA (800 mg) and pyridoxine (80 mg) in patients with diabetic nephropathy. [9] There are two studies with contrasting findings to our results. In one of them, Sola et al. investigated the effect of ALA, Irbesartan and their combination versus placebo on BP in patients with metabolic syndrome and observed no significant effect. ...
Article
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Background Stroke as a devastating condition is one of the major causes of death worldwide. It is accountable for long time disability with high personal and social cost in adults. There are several risk factors for stroke such as diabetes and hypertension. Alpha-lipoic acid (ALA) as an antioxidant can be a risk modifier in these patients. We designed this trial to scrutinize the possible effects of ALA consumption on some cardiovascular risk factors in patients experienced stroke. Methods In this randomized, double-blind, placebo-controlled clinical trial, 67 patients experienced stroke were randomly allocated into two groups (taking a 600 mg ALA supplement or placebo daily for 12 weeks). Fasting blood sugar (FBS), fasting insulin and systolic (SBP), and diastolic blood pressure (DBP) were measured before and after intervention in this study. Statistical analyses were performed using SPSS version 16 (SPSS Inc., Chicago, IL, USA) software. Results Primary features were similar in the intervention and placebo groups (P > 0.05). After the intervention period, SBP (P < 0.001), DBP (P < 0.001) and FBS (P < 0.001) reduced in ALA group compared with placebo group, significantly. No significant change was seen in insulin level (P = 0.82). Conclusions Results of this trial indicated that 12 weeks supplementation with 600 mg ALA has beneficial effects on SBP, DBP, and FBS but has no effect on insulin level.
... In human studies, upon LA supplementation, a small number of positive effects were identified, such as decrease in body weight [36,45,48], increased visual acuity [53] and protection against glomerular podocyte injury [51], in diabetic subjects. However, they have not identified any action on glucose [49], [50,52] or lipid profile [48]. In fact, adverse effects were observed, like increased low-density lipoproteins (LDL) oxidation [47] and carboxymethyl lysine levels [50], nullification of the positive effects of exercise on blood pressure [47] and worsening of diabetic peripheral neuropathy [57]. ...
... However, they have not identified any action on glucose [49], [50,52] or lipid profile [48]. In fact, adverse effects were observed, like increased low-density lipoproteins (LDL) oxidation [47] and carboxymethyl lysine levels [50], nullification of the positive effects of exercise on blood pressure [47] and worsening of diabetic peripheral neuropathy [57]. An exception is observed in the study of Porasuphatana [55], with type 2 diabetes patients who received LA (300, 600, 900 or 1200 mg/day), for a period of 6 months. ...
... Another complicating factor in the analysis of the data presented in this review was the fact that 50% of the studies for humans, used LA along with antioxidant vitamins or not [47,49,50,54,81,93], with substances with antioxidant effects [58][59][60]62,65,69,70] or physiotherapy [60]. As previously discussed, the use of combinatorial therapy made it difficult to discriminate the specific role of each component, raising difficulties to attribute beneficial, synergistic or antagonistic effects. ...
Article
Lipoic acid (LA) is an antioxidant able to produce its effects in aqueous or lipophilic environments. Lipoate is the conjugate base of lipoic acid, and the most prevalent form of LA under physiological conditions. It presents a highly negative reduction potential, increases the expression of antioxidant enzymes and participates in the recycling of vitamins C and E. Due to these properties, LA is called the "universal antioxidant". LA is also involved with anti-inflammatory action, independently of its antioxidant activity. This review was carried out, aiming to identify, analyze, and rationalize the various clinical, physiopathological and/or physiological situations in which LA, through oral supplementation, was tested on human and animal (rats and mice) models. LA was mainly tested in cardiovascular diseases (CVD), obesity, pain, inflammatory diseases and aging. LA uses in CVD and obesity, in humans, are controversial. On the other hand, beneficial effects on inflammation and pain were observed. LA supplementation in animal models may prolong life, has neuroprotective effects and presents positive effects against cancer. Differences observed in human and animal models can be due, in part, to different treatments (LA combined with other antioxidants, different doses) and to the variety of biomarkers investigated in animal experiments. These results suggest the need for further clinical trials to guide health professionals regarding the safety of prescription of this supplement.
... [14,15] Besides the antioxidant properties of ALA, nitric oxide synthesis can be increased by ALA, which may improve endothelial function. [16] Several animal [17][18][19] and human [20][21][22] studies investigated the effect of ALA on BP and some introduced it as a potential BP regulator. To the best of our knowledge, there is no systematic review in this field; moreover, the results of studies are contradictory. ...
... Based on scientific evidence, ALA is a powerful antioxidant with both aqueous and lipid solubility and performance characteristics. [13,14] In addition, ALA can increase nitric oxide production and improve endothelial function, therefore affects BP. [21] Mohammadi et al., [20] in their study on chronic spinal cord injury patients, reported a significant reduction in SBP and DBP within ALA group and in comparison with placebo. These findings can be explained by rising effect of the supplement on reduced GSH levels in tissues GSH peroxidase activity and nitric oxide production in endothelial cells. ...
... Growing evidence from human and animal studies shows that administration of ALA is protective against DN development and progression. In a randomized control trial involving 34 patients with DN, oral administration of ALA (800 mg/day) with pyridoxine (80 mg/day) for 12 weeks resulted in significant decrease in advanced glycation endproducts, albuminuria and systolic blood pressure, and improved antioxidant and glycemic status, along with increased serum nitric oxide compared to placebo-treated control group (Noori et al., 2013). The same salutary effect was observed in other randomized controlled trials with more than 60 DN patients in which ALA was administered for 2-8 weeks (Sun et al., 2017;Hong et al., 2017;Qu et al., 2018;Cao and Chen, 2021). ...
Article
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Kidney diseases have rapidly increased in prevalence over the past few decades, and have now become a major global public health concern. This has put economic burden on the public healthcare system and causing significant morbidity and mortality worldwide. Unfortunately, drugs currently in use for the management of kidney diseases have long-term major adverse effects that negatively impact the quality of life of these patients, hence making these drugs a “necessary evil”. In recent times, antioxidant therapy has been explored as a potential pharmacological avenue for treatment of kidney diseases, and could offer a better therapeutic option with less adverse effect profile. One of such antioxidants is alpha-lipoic acid (ALA), a sulphur-containing multifunctional antioxidant that is endogenously produced by lipoic acid synthase in the mitochondria of many tissues, including the kidney. Burgeoning evidence indicates that ALA is showing clinical promise in the treatment and pharmacological management of many kidney diseases through its antioxidant and other therapeutic properties by activating several protective mechanisms while inhibiting deleterious signaling pathways. In this review, we present ALA as a potent naturally occurring antioxidant, its mitochondrial biosynthesis and pharmacological properties. In addition, we also discuss within the limit of present literature, ALA and its underlying molecular mechanisms implicated in experimental and clinical treatment of various kidney conditions, and thus, may offer nephrologists an additional and/or alternative avenue in the pharmacological management and treatment of kidney diseases while giving hope to these patients.
... Growing evidence from human and animal studies shows that administration of ALA is protective against DN development and progression. In a randomized control trial involving 34 patients with DN, oral administration of ALA (800 mg/day) with pyridoxine (80 mg/day) for 12 weeks resulted in significant decrease in advanced glycation endproducts, albuminuria and systolic blood pressure, and improved antioxidant and glycemic status, along with increased serum nitric oxide compared to placebo-treated control group (Noori et al., 2013). The same salutary effect was observed in other randomized controlled trials with more than 60 DN patients in which ALA was administered for 2-8 weeks (Sun et al., 2017;Hong et al., 2017;Qu et al., 2018;Cao and Chen, 2021). ...
... have shown inconsistent results, strongly indicating that the beneficial effects of antioxidants on DN progression are controversial [40][41][42][43][44][45][46][47][48][49][50][51][52]. Why are there so many inconclusive trials on antioxidant therapy? ...
Article
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Oxidative stress can cause generation of uncontrolled reactive oxygen species (ROS) and lead to cytotoxic damage to cells and tissues. Recently, it has been shown that transient ROS generation can serve as a secondary messenger in receptor-mediated cell signaling. Although excessive levels of ROS are harmful, moderated levels of ROS are essential for normal physiological function. Therefore, regulating cellular ROS levels should be an important concept for development of novel therapeutics for treating diseases. The overexpression and hyperactivation of NADPH oxidase (Nox) can induce high levels of ROS, which are strongly associated with diabetic nephropathy. This review discusses the theoretical basis for development of the Nox inhibitor as a regulator of ROS homeostasis to provide emerging therapeutic opportunities for diabetic nephropathy.
... α-lipoic acid (ALA) is an antioxidant that was shown to up-regulate the expression of Nrf2-mediated antioxidant genes, peroxisome proliferator-activated receptorsregulated genes, and was used to treat diabetes [81]. In this case, ALA improved insulin sensitivity, protecting remaining β-cells by reducing their oxidative stress, reducing lipid peroxidation, and inhibiting protein glycation [81,82]. Meta-analysis of the combination of ALA and valsartan in DN showed that this combination significantly reduces urinary albumin, level of oxidative stress markers, increases antioxidant capacity, and alleviates renal function damage [83]. ...
Article
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Chronic kidney disease is generally progressive and currently has no reliable treatment to reverse a decline in kidney function or to slow the progression of the disease. Diabetic nephropathy is one of the leading causes of end-stage kidney failure. Kidney damage in diabetic nephropathy is largely attributed to the increased oxidative stress, affecting its metabolic activity, metabolic pathways, and hemodynamic pathways. In diabetic patients, hyperglycemia causes an increase in the production of reactive oxygen species that further increase oxidative stress. These reactive oxygen species are created through a variety of pathways, providing the opportunity for treatment using anti-oxidative defense mechanisms to prevent vascular injury. This review will give an overview of oxidative stress, along with the current treatments and limitations of diabetic nephropathy. We will also discuss the potential of antioxidative therapies, with an emphasis on the nuclear factor erythroid 2–related factor 2 (Nrf2) pathway.
... In a recent DN study in rats, Zhang et al [69] also reported that gliclazide administration inhibited endoplasmic reticulum (ER) stress via downregulation of the renal ER stress proteins GRP78 and sXBP1 and mRNA expression, which contributed to renal protection. Therefore, it is likely that the significant renal protection by the triple combination therapy observed in the present study is via the same mechanisms including lipid control mechanisms and possibly via other unidentified protective pathways that restored renal antioxidant status as was also observed in other preclinical and clinical studies [24,40,58,[69][70][71]. These pieces of empirical evidence suggest that interrupting the overproduction of ROS would be a promising approach to normalize these pathological pathways in the treatment of DN and other diabetic complications. ...
Article
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Background Diabetic nephropathy (DN) is the leading cause of end-stage renal disease. Current pharmacological interventions only retard DN progression. Alpha-lipoic acid (ALA) is a potent antioxidant with beneficial effect in other diabetic complications. This study investigates whether ALA supplementation prevents early development and progression of DN. Method Fifty-eight male Sprague-Dawley rats were randomly assigned to healthy control and diabetic groups and subjected to overnight fasting. Type 2 diabetes mellitus (T2DM) was induced in diabetic group by intraperitoneal administration of nicotinamide (110 mg/kg) and streptozotocin (55 mg/kg). On day 3 after T2DM induction, diabetic rats received oral daily administration of ALA (60 mg/kg), gliclazide (15 mg/kg), ramipril (10 mg/kg) or drug combinations for 6 weeks. Untreated diabetic rats served as diabetic control. Blood, kidneys and pancreas were harvested for biochemical and histological analyses. Result Induction of T2DM resulted in hypoinsulinemia, hyperglycemia and renal pathology. ALA supplementation maintained β-cell function, normoinsulinemia and normoglycemia in diabetic rats, and prevented renal pathology (PAS, KIM-1, plasma creatinine, total protein, blood urea nitrogen, uric acid and urine albumin/creatinine ratio) and triglycerides level compared to diabetic control (p < 0.001). Additionally, ALA supplementation significantly prevented elevated serum and tissue malondialdehyde, collagen deposition, α-SMA expression, apoptosis and serum IL-1β and IL-6 levels while it markedly increased renal glutathione content and plasma HDL-C compared to diabetic control group (p < 0.001). Conclusion ALA supplementation prevents early development and progression of DN by exerting anti-hyperglycemic, antioxidant, anti-inflammatory, anti-fibrotic and anti-apoptotic effects. Our findings provide additional option for clinical treatment of DN in T2DM patients.
... Further study found that lipoic acid could lower the concentration of proteinuria and mitigate oxidative stress and renal damage in diabetic rats [16]. One RCT reported that lipoic acid combined with pyridoxine could reduce oxidative stress and albuminuria in patients with DN [17]. ...
Article
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Abstract Background Diabetic nephropathy (DN) is one of the most serious microvascular complications of diabetes, valsartan and α-lipoic acid alone or in combination has been used for the treatment of patients with DN. However, some results in these clinical reports were still controversial. The purpose of this study was to evaluate the efficacy of valsartan combined with α-lipoic acid on renal function in patients with DN. Methods We searched the electronic databases including PubMed, Sciencedirect, EMBASE, Cochrane library, Chinese national knowledge infrastructure (CNKI) and Wanfang databases, and the publication deadline was limited to January 2020. Randomized controlled trials (RCTs) evaluating the effects of valsartan combined with α-lipoic acid in DN patients were included. Pooled estimates were conducted using a fixed or random effect model. The outcomes included urinary albumin excretion rate (UAER), and the level of urinary albumin, β2-microglobulin (β2-MG), hypersensitive C-reactive protein (hs-CRP) and oxidative stress. Results 11 studies with 1294 participants were included in this study. The pooled analysis indicated that α-lipoic acid combined with valsartan could remarkably reduce UAER (P
... De Cicco and colleagues (19) found that the combination therapy with ALA and myoinositol significantly reduces BMI in women with polycystic ovary syndrome. Noori and colleagues (20) found that consumption of 800 mg of ALA in diabetic nephropathy significantly decreases systolic blood pressure in the supplement group compared with the placebo group. ...
Article
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Background: Evidence suggests that Oxidative stress has been shown to plays an important role in gestational diabetes mellitus (GDM) etiology. On the other hand, women with GDM are at an increased risk for complications such as endothelial dysfunction and cardiovascular diseases. Objective: To investigate the effects of alpha-lipoic acid (ALA) on the maternal circulating values of lipid profile and lipid ratios in women with GDM. Materials and Methods: Sixty women with GDM were participated in the present study. The ALA group (n = 30) received ALA (100 mg/day) and the placebo group (n = 30) received cellulose acetate (100 mg/day) for eight wk. The maternal circulating values of hemoglobin A1C, triglyceride (TG), total cholesterol, high-density lipoprotein cholesterol (HDL-C), low-density lipoprotein cholesterol, triglyceride-glucose (TyG) index, atherogenic index of plasma (AIP), non-HDL-C, and lipid ratios were assessed before and after the intervention. P-value < 0.05 was considered as statistically significant. Results: The values of TyG index (p < 0.001), TG (p = 0.006), TG/HDL-C (p = 0.003), and AIP (p = 0.005) decreased significantly in the ALA group after the intervention. Conclusion: Maternal circulating values of TyG index, TG, TG/HDL, AIP decreased after eight wk of ALA supplementation in women with GDM.
... Xiang, Pu, Yue, Hou, & Sun, 2011;G. D. Xiang, Sun, et al., 2008;Yadav et al., 2005), three studies intervened ALA combined with other compounds(McMackin et al., 2007;Noori, Tabibi, Hosseinpanah, Hedayati, & Nafar, 2013;Wray et al., 2012) and one study did not have control group (S. R.Lee, Jeong, et al., 2006). ...
Article
There is evidence that alpha-lipoic acid (ALA) supplementation plays an important role in preventing cardiovascular diseases. However, its effect, specifically, on endothelial function (EF) is unclear. Therefore, this systematic review and meta-analysis aimed to evaluate the effects of ALA supplementation on EF. Databases including PubMed/Medline, Scopus, and ISI Web of Science were searched to identify eligible publications from inception up to April 2020. Randomized controlled trials assessing the effect of ALA supplementation on flow-mediated dilation (FMD) levels in adults were included. The pooled results were obtained using the random-effects model and are expressed as weighted mean differences (WMD) with 95% confidence intervals (CI). Five studies including six effect sizes and 300 participants were included. ALA supplementation significantly increased FMD levels by 2.36% (95% CI: 1.21-3.51; p < .001), compared with the control. Subgroup analyses suggested that the effects of ALA on FMD could be changed by age and health status of the participants. Dose-response analysis also showed that ALA dosage had a significant non-linear effect on FMD levels. The results showed that ALA supplementation appears to improve the EF. However, the role of ALA supplementation in improving other biomarkers of EF requires further research.
... 88 In patients with DN, the combined supplementation of α-lipoic acid (800 mg) and pyridoxine (80 mg) for 12 weeks significantly decreased albuminuria, compared to the placebo group (p = < 0.05), through the reduction of the OS, AGEs, and systolic arterial pressure. 89 Iranian Journal of Kidney Diseases | Volume 14 | Number 2 | March 2020 ...
Article
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Diabetic nephropathy (DN) is the leading cause of end-stage renal disease and oxidative stress (OS) has been recognized as a key factor in the pathogenesis and progression. Hyperglycemia, reactive oxygen species, advanced glycation end products, arterial pressure, insulin resistance, decrease in nitric oxide, inflammatory markers, and cytokines, among others; are involved in the presence of OS on DN. This revision focus on diverse studies in experimental and human models with diabetes and DN that has been demonstrated beneficial effects of different dietary antioxidant as resveratrol, curcumin, selenium, soy, catechins, α-lipoic acid, coenzyme Q10, omega-3 fatty acids, zinc, vitamins E and C, on OS and the capacity for antioxidant response. Therefore, this interventions could have a positive clinical impact on DN.
... Several recent studies proved its efficiency in promoting weight and fat loss, probably by stimulating the breakdown of fat and inhibiting formation of new fat cells [4,5]. Current trials are investigating whether the above-mentioned beneficial properties of ALA make it an appropriate treatment for the prevention of hypertension, inflammation, and vascular disease [6,7]. Proposed mechanisms of action involve the antioxidant activity of ALA, mediated by its direct radical scavenging activity, regeneration of other antioxidants, and metal chelating activity [2]. ...
Article
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Background: Oral dietary supplementation is becoming increasingly popular as an addition to classical approaches for the prevention and treatment of hemorrhoidal disease. Aim: To examine the effect of orally administrated alpha lipoic acid (ALA), known for its antioxidant and anti-inflammatory properties, in the treatment of patients with permanent symptoms of hemorrhoidal disease. Methods: Patients with second- and third-degree hemorrhoids (n = 100) were enrolled into a randomized, open label, single-center trial. The study group (n = 50) was treated with 200 mg of orally administered ALA once a day during the 12-week period, the control group (n = 50) did not receive any treatment. Results: There were no significant differences in demographics, diagnosis, or exposure to major risk factors between the study and placebo group at baseline. ALA significantly improved subjective efficacy variables, such as pain and discomfort (p < 0.01) as well as objective signs of the disease, such as bleeding (p < 0.01), in comparison to the control group. Furthermore, the 3-month treatment significantly reduced the number of patients with positive C-reactive protein (CRP) value (serum CRP > 5 mg/L) from 18% before to only 2% after the treatment (χ2 = 4.65; p < 0.01). Average leukocyte count has also been significantly reduced in the treatment group (p < 0.01) from 7.29 × 109/L before to 6.18 × 109/L after treatment. Conclusions: The obtained results indicate that ALA is effective in the treatment of second- and third-degree hemorrhoids. Larger, double-blind controlled trials are needed to confirm the results and to investigate optimal treatment regimens.
... 75 The association of the effects of pyridoxine and lipoid acid in patients with DN was associated with significant abatement of albuminuria, which was ascribed to reduction in oxidative stress, AGE accumulation, and systolic blood pressure. 76 Administration of lipoic acid alone improves urinary albumin excretion and plasma thrombomodulin levels without normalizing glucose metabolism. 77 ...
... Such supplementation resulted in significant decrease in albumin excretion. This finding was ascribed to both substances, as previously observed in the experimental setting, possibly via a decrease in oxidative and carbonyl stress [80]. However, two 24-week multicenter phase 2 trials investigating the effects of the administration of lipoic acid alone showed lack of efficacy on albuminuria excretion [81]. ...
Chapter
Obesity, metabolic syndrome, and diabetes mellitus have reached epidemic proportions in developed countries, where they constitute a major health challenge in the adult population. Treatment of diabetes relies on a combination of strict control of hyperglycemia and hypertension, changes in dietary and activity habits, and obesity reduction. Although long‐term marked weight loss is a difficult goal to achieve because of poor compliance, diet adjustments consisting of intake of functional foods and supplements are often more acceptable for the patient in view of their naturopathic connotation. This chapter deals with the vast literature that has appeared in the last decade on specific food nutrients with purported beneficial effects to prevent type 2 diabetes and its microvascular and macrovascular complications, including nephropathy, retinopathy, ischemic heart disease, and cerebrovascular disease. Numerous clinical and experimental studies support the favorable effects of nutraceuticals, more often of plant origin. This is hardly surprising because scientific interest in these foods has often been prompted by folk medicine tenets and traditional, ethnic fare. Non‐plant‐derived dietary supplements are also discussed. However, the challenging step, which has not been attained yet, remains the preparation of adequate diet protocols that may efficaciously convey the collected data. On one hand, these protocols should suit the individual patient's medical needs, life habits, and cultural/religious beliefs. On the other hand, they should combine, based on a sound scientific rationale, a spectrum of food supplements of proved beneficial properties to reach an optimal, synergistic effect.
... If no improvement can be achieved through the regimens described above, the last hope for the patients are renal replacement therapy, dialysis, or kidney transplantation in the extreme cases of diabetic nephropathy [22]. Recently, some patients with diabetic nephropathy are treated with drugs of targeted biological functions, such as, pyridorin with anti-AGE activity [23], suloexide with anti-fibrosis effects [24], and atrasentan that antagonizes endothelin receptor signaling [25]. Although several positive effects have been reported for these drugs, 3). ...
Article
Objective: To evaluate the protective effect of catalpol against diabetic nephropathy in db/db mouse. Methods: 8 week old C57BLKS/J db/db mice (type 2 diabetic mouse model) were divided into three groups to feed for 16 weeks on chow diet with or without catalpol supplementation. Their food intake, water consumption, body weight, and fasting glucose levels were recorded every 4 weeks. At the end of study, urine and blood samples were examined for several metabolic variables, and kidneys were harvested for structural characterization and microarray analysis. Results: Catalpol efficiently lowers the fasting glucose and the 24 h urinary albumin excretion rate. Catalpol significantly lowers serum triglycerides, increases high-density lipoproteins, and improves serum creatinine and urea nitrogen. Catalpol-fed mice preserve their kidney structure and renal function better than chow fed db/db mice. Microarray data indicates that lipid metabolism is a potential target of catalpol in exerting protective effect. Conclusion: Catalpol has a renal protective effect in diabetic db/db mice.
... The actual mechanism remains unclear, but may be partially explained by their antioxidant properties [144,145]. Speaking of antioxidant activity, α-lipoic acid which is a potent antioxidant can also confer AGE-lowering effect in diabetic patients when it is used together with other potential AGE inhibitors like benfotiamine and pyridoxine [126,146]. However, these studies did not include an "α-lipoic acid only" cohort and hence, its effect on AGE-RAGE axis independent from the interaction with other compounds is unclear. ...
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Advanced Glycation End Products (AGEs), together with its receptor (RAGE) are known to play a predominant role in the onset of diabetic micro-and macrovascular diseases. Therefore, therapeutic interventions which can target AGE-RAGE axis are of great interest in diabetic therapy. Animal studies demonstrated promising results for most of the AGE-RAGE inhibitors but their actual clinical values are not fully elaborated. Therefore, this review aimed to summarize clinical findings of well-known AGE-RAGE antagonists including AGE cross-link breaker (alagebrium), dicarbonyl scavengers (aminoguanidine), antidiabetic drugs (metformin, thiazolidinediones, meglitinides, sulfonylureas and dipeptidyl peptidase 4 inhibitor), lipid-lowering drugs (statins), antihypertensive agents (angiotensin receptor blockers, angiotensin converting enzyme inhibitors and calcium channel blockers), vitamin B1 (thiamine and benfotiamine) and B6 (pyridoxine and pyridoxamine) as well as other investigational pharmacotherapy. The inhibitory mechanism of the anti-AGE-RAGE agents are also discussed. To date, most of the therapeutic interventions targeting at AGE-RAGE axis produced conflicting clinical findings. Some of the most promising agents are metformin, thiazolidinediones and statins. It is postulated that the inhibition of AGE-RAGE axis may be more beneficial at the early stage of diabetes so as to delay the progression of the associated vascular complications. Future studies should aim to identify the subsets of diabetic patients whom will be truly benefited from AGE-RAGE inhibition.
... Based on scientific evidence, ALA is a powerful antioxidant with both aqueous and lipid solubility and performance characteristics.[13,14]In addition, ALA can increase nitric oxide production and improve endothelial function, therefore affects BP.[21]Mohammadi et al.,[20]in their study on chronic spinal cord injury patients, reported a significant reduction in SBP and DBP within ALA group and in comparison with placebo. These findings can be explained by rising effect of the supplement on reduced GSH levels in tissues GSH peroxidase activity and nitric oxide production in endothelial cells.[13,14,30]Authors ...
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Although several animal and human studies have investigated the effect of alpha-lipoic acid (ALA) on blood pressure (BP), these findings are inconsistent. This systematic review of randomized clinical trials was conducted to summarize the evidence on the effect of ALA on BP. PubMed, SCOPUS, and Google Scholar databases were searched based on MESH term (“Thioctic acid” in combination with “Hypertension” and “Blood pressure”) to identify related papers published up to December 2015. We summarized the results of the relevant studies in this review. In total, nine studies included in this review, seven parallel-designed trials and two crossover-designed trials. The results of parallel-designed studies are inconsistent. Five studies indicate no significant effects for ALA supplementation on BP, but two trials show effects on BP. Unlike parallel-designed trials, two crossover-designed trials have shown similar results and both report no effect for ALA on BP. Several studies investigated the effect of ALA on BP. Most of the papers show no significant effect for supplementation and the studies have shown that associations are limited. However, these findings are limited and there is a need for further and more accurate researches to be clarified.
... 251 Vitamin B 6 supplementation is known to correct the methionine load test in women at risk of pre-eclampsia, 216 to reduce urinary 8-hydroxy-2 0 -deoxyguanosine concentrations in normal Japanese men, 250 to reduce multiple plasma inflammatory biomarkers in US men and women, [253][254][255] to reduce homocysteine in women, 255 and to decrease systolic blood pressure and increase serum nitric oxide in diabetic patients. 256 Furthermore, vitamin B 6 may reduce oxidative damage by facilitating the synthesis of glutathione, a natural antioxidant. 257 Vitamin B 12 deficiency may cause hyperhomocysteinemia. 258,259 Additionally, the relationship between one-carbon biomarkers, mainly choline, betaine, vitamin B 6 , and vitamin B 12, and global DNA methylation in American postmenopausal women before and after folic acid fortification is reported to depend on folate availability. ...
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Dietary deficiencies of folate and other B vitamin cofactors involved in one-carbon metabolism, together with genetic polymorphisms in key folate-methionine metabolic pathway enzymes, are associated with increases in circulating plasma homocysteine, reduction in DNA methylation patterns, and genome instability events. All of these biomarkers have also been associated with pre-eclampsia. The aim of this review is to explore the literature and identify potential knowledge gaps in relation to the role of folate at the genomic level in either the etiology or the prevention of pre-eclampsia. A systematic search strategy was designed to identify citations in electronic databases for the following terms: folic acid supplementation AND pre-eclampsia, folic acid supplementation AND genome stability, folate AND genome stability AND pre-eclampsia, folic acid supplementation AND DNA methylation, and folate AND DNA methylation AND pre-eclampsia. Forty-three articles were selected according to predefined selection criteria. The studies included in the present review were not homogeneous, which made pooled analysis of the data very difficult. The present review highlights associations between folate deficiency and certain biomarkers observed in various tissues of women at risk of pre-eclampsia. Further investigation is required to understand the role of folate in either the etiology or the prevention of pre-eclampsia.
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Diabetes mellitus, a well-established risk factor for stroke, is related to higher mortality and poorer outcomes following the stroke event. Advanced glycation end products(AGEs), their receptors RAGEs, other ligands, and several other processes contribute to the cerebrovascular pathomechanism interaction in the diabetes-ischemic stroke combination. Critical reappraisal of molecular targets and therapeutic agents to mitigate them is required to identify key elements for therapeutic interventions that may improve patient outcomes. This scoping review maps evidence on the key roles of AGEs, RAGEs, other ligands such as Leukotriene B4 (LTB4), High-mobility group box 1 (HMGB1) nuclear protein, brain-kidney-muscle crosstalk, alternate pathomechanisms in neu-rodegeneration, and cognitive decline related to diabetic ischemic stroke. RAGE, HMGB1, nitricox-ide, and polyamine mechanisms are important therapeutic targets, inflicting common consequences of neuroinflammation andoxidative stress. Experimental findings on a numberof existing-emerging therapeutic agents and natural compounds against key targets are promising. The lackof large clinical trials with adequate follow-up periods is a gap that requires addressing to validate the emerging therapeutic agents. Five therapeutic components, which include agents to mitigate the AGE-RAGE axis, improved biomarkers for risk stratification, better renal dysfunction management, adjunctive anti-inflammatory-antioxidant therapies, and innovative neuromuscular stimulation for rehabilitation , are identified. A comprehensive therapeutic strategy that features all the identified components is needed for outcome improvement in diabetic stroke patients.
Chapter
The progression of kidney disease is the consequence of a reduction in the number of functioning filtration units or nephrons that can handle the complex tasks of filtering wastes and recycling body fluids. As this number diminishes other nephrons must take over this function and hyperfilter. This subsequently leads to further kidney damage. By controlling the diet by switching to a more plant dominant diet, we can help alleviate the burden to remaining nephrons and extend their life. Since hypertension and abnormal sugar metabolism play key roles in CKD progression, dietary changes that can reduce the consequences of these disorders are also examined. When the kidney function starts to decline, the ability to eliminate body acids also decreases, resulting in bone being used as a buffer. This results in both a weakening of bone and the deposition of calcium in other body tissues. Ultimately, metabolic acidosis leads to muscle and bone wasting, and further results in damage to the kidney cells. CKD is further complicated by a dysfunction in how the body handles minerals such as calcium and phosphorus, signaling hormones to excrete excess phosphorus from the kidney and to reabsorb additional calcium from bone. This chapter discusses dietary options that can help reduce kidney disease complications and progression.
Article
Background Diabetic nephropathy (DN) is a kidney dysfunction, which occurs due to elevated urine albumin excretion rate and reduced glomerular filtration rate. Studies in animals have shown that alpha-lipoic acid (ALA) supplementation can reduce the development of DN. Objectives We performed a systematic review and meta-analysis to examine the effects of ALA supplementation on biological indices (albumin, creatinine etc.) indicative of human DN. Methods The searching procedure included the databases PubMed Central, Embase, Cochrane Library (trials) and Web of Science, (protocol registration: INPLASY 202060095). Results We found that ALA supplementation decreased urine albumin 24h excretion rate in patients with diabetes [standardized mean difference=-2.27; confidence interval (CI)=(-4.09)–(-0.45); I2=98%; Z=2.44; p=0.01]. A subgroup analysis revealed that the studies examining only ALA, did not differ from those examined ALA in combination with additional medicines (Chi-squared=0.19; p=0.66; I2=0%), while neither ALA nor ALA plus medication had an effect on urine albumin 24h excretion rate (p>0.05). Also, ALA supplementation decreased urine albumin mg/l [mean difference (MD)=-12.95; CI=(-23.88)–(-2.02); I2=44%; Z=2.32; p=0.02] and urine albumin to creatinine ratio [MD=-26.96; CI=(-35.25)–(-18.67); I2=0%; Z=6.37; p<0.01] in patients with diabetes. When the studies that examined ALA plus medication were removed, ALA supplementation had no effect on urine albumin mg/l (p>0.05), but did significantly decrease urine albumin to creatinine ratio [MD=-25.88, CI=(34.40–(-17.36), I2=0%, Z=5.95, p<0.00001]. Conclusion The available evidence suggests that ALA supplementation does not improve biological indices that reflect DN in humans. Overall, we identified limited evidence and therefore, the outcomes should be considered with caution.
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Microvascular complications are responsible for a major proportion of the burden associated with diabetes contributing to substantial morbidity, mortality, and healthcare costs in people with diabetes. Retinopathy, nephropathy, and neuropathy constitute the leading causes of blindness, end-stage renal disease, and lower-extremity amputations, respectively. Since the efficacy of causal therapies of diabetic microvascular complications is limited, especially in type 2 diabetes, there is an unmet need for adjunct treatments which should be effective despite ongoing hyperglycemia. Experimental studies indicate that diabetic microvascular complications can be prevented or ameliorated by various biofactors in animal models by interfering with the pathophysiology of the underlying condition. Some of the findings related to biofactors like α-lipoic acid and benfotiamine could be translated into the clinical arena and confirmed in clinical trials, especially in those focusing on diabetic polyneuropathy. Given the micronutrient nature of these compounds, their safety profile is excellent. Thus, they have the potential to favorably modify the natural history of the underlying complication, but large long-term clinical trials are required to confirm this notion. Ultimately, biofactors should expand our therapeutic armamentarium against these common, debilitating, and even life-threatening sequelae of diabetes.
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Background Pyridoxine has reduction and prevention against the levels of reactive oxygen species in in vitro studies. However, the biochemical mechanism that explains this behavior has not yet been fully clarified. Objective To evaluate the effect of pyridoxine against oxidative damage on the membrane of human erythrocytes. Methods Cumene hydroperoxide was used to induce oxidative stress in protein and lipid. Human erythrocytes were incubated with pyridoxine and cumene hydroperoxide, either alone or together for 8 h. Oxidative damage was determined by measuring lipid peroxidation and membrane protein carbonylation. Results The results indicate that the malondialdehyde concentration decreased with increasing concentration of pyridoxine. The membrane protein content also decreased with increasing concentration of vitamin B6, which was confirmed by the decreased signal intensity in the western blot when compared to control without pyridoxine. Results demonstrate that pyridoxine can significantly decrease lipid peroxidation and protein carbonylation in red cell membrane exposed to high concentrations of oxidant agent. Conclusion Pyridoxine showed a protective effect against the oxidative stress in human erythrocytes in vitro , inhibiting the carbonylation and the oxidative damage of erythrocyte membrane proteins. To date, such an effect has not yet been reported in terms of protein oxidation.
Article
Background: Cardiovascular disease (CVD) is the main cause of death in hemodialysis (HD) patients and oxidative stress is an important risk factor for CVD. Superoxide dismutase (SOD), catalase (CAT), and glutathione peroxidase (GPx) are primary antioxidant enzymes in human cells acting against toxic reactive oxygen species (ROS) and their reduced activity may contribute to oxidative disorders in HD patients. Alpha lipoic acid (ALA) as a potent strong antioxidant may affect these enzymes. Objective: We examined the effects of ALA supplementation on antioxidant enzyme activities in HD patients. Method: In this double-blinded, randomized clinical trial, 63 HD patients (43 males and 20 females; age range: 22–79 years) were assigned into the ALA group (n: 31), receiving a daily dose of ALA (600 mg), or a control group (n: 32), receiving placebo for 8 weeks. Body mass index (BMI), antioxidant enzymes, albumin (Alb) and hemoglobin (Hb) were determined before and after intervention. Results: At baseline, the mean blood activities of SOD, GPx, and CAT in ALA group were 1032±366, 18.9±5.09 and 191±82.7 U/gHb which increased at the end of study to 1149±502, 19.1±7.19 and 208±86.6 U/gHb respectively. However, only the increase of SOD was statistically significant in comparison with placebo group (P = 0.04). The mean levels of Alb, Hb, weight and BMI were not significantly changed in study groups (P>0.05). Conclusion: ALA may be beneficial for HD patients by increasing the activity of antioxidant enzymes; however, further studies are needed to achieve precise results.
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Pyridoxine (vitamin B6)-responsive epilepsies are severe forms of epilepsy that manifest as seizures immediately after birth, sometimes in utero, sometimes months, or years after birth. Seizures may be treated efficiently by life-long supplementation with pyridoxine or its biologically active form, pyridoxal phosphate, but even so patients may become intellectually disabled, for which there currently is no effective treatment. The condition may be caused by mutations in several genes (TNSALP, PIGV, PIGL, PIGO, PNPO, PROSC, ALDH7A1, MOCS2, or ALDH4A1). Mutations in ALDH7A1, MOCS2, and ALDH4A1 entail build-up of reactive aldehydes (α-aminoadipic semialdehyde, γ-glutamic semialdehyde) that may react non-enzymatically with macromolecules of brain cells. Such reactions may alter the function of macromolecules, and they may produce “advanced glycation end products” (AGEs). AGEs trigger inflammation in the brain. This understanding points to aldehyde-quenching, anti-AGE, or anti-inflammatory therapies as possible strategies to protect cognitive development and prevent intellectual disability in affected children. Studies on how aldehydes traverse cell membranes and how they affect brain function could further the development of therapies for patients with pyridoxine-responsive epilepsies.
Article
Rheumatoid arthritis (RA) is a chronic inflammatory disease in which oxidative stress could play a substantial pathological role. Alpha-lipoic acid (ALA) has been known as a "universal" and "ideal" antioxidant. The purpose of this study was to investigate the effects of oral administration of Alpha-lipoic acid (ALA) on lipid peroxidation and antioxidant biomarkers in Rheumatoid arthritis (RA) patients. The study was a randomized, double-blinded, placebo-controlled clinical trial. 70 RA patients were randomized 1:1 to two groups using blocked randomization method and received 1200 mg/day ALA or placebo for 8 weeks. Fasting blood samples were obtained before and after the intervention to analyze total antioxidant capacity (TAC), antioxidant enzymes [superoxide dismutase (SOD), glutathione peroxidase (GSH-Px) and arylesterase (ARE) activities] and malondialdehyde (MDA). We observed significant increase in serum TAC (0.11 mmol/L; p=0.033) and ARE (13.76 U/mL; p=0.046) and significant decline in MDA (-0.36 nmol/L; p=0.002), in ALA group. However, these changes in ALA-treated group were not statistically significant when compared with placebo-treated group (p > 0.05). Also, within- and between-group differences of whole blood SOD and GSH-Px were not statistically significant (p > 0.05). In conclusion, unexpectedly, ALA therapy did not affect the oxidative status of RA patients in the present clinical trial. It seems that more comprehensive clinical trials in RA patients are still warranted to clarify the effectiveness of ALA which has been known as a potent antioxidant.
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Background Oxidative stress is a key player in the genesis and worsening of diabetic kidney disease (DKD). We aimed at collecting all available information on possible benefits of chronic antioxidant supplementations on DKD progression. Study design Systematic review and meta-analysis. Population Adults with DKD (either secondary to type 1 or 2 diabetes mellitus) Search strategy and sources Cochrane CENTRAL, Ovid-MEDLINE and PubMed were searched for randomized controlled trials (RCTs) or quasi-RCTs without language or follow-up restriction. Intervention Any antioxidant supplementation (including but not limited to vitamin A, vitamin C, vitamin E, selenium, zinc, methionine or ubiquinone) alone or in combination. Outcomes Primary outcome was progression to end-stage kidney disease (ESKD). Secondary outcomes were change in albuminuria, proteinuria, serum creatinine and renal function. Results From 13519 potentially relevant citations retrieved, 15 articles referring to 14 full studies (4345 participants) met the inclusion criteria. Antioxidant treatment significantly decreased albuminuria as compared to control (8 studies, 327 participants; SMD: -0.47; 95% CI -0.78, -0.16) but had apparently no tangible effects on renal function (GFR) (3 studies, 85 participants; MD -0.12 ml/min/1.73m²; 95% CI -0.06, 0.01). Evidence of benefits on the other outcomes of interest was inconclusive or lacking. Limitations Small sample size and limited number of studies. Scarce information available on hard endpoints (ESKD). High heterogeneity among studies with respect to DKD severity, type and duration of antioxidant therapy. Conclusions In DKD patients, antioxidants may improve early renal damage. Future studies targeting hard endpoints and with longer follow-up and larger sample size are needed to confirm the usefulness of these agents for retarding DKD progression.
Article
Diabetic nephropathy (DN) is one of the most common microvascular complication of diabetes mellitus (DM) as well as the main reason resulting in chronic renal failure. Transmembrane protein 16A (TMEM16A) plays an important role in multiple physiological actions. Here we found that it was up-regulated in high-fat diet (HFD)/streptozotocin (STZ)-induced diabetic mice. Moreover, reverse transcription-polymerase chain reaction (RT-PCR) amplification, Western blot detection, Periodic Acid Schiff (PAS) staining and immunohistochemical analysis confirmed that TMEM16A deficiency alleviated renal injury in diabetic mice and TMEM16A knockout diabetic mice were protected from the HFD-induced reduction in Nephrin expression. To understand further the molecular mechanism of its function, podocytes treated with high glucose (HG, 30 mmol/L glucose) in vitro was chosen as a model to study its signal transduction pathway. Nephrin expression level in siRNA-TMEM16A group was significantly higher than that of the HG group (also called Model group). Flow cytometric analysis revealed that podocyte apoptosis in siRNA-TMEM16A group was significantly lower than that of the Model group. RT-PCR and Western blot exhibited that apoptosis-related genes including apoptosis-inducing factor (AIF) and cystinylaspartate specific protease-3/-9 (caspase-3/-9) were dramatically down regulated in siRNA-TMEM16A group, compared with Model group. Phosphorylation levels of P38 and JNK in siRNA-TMEM16A group were lower than that of the Model group. Thus, TMEM16A is one of the critical components of a signal transduction pathway that links renal injury to podocyte apoptosis in DN.
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This article is a critical overview of recent contributions on the dietary corrections and the foods that have been claimed to delay or hinder the onset of diabetic nephropathy (DN) and its progression to end-stage renal disease. Innovative dietary and behavioral approaches to the prevention and therapy of DN appear the more captivating in consideration of the rather well established protocols for glucose and blood pressure control in use. In addition to restricted caloric intake to contrast obesity and the metabolic syndrome, adjustments in the patient's macronutrients intake, and in particular some degree of reduction in protein, have been long considered in the prevention of DN progression. More recently, the focus has shifted to the source of proteins and the content of glycotoxins in the diet as well as to the role of specific micronutrients. Few clinical trials have specifically addressed the role of those micronutrients associated with diet proteins that show the most protective effect against DN. Research on clinical outcome and mechanisms of action of such micronutrients appears the most promising in order to develop both effective intervention on nutritional education of the patient and selection of functional foods capable of contrasting the onset and progression of DN.
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Excess of saturated free fatty acids, such as palmitic acid (PA), in hepatocytes has been implicated in non-alcoholic fatty liver disease. α-lipoic acid (LA) is an antioxidant that protects against oxidative stress conditions. We have investigated the effect of LA in the early activation of oxidative and endoplasmic reticulum stress, lipid accumulation and Nrf2-mediated antioxidant defenses in hepatocytes treated with PA or in rats fed with high fat diet. In primary human hepatocytes, a lipotoxic concentration of PA triggered endoplasmic reticulum stress, induced the apoptotic transcription factor CHOP and increased the percentage of apoptotic cells. Co-treatment with LA prevented these effects. Similar results were found in mouse hepatocytes where LA attenuated PA-mediated activation of caspase 3, reduced lipid accumulation by decreasing PA uptake and increasing fatty acid oxidation and lipophagy, thereby, preventing lipoapoptosis. Moreover, LA augmented the proliferation capacity of hepatocytes after PA challenge. Antioxidant effects of LA ameliorated reactive oxygen species production, endoplasmic reticulum stress and protected against mitochondrial apoptosis in hepatocytes treated with PA. Co-treatment with PA and LA induced an early nuclear translocation of Nrf2 and activated antioxidant enzymes, whereas reduction of Nrf2 by siRNA abolished the benefit of LA on PA-induced lipoapoptosis. Importantly, post-treatment with LA reversed the established damage induced by PA in hepatocytes, as well as prevented obesity-induced oxidative stress and lipoapoptosis in rat liver. In conclusion, our work has revealed that in hepatocytes, Nrf2 is an essential early player in the rescue of oxidative stress by LA leading to protection against PA-mediated lipoapoptosis. Copyright © 2015. Published by Elsevier Inc.
Article
Study design: A randomized, double-blind, placebo-controlled clinical trial. Objective: To assess the effect of alpha-lipoic acid (ALA) supplementation on IL-6, hs-CRP, FBS, anthropometric indices, food intake and blood pressure in male patients with chronic spinal cord injury (SCI). Setting: Imam Khomeini Hospital, Tehran University of Medical Sciences, Tehran, Iran. Methods: Fifty-eight men with chronic SCI participated in the study. Participants were divided in two groups: one group received 600 mg of supplemental ALA (n=28) and the other group received placebo (n=30) for 12 weeks. At the beginning and end of the study, biochemical parameters, anthropometric indices, blood pressure and dietary intakes were measured. Dietary intake was measured using N4 software, and statistical analyses were carried out using SPSS16. Results: No significant reduction was found in IL-6 (P=0.97) and hs-CRP levels (P=0.23). There was significant reduction in fasting blood sugar (P=0.001), body weight (P=0.001), BMI (P=0.001), waist circumference (P=0.001) and blood pressure (P=0.001). Dietary intake was significantly reduced, including fat (P=0.001), carbohydrate (P=0.001), protein (P=0.002) and energy intakes (P=0.001). Conclusion: Lipoic acid supplementation had no significant effect on the measured inflammatory markers but it reduces fasting blood sugar, anthropometric parameters, food intake and blood pressure in men with chronic SCI.
Article
Introduction: Neuropathy is a serious complication of diabetes. Its management focuses on glycaemic control, multifactorial cardiovascular risk intervention, pathogenesis-oriented therapy, and analgesics where needed. Areas covered: The objective of this review is assessment of efficacy and safety of α lipoic acid (ALA, also thioctic acid) in pathogenesis-oriented treatment of diabetic neuropathy. The mechanisms of action of ALA in experimental diabetic neuropathy include reduction of oxidative stress along with improvement in nerve blood flow, nerve conduction velocity, and several other measures of nerve function. There is ample evidence from randomised, double-blind, placebo-controlled clinical trials and meta-analyses, suggesting that ALA is efficacious and safe for the diabetic neuropathy, accomplishing clinically meaningful improvements. Expert opinion: ALA is a valuable therapeutic option for diabetic neuropathy. When compared with currently licensed analgesic drugs, it is better tolerated, has a more rapid onset of action, and improves paraesthesiae, numbness, sensory deficits, and muscle strength in addition to neuropathic pain. In clinical practice, ALA may be chosen in patients with early neuropathic deficits and symptoms, in whom clinical improvement is more likely. ALA should also be considered when comorbidities render other analgesics less appropriate or in the presence of cardiovascular autonomic neuropathy.
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An extensive number of pathologies are associated with mitochondrial dysfunction (MDF) and oxidative stress (OS). Thus, mitochondrial cofactors termed "mitochondrial nutrients" (MN), such as α-lipoic acid (ALA), Coenzyme Q10 (CoQ10), and l-carnitine (CARN) (or its derivatives) have been tested in a number of clinical trials, and this review is focused on the use of MN-based clinical trials. The papers reporting on MN-based clinical trials were retrieved in MedLine up to July 2014, and evaluated for the following endpoints: (a) treated diseases; (b) dosages, number of enrolled patients and duration of treatment; (c) trial success for each MN or MN combinations as reported by authors. The reports satisfying the above endpoints included total numbers of trials and frequencies of randomized, controlled studies, i.e., 81 trials testing ALA, 107 reports testing CoQ10, and 74 reports testing CARN, while only 7 reports were retrieved testing double MN associations, while no report was found testing a triple MN combination. A total of 28 reports tested MN associations with "classical" antioxidants, such as antioxidant nutrients or drugs. Combinations of MN showed better outcomes than individual MN, suggesting forthcoming clinical studies. The criteria in study design and monitoring MN-based clinical trials are discussed.
Article
Nitric oxide (NO) is a gas with biological and regulatory properties, produced from arginine by the way of nitric oxide synthases (NOS), and with a very short half-life (few seconds). A "coupled" NOS activity leads to NO generation, whereas its uncoupling produces the reactive oxygen species peroxynitrite (ONOO(-)). Uncoupling is usually due to inflammation, oxidative stress, decreased cofactor availability, or excessive NO production. Competitive inhibitors of NO production are post-translationally methylated arginine residues in proteins, which are constantly released into the circulation. NO availability is altered in many clinical conditions associated with vascular dysfunction, such as diabetes mellitus. The kidney plays an important role in body NO homeostasis. This article provides an overview of current literature, on NO production/availability, with a focus on diabetic nephropathy. In diabetes, NO availability is usually decreased (with exception of the early, hyper filtration phase of nephropathy in Type 1 diabetes), and it could constitute a factor of the generalized vasculopathy present in diabetic nephropathy. NO generation in Type 2 diabetes with nephropathy is inversely associated with the dimethyl-arginine concentrations, which are therefore important modulators of NO synthesis independently from the classic stimulatory pathways (such as the insulin effect). A disturbed NO metabolism is present in diabetes associated with nephropathy. Although modulation of NO production is not yet a common therapeutical strategy, a number of yet experimental compounds need to be tested as potential interventions to treat the vascular dysfunction and nephropathy in diabetes, as well as in other diseased states. Finally, in diabetic nephropathy NO deficiency may be associated to that of hydrogen sulfide, another interesting gaseous mediator which is increasingly investigated.
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In the present cross-sectional study, the influence of alpha-lipoic acid on markers of oxidative stress, assessed by measurement of plasma lipid hydroperoxides (ROOHs), and on the balance between oxidative stress and antioxidant defence, determined by the ratio ROOH/(alpha-tocopherol/cholesterol), was examined in 107 patients with diabetes mellitus. Patients receiving alpha-lipoic acid (600 mg/day for > 3 months) had significant lower ROOHs and a lower ROOH/(alpha-tocopherol/cholesterol) ratio than those without alpha-lipoic acid treatment [ROOH: 4.76 +/- 2.49 vs. 7.16 +/- 3.22 mumol/l; p < .0001] and [ROOH/(alpha-tocopherol/cholesterol): 1.37 +/- 0.72 vs. 2.16 +/- 1.17; p < 0.0001]. In addition, the influence of glycemic control and albuminuria on ROOHs and on the ratio of ROOH/(alpha-tocopherol/cholesterol) was examined in the presence and absence of alpha-lipoic acid treatment. Patients were subdivided into three groups based on (1) their HbA1 levels (< 7.5, 7.5-9.5, and > 9.5%) and (2) their urinary albumin concentrations (< 20, 20-200, and > 200 mg/l). Neither poor glycemic control, nor the presence of micro- or macroalbuminuria prevented the antioxidant effect of alpha-lipoic acid. Using stepwise multiple regression analysis, alpha-lipoic acid was found to be the only factor significantly predicting low ROOHs and a low ratio of ROOH/(alpha-tocopherol/cholesterol). These data provide evidence that treatment with alpha-lipoic acid improves significantly the imbalance between increased oxidative stress and depleted antioxidant defence even in patients with poor glycemic control and albuminuria.
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α-lipoic acid (ALA), a naturally occurring compound and a radical scavenger was shown to enhance glucose transport and utilization in different experimental and animal models. Clinical studies described an increase of insulin sensitivity after acute and short-term (10 d) parenteral administration of ALA. The effects of a 4-week oral treatment with α-lipoic acid were evaluated in a placebo-controlled, multicenter pilot study to determine see whether oral treatment also improves insulin sensitivity. Seventy-four patients with type-2 diabetes were randomized to either placebo (n = 19); or active treatment in various doses of 600 mg once daily (n = 19), twice daily (1200 mg; n = 18), or thrice daily (1800 mg; n = 18) α-lipoic acid. An isoglycemic glucose-clamp was done on days 0 (pre) and 29 (post). In this explorative study, analysis was done according to the number of subjects showing an improvement of insulin sensitivity after treatment. Furthermore, the effects of active vs. placebo treatment on insulin sensitivity was compared. All four groups were comparable and had a similar degree of hyperglycemia and insulin sensitivity at baseline. When compared to placebo, significantly more subjects had an increase in insulin-stimulated glucose disposal (MCR) after ALA treatment in each group. As there was no dose effect seen in the three different α-lipoic acid groups, all subjects receiving ALA were combined in the 'active' group and then compared to placebo. This revealed significantly different changes in MCR after treatment (+27% vs. placebo; p < .01). This placebo-controlled explorative study confirms previous observations of an increase of insulin sensitivity in type-2 diabetes after acute and chronic intravenous administration of ALA. The results suggest that oral administration of α-lipoic acid can improve insulin sensitivity in patients with type-2 diabetes. The encouraging findings of this pilot trial need to be substantiated by further investigations.
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Previous studies demonstrated that 2 mo of dietary supplementation with alpha-lipoic acid (LA) prevented early glomerular injury in non-insulin-treated streptozotocin diabetic rats (D). The present study examined the effects of chronic LA supplementation (30 mg/kg body wt per d) on nephropathy in D after 7 mo of diabetes. Compared with control rats, D developed increased urinary excretion of albumin and transforming growth factor beta, renal insufficiency, glomerular mesangial matrix expansion, and glomerulosclerosis in association with depletion of glutathione and accumulation of malondialdehyde in renal cortex. LA prevented or ameliorated all of these changes in D. Because chronic LA supplementation also attenuated hyperglycemia in D after 3 mo, its effects on renal injury were compared with treatment of rats with sufficient insulin to maintain a level of glycemic control for the entire 7-mo period (D-INS) equivalent to that observed with LA during the final 4 mo. Despite superior longitudinal glycemic control in D-INS, urinary excretion of albumin and transforming growth factor beta, glomerular mesangial matrix expansion, the extent of glomerulosclerosis, and renal cortical malondialdehyde content were all significantly greater, whereas cortical glutathione content was lower than corresponding values in D given LA. Thus, the renoprotective effects of LA in D were not attributable to improved glycemic control alone but also likely reflected its antioxidant activity. The combined antioxidant and hypoglycemic actions of LA both may contribute to its utility in preventing renal injury and other complications of diabetes.
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To determine the pharmacokinetics, safety, and tolerability of a novel, controlled-release oral formulation of alpha-lipoic acid (LA) and to investigate whether sustaining the concentration of LA in plasma would have a beneficial effect on glycemic control in patients with type 2 diabetes. For the pharmacokinetic study, a single, 600-mg dose of either controlled-release LA (CRLA) or quick-release LA (QRLA) was administered orally to 12 normal human subjects. The plasma profile of LA was determined for 24 hours after administration of the dose,and pharmacokinetic analyses were performed. For the safety and tolerability study, 21 patients with type 2 diabetes were given 900 mg of CRLA daily for 6 weeks, followed by 1,200 mg of CRLA daily for an additional 6 weeks. Active treatment was followed by a 3-week washout period. Throughout the study, patients continued to take their prestudy antidiabetic medications, which included metformin (Glucophage), sulfonylureas (Amaryl, glyburide, and Glucotrol), acarbose (Precose), troglitazone (Rezulin), and insulin (either as monotherapy or in combination). CRLA was evaluated for safety and tolerability as well as for effects on glycemic control. The Tmax (time to maximal plasma concentration) of LA administered as CRLA was 1.25 hours and was approximately 2.5-fold longer in comparison with the Tmax for QRLA (Tn,5X = 0.5 hour; P<0.02). No severe side effects or changes in either liver or kidney function or hematologic profiles were noted after the administration of CRLA. In 15 patients, the mean plasma fructosamine concentration was reduced from 313 to 283 micromol/L(P<0.05) after 12 weeks of treatment with CRLA. CRLA increased the plasma concentration of LA over time in healthy subjects, and CRLA was safe, well tolerated, and effective in reducing plasma fructosamine in patients with type 2 diabetes.
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Diabetic nephropathy is characterized by excessive deposition of extracellular matrix proteins in the mesangium and basement membrane of the glomerulus and in the renal tubulointerstitium. This review summarizes the main changes in protein composition of the glomerular mesangium and basement membrane and the evidence that, in the mesangium, these are initiated by changes in glucose metabolism and the formation of advanced glycation end products. Both processes generate reactive oxygen species (ROS). The review includes discussion of how ROS may activate intracellular signaling pathways leading to the activation of redox-sensitive transcription factors. This in turn leads to change in the expression of genes encoding extracellular matrix proteins and the protease systems responsible for their turnover.
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Diabetic nephropathy is the leading cause of kidney disease in patients starting renal replacement therapy and affects approximately 40% of type 1 and type 2 diabetic patients. It increases the risk of death, mainly from cardiovascular causes, and is defined by increased urinary albumin excretion (UAE) in the absence of other renal diseases. Diabetic nephropathy is categorized into stages: microalbuminuria (UAE >20 microg/min and < or =199 microg/min) and macroalbuminuria (UAE > or =200 microg/min). Hyperglycemia, increased blood pressure levels, and genetic predisposition are the main risk factors for the development of diabetic nephropathy. Elevated serum lipids, smoking habits, and the amount and origin of dietary protein also seem to play a role as risk factors. Screening for microalbuminuria should be performed yearly, starting 5 years after diagnosis in type 1 diabetes or earlier in the presence of puberty or poor metabolic control. In patients with type 2 diabetes, screening should be performed at diagnosis and yearly thereafter. Patients with micro- and macroalbuminuria should undergo an evaluation regarding the presence of comorbid associations, especially retinopathy and macrovascular disease. Achieving the best metabolic control (A1c <7%), treating hypertension (<130/80 mmHg or <125/75 mmHg if proteinuria >1.0 g/24 h and increased serum creatinine), using drugs with blockade effect on the renin-angiotensin-aldosterone system, and treating dyslipidemia (LDL cholesterol <100 mg/dl) are effective strategies for preventing the development of microalbuminuria, in delaying the progression to more advanced stages of nephropathy and in reducing cardiovascular mortality in patients with type 1 and type 2 diabetes.
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Advanced glycation end products (AGEs) are a heterogeneous group of protein and lipids to which sugar residues are covalently bound. AGE formation is increased in situations with hyperglycemia (e.g., diabetes mellitus) and is also stimulated by oxidative stress, for example in uremia. It appears that activation of the renin-angiotensin system may contribute to AGE formation through various mechanisms. Although AGEs could nonspecifically bind to basement membranes and modify their properties, they also induce specific cellular responses including the release of profibrogenic and proinflammatory cytokines by interacting with the receptor for AGE (RAGE). However, additional receptors could bind AGEs, adding to the complexity of this system. The kidney is both: culprit and target of AGEs. A decrease in renal function increases circulating AGE concentrations by reduced clearance as well as increased formation. On the other hand, AGEs are involved in the structural changes of progressive nephropathies such as glomerulosclerosis, interstitial fibrosis, and tubular atrophy. These effects are most prominent in diabetic nephropathy, but they also contribute to renal pathophysiology in other nondiabetic renal diseases. Interference with AGE formation has therapeutic potential for preventing the progression of chronic renal diseases, as shown from data of animal experiments and, more recently, the first clinical trials.
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Chronic kidney disease is a worldwide public health problem that affects approximately 10% of the US adult population and is associated with a high prevalence of cardiovascular disease and high economic cost. Chronic renal insufficiency, once established, tends to progress to end-stage kidney disease, suggesting some common mechanisms for ultimately causing scarring and further nephron loss. This review defines the term reactive oxygen metabolites (ROM), or oxidants, and presents the available experimental evidence in support of the role of oxidants in diabetic and nondiabetic glomerular disease and their role in tubulointerstitial damage that accompanies progression. It concludes by reviewing the limited human data that provide some proof of concept that the observations in experimental models may be relevant to human disease.
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We have demonstrated that pyridoxal 5'-phosphate (PLP), an active form of vitamin B6, inhibits formation of advanced glycation end-products (AGEs) by trapping 3-deoxyglucosone. The present study aimed to clarify if PLP could exert beneficial effects on nephropathy in diabetic rats. Streptozotocin (STZ)-induced diabetic rats were treated by oral administration of PLP or pyridoxamine (PM), another active form of vitamin B6, at a dose of 600 mg/kg/day for 16 weeks. AGEs [imidazolone, N(epsilon)-(carboxymethyl)lysine (CML) and N(2)-carboxyethyl-2'-deoxyguanosine (CEdG)], transforming growth factor-beta1 (TGF-beta1), type 1 collagen and fibronectin were detected in the kidneys using immunohistochemistry. Gene expression of TGF-beta1 and receptor for AGEs (RAGEs) in the kidneys was determined using real-time quantitative polymerase chain reaction. Administration of PLP significantly inhibited albuminuria, glomerular hypertrophy, mesangial expansion, and interstitial fibrosis as compared with diabetic rats. PLP markedly inhibited accumulation of AGEs such as imidazolone, CML and CEdG, a DNA-linked AGE, in glomeruli. PLP significantly inhibited expression of TGF-beta1, type 1 collagen, fibronectin and RAGE in the kidneys. PLP was superior to PM in inhibiting accumulation of AGEs, expression of TGF-beta1, type 1 collagen, and fibronectin, and the development of diabetic nephropathy. PLP prevented progression of nephropathy in STZ-induced diabetic rats by inhibiting formation of AGEs. PLP is considered a promising active form of vitamin B6 for the treatment of AGE-linked disorders such as diabetic nephropathy.
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The popularity of high-protein diets has surged recently as obesity has become more and more common in the United States and other developed nations. In view of the high prevalence of type 2 diabetes and chronic kidney disease among obese people, it is important to understand potential effects of high-protein diets on the kidney. The hypothesis that high-protein diets are nephrotoxic because of their excessive dietary advanced glycation end product (AGE) content and an increased amino acid load that enhances AGE formation in situ was explored. This review discusses the following evidence: (1) High-protein diets are deleterious to the kidney; (2) AGE are metabolic mediators of kidney damage; (3) dietary protein-derived AGE contribute to proinflammatory and pro-oxidative processes in diabetes and kidney disease; and (4) dietary protein-derived AGE produce functional and structural abnormalities that are involved in kidney damage. Future research should consider dietary AGE as a potential therapeutic target for kidney disease in obesity, diabetes, and perhaps other causes of chronic kidney disease.
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Diabetic nephropathy is characterized by excessive amassing of extracellular matrix (ECM) with thickening of glomerular and tubular basement membranes and increased amount of mesangial matrix, which ultimately progress to glomerulosclerosis and tubulo-interstitial fibrosis. In view of this outcome, it would mean that all the kidney cellular elements, i.e., glomerular endothelia, mesangial cells, podocytes, and tubular epithelia, are targets of hyperglycemic injury. Conceivably, high glucose activates various pathways via similar mechanisms in different cell types of the kidney except for minor exceptions that are related to the selective expression of a given molecule in a particular renal compartment. To begin with, there is an obligatory excessive channeling of glucose intermediaries into various metabolic pathways with generation of advanced glycation products (AGEs), activation of protein kinase C (PKC), increased expression of transforming growth factor-beta (TGF-beta), GTP-binding proteins, and generation of reactive oxygen species (ROS). The ROS seem to be the common denominator in various pathways and are central to the pathogenesis of hyperglycemic injury. In addition, there are marked alterations in intraglomerular hemodynamics, i.e., hyperfiltration, and this along with metabolic derangements adversely compounds the hyperglycemia-induced injury. Here, the information compiled under various subtitles of this article is derived from an enormous amount of data summarized in several excellent literature reviews, and thus their further reading is suggested to gain in-depth knowledge of each of the subject matter.
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A common endpoint of hyperglycemia dependent cellular changes is the generation of reactive oxygen intermediates (ROIs) and the presence of elevated oxidative stress. Therefore, oxidative stress is supposed to play an important role in the development of late diabetic complications. Formation of advanced glycation end products (AGE's) due to elevated nonenzymatic glycation of proteins, lipids and nucleic acids is accompanied by oxidative, radical-generating reactions and thus represents a major source for oxygen free radicals under hyperglycemic conditions. Once formed, AGE's can influence cellular function by binding to several binding sites including the receptor for AGE's, RAGE. Binding of AGE's (and other ligands) to RAGE results in generation of intracellular oxidative stress and subsequent activation of the redox-sensitive transcription factor NF-κB in vitro and in vivo. Consistently, activation of NF-κB in diabetic patients correlates with the quality of glycemic control and can be reduced by treatment with the antioxidant -lipoic acid. The development of techiques allowing for a tissue culture independent measurement of NF-κB activation in patients with diabetes mellitus gives insights into the molecular mechanisms linking diabetes mellitus and hyperglycemia with formation of advanced glycated endproducts and generation of oxidative stress finally resulting in oxidative stress mediated cellular activation.
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In experimental and human diabetic nephropathy (DN), it has been shown that advanced glycation end products (AGEs), in particular, carboxymethyl-lysine and pentosidine, accumulate with malondialdehyde in glomerular lesions in relation to disease severity and in the presence of an upregulated receptor for AGE (RAGE) in podocytes. Toxic effects of AGEs result from structural and functional alterations in plasma and extracellular matrix (ECM) proteins, in particular, from cross-linking of proteins and interaction of AGEs with their receptors and/or binding proteins. In mesangial and endothelial cells, the AGE-RAGE interaction caused enhanced formation of oxygen radicals with subsequent activation of nuclear factor-κB and release of pro-inflammatory cytokines (interleukin-6, tumor necrosis factor-α), growth factors (transforming growth factor-β1 [TGF-β1], insulin-like growth factor-1), and adhesion molecules (vascular cell adhesion molecule-1, intercellular adhesion molecule-1). In tubular cells, incubation with AGE albumin was followed by stimulation of the mitogen-activating protein (MAP) kinase pathway and its downstream target, the activating protien-1 (AP-1) complex, TGF-β1 overexpression, enhanced protein kinase C activity, decreased cell proliferation, and impaired protein degradation rate, in part caused by decreased cathepsin activities. The pathogenic relevance of AGEs was further verified by in vivo experiments in euglycemic rats and mice by the parenteral administration of AGE albumin, leading in the glomeruli to TGF-β1 overproduction, enhanced gene expression of ECM proteins, and morphological lesions similar to those of DN. Evidence for the pathogenic relevance of AGEs in DN also comes from experimental studies in which the formation and/or action of AGEs was modulated by aminoguanidine, OPB-9195, pyridoxamine, soluble RAGEs, serine protease trypsin, and antioxidants, resulting in improved cell and/or renal function.
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Oxidative stress and protein glycation can contribute to the development of insulin resistance and complications associated with type 2 diabetes mellitus. The antioxidant alpha-lipoic acid (ALA) reduces oxidative stress and the formation of advanced glycation end products (AGEs) and improves insulin sensitivity in skeletal muscle and liver. The AGE inhibitor pyridoxamine (PM) prevents irreversible protein glycation, thereby reducing various diabetic complications. The potential interactive effects of ALA and PM in the treatment of whole-body and skeletal muscle insulin resistance have not been investigated. Therefore, this study was designed to determine the effects of combined ALA and PM treatments on reducing muscle oxidative stress and ameliorating insulin resistance in prediabetic obese Zucker rats. Obese Zucker rats were assigned to either a control group or to a treatment group receiving daily injections of the R-(+)-enantiomer of ALA (R-ALA, 92 mg/kg) or PM (60 mg/kg), individually or in combination, for 6 weeks. The individual and combined treatments with R-ALA and PM were effective in significantly (P < .05) reducing plantaris muscle protein carbonyls (33%-40%) and urine-conjugated dienes (22%-38%), markers of oxidative stress. The R-ALA and PM in combination resulted in the largest reductions of fasting plasma glucose (23%), insulin (16%), and free fatty acids (24%) and of muscle triglycerides (45%) compared with alterations elicited by individual treatment with R-ALA or PM. Moreover, the combination of R-ALA and PM elicited the greatest enhancement of whole-body insulin sensitivity both in the fasted state and during an oral glucose tolerance test. Finally, combined R-ALA/PM treatments maintained the 44% enhancement of in vitro insulin-mediated glucose transport activity in soleus muscle of obese Zucker rats treated with R-ALA alone. Collectively, these results document a beneficial interaction of the antioxidant R-ALA and the AGE inhibitor PM in the treatment of whole-body and skeletal muscle insulin resistance in obese Zucker rats.
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Antioxidants, in particular vitamin E (VE), have been reported to protect against diabetic renal injury. alpha-Lipoic acid (LA) has been found to attenuate diabetic peripheral neuropathy, but its effects on nephropathy have not been examined. In the present study, parameters of glomerular injury were examined in streptozotocin diabetic rats after 2 mo on unsupplemented diets and in diabetic rats that received the lowest daily dose of dietary LA (30 mg/kg body wt), VE (100 IU/kg body wt), or vitamin C (VC; 1 g/kg body wt), which detectably increased the renal cortical content of each antioxidant. Blood glucose values did not differ among the diabetic groups. At 2 mo, inulin clearance, urinary albumin excretion, fractional albumin clearance, glomerular volume, and glomerular content of immunoreactive transforming growth factor-beta (TGF-beta) and collagen alpha1 (IV) all were significantly increased in unsupplemented D compared with age-matched nondiabetic controls. With the exception of inulin clearance, LA prevented or significantly attenuated the increase in all of these glomerular parameters in D, as well as the increases in renal tubular cell TGF-beta seen in D. At the dose used, VE reduced inulin clearance in D to control levels but failed to alter any of the other indices of glomerular injury or to suppress renal tubular cell TGF-beta in D. VC suppressed urinary albumin excretion, fractional albumin clearance, and glomerular volume but not glomerular or tubular TGF-beta or glomerular collagen alpha1 (IV) content. LA but not VE or VC significantly increased renal cortical glutathione content in D. These data indicate that LA is effective in the prevention of early diabetic glomerular injury and suggest that this agent may have advantages over high doses of either VE or VC.
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Maillard products or advanced glycation end products (AGEs) are generated by a nonenzymatic reaction of a sugar ketone or aldehyde group with a free amino group of proteins or amino acids. In the first step, a labile Schiff base is formed, which subsequently rearranges into the Amadori product. Finally, AGEs are formed as a mixture of protein-bound nitrogen and oxygen-containing heterocyclic compounds through a complex cascade of dehydration, condensation, fragmentation, oxidation and cyclization reactions [1]. Common characteristics of AGEs include a yellow-brownish color corresponding to a diffuse absorption spectrum without discrete peaks and characteristic fluorescent properties. Many of the AGEs can cross-link proteins. AGE-mediated cross-links accumulate in cells and tissues in the normal aging process, in diabetes, renal failure and other degenerative diseases such as Alzheimer’s disease [2, 3]. Recent progress in the understanding of this age-related process has affirmed the hypothesis that AGEs play an important role in the pathogenesis of accelerated vascular complications in diabetes and end-stage renal failure. AGEs have been identified in a variety of vascular wall, lipoprotein and lipid constituents leading to diabetic complications with macro- and microangiopathy as well as amyloidosis [4, 5, 6].
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Oxidative stress plays a central role in the pathogenesis and progression of late microangiopathic complications (diabetic nephropathy) in diabetes mellitus. Previous studies suggested that treatment of diabetic patients with the antioxidant alpha-lipoic acid reduce oxidative stress and urinary albumin excretion. In this prospective, open and non-randomized study, the effect of alpha-lipoic acid on the progression of endothelial cell damage and the course of diabetic nephropathy, as assessed by measurement of plasma thrombomodulin and urinary albumin concentration (UAC), was evaluated in 84 patients with diabetes mellitus over 18 months. Forty-nine patients (34 with Type 1 diabetes, 15 with Type 2 diabetes) had no antioxidant treatment and served as a control group. Thirty-five patients (20 with Type 1 diabetes, 15 with Type 2 diabetes) were treated with 600 mg alpha-lipoic acid per day. Only patients with an urinary albumin concentration <200 mg/l were included into the study. After 18 months of follow up, the plasma thrombomodulin level increased from 35.9+/-9.5 to 39.7+/-9.9 ng/ml (P<0.05) in the control group. In the alpha-lipoic acid treated group the plasma thrombomodulin level decreased from 37.5+/-16.2 to 30.9+/-14.5 ng/ml (P<0.01). The UAC increased in patients without alpha-lipoic acid treatment from 21.2+/-29.5 to 36.9+/-60.6 ng/l (P<0.05), but was unchanged with alpha-lipoic acid. It is postulated that the significant decrease in plasma thrombomodulin and failure of UAC to increase observed in the alpha-lipoic acid treated group is due to antioxidative effects of alpha-lipoic acid, and if so that oxidative stress plays a central role in the pathogenesis of diabetic nephropathy. Furthermore, progression of the disease might be inhibited by antioxidant drugs. A placebo-controlled study is needed.
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Alpha-lipoic acid (LA) and its reduced form, dihydrolipoic acid, are powerful antioxidants. LA scavenges hydroxyl radicals, hypochlorous acid, peroxynitrite, and singlet oxygen. Dihydrolipoic acid also scavenges superoxide and peroxyl radicals and can regenerate thioredoxin, vitamin C, and glutathione, which in turn can recycle vitamin E. There are several possible sources of oxidative stress in diabetes including glycation reactions, decompartmentalization of transition metals, and a shift in the reduced-oxygen status of the diabetic cells. Diabetics have increased levels of lipid hydroperoxides, DNA adducts, and protein carbonyls. Available data strongly suggest that LA, because of its antioxidant properties, is particularly suited to the prevention and/or treatment of diabetic complications that arise from an overproduction of reactive oxygen and nitrogen species. In addition to its antioxidant properties, LA increases glucose uptake through recruitment of the glucose transporter-4 to plasma membranes, a mechanism that is shared with insulin-stimulated glucose uptake. Further, recent trials have demonstrated that LA improves glucose disposal in patients with type II diabetes. In experimental and clinical studies, LA markedly reduced the symptoms of diabetic pathologies, including cataract formation, vascular damage, and polyneuropathy. To develop a better understanding of the preventative and therapeutic potentials of LA, much of the current interest is focused on elucidating its molecular mechanisms in redox dependent gene expression.
Article
Nonenzymatic reactions between sugars or lipids and protein and formation of advanced glycation and lipoxidation end products (AGE/ALEs) contribute to the chemical modification and cross-linking of tissue proteins with age. Accelerated formation of AGE/ALEs during hyperglycemia is implicated in the development of diabetic complications. In this study, we examined the effect of the AGE/ALE inhibitor pyridoxamine on chemical modification and cross-linking of collagen and development of renal disease in the streptozotocin-diabetic rat. Diabetic rats were treated with pyridoxamine; parallel experiments were conducted with aminoguanidine, the prototype AGE inhibitor. Progression of renal disease was evaluated by measurements of albuminuria and plasma creatinine concentration. Plasma triglycerides, cholesterol, lactate and pyruvate were measured by enzymatic assays, and AGE/ALEs in skin collagen by HPLC and GC-MS assays. Pyridoxamine significantly inhibited the increase in albuminuria, plasma creatinine, hyperlipidemia and plasma lactate/pyruvate ratio in diabetic rats, without an effect on blood glucose or glycated hemoglobin. AGE/ALEs, fluorescence and cross-linking of skin collagen increased approximately twofold in diabetic versus control rats after seven months of diabetes. Pyridoxamine caused a significant (25 to 50%) decrease the AGE/ALEs, carboxymethyllysine and carboxyethyllysine, cross-linking and fluorescence in skin collagen of diabetic rats, but did not affect pentosidine. Pyridoxamine inhibits the progression of renal disease, and decreases hyperlipidemia and apparent redox imbalances in diabetic rats. Pyridoxamine and aminoguanidine had similar effects on parameters measured, supporting a mechanism of action involving AGE/ALE inhibition.
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Aged spontaneously hypertensive rats (SHR) develop end-stage renal disease resembling that of uncontrolled essential hypertension in humans. Nitric oxide (NO) and angiotensin II (Ang II) play an important role in the regulation of blood pressure and the growth of vascular smooth muscle and renal mesangial cells. The relationship between renal NO system, Ang II activity and renal injury in aged SHR is not fully understood. The 8-week-old SHR were randomized into losartan-treated (30 mg/kg/day for 55 weeks) and vehicle treated groups. The age-matched Wistar-Kyoto rats (WKY) served as controls. Renal histology and tissue expressions of endothelial and inducible NO synthases (eNOS and iNOS) and nitrotyrosine were examined at 63-weeks of age. Compared to the WKY group, untreated SHR showed severe hypertension, proteinuria, renal insufficiency, a twofold decrease in renal tissue eNOS and iNOS expressions and massive nitrotyrosine accumulation. This was associated with severe glomerulosclerosis, tubular atrophy and interstitial fibrosis. Losartan therapy normalized blood pressure, prevented proteinuria and renal insufficiency, abrogated the fall in renal eNOS and iNOS protein contents, mitigated renal nitrotyrosine accumulation, and prevented the histological abnormalities found in the untreated SHR. Aged SHR exhibit severe renal lesions with acquired NO deficiency that are prevented by hypertension control with AT1 blockade. These findings point to the possible role of NO deficiency in the pathogenesis of renal lesions in aged SHR.
Article
Oxidative stress is implicated in the pathogenesis of diabetic nephropathy. The attempts to identify early markers of diabetes-induced renal oxidative injury resulted in contradictory findings. We characterized early oxidative stress in renal cortex of diabetic rats, and evaluated whether it can be prevented by the potent antioxidant, DL-alpha-lipoic acid. The experiments were performed on control rats and streptozotocin-diabetic rats treated with/without DL-alpha-lipoic acid (100 mg/kg i.p., for 3 weeks from induction of diabetes). Malondialdehyde plus 4-hydroxyalkenal concentration was increased in diabetic rats vs. controls (p <.01) and this increase was partially prevented by DL-alpha-lipoic acid. F(2) isoprostane concentrations (measured by GCMS) expressed per either mg protein or arachidonic acid content were not different in control and diabetic rats but were decreased several-fold with DL-alpha-lipoic acid treatment. Both GSH and ascorbate (AA) levels were decreased and GSSG/GSH and dehydroascorbate/AA ratios increased in diabetic rats vs. controls (p <.01 for all comparisons), and these changes were completely or partially (AA) prevented by DL-alpha-lipoic acid. Superoxide dismutase, glutathione peroxidase, glutathione reductase, glutathione transferase, and NADH oxidase, but not catalase, were upregulated in diabetic rats vs. controls, and these activities, except glutathione peroxidase, were decreased by DL-alpha-lipoic acid. In conclusion, enhanced oxidative stress is present in rat renal cortex in early diabetes, and is prevented by DL-alpha-lipoic acid.
Article
Increased oxidative stress and impaired antioxidant defense mechanisms are important factors in the pathogenesis and progression of diabetes mellitus and other oxidant-related diseases. This study was designed to determine whether alpha-lipoic acid, which has been shown to have substantial antioxidant properties, when administered (10 mg/kg ip) once daily for 14 days to normal and diabetic female Sprague-Dawley rats would prevent diabetes-induced changes in biomarkers of oxidative stress in liver, kidney and heart. Serum glucose concentrations, aspartate aminotransferase activity, and glycated hemoglobin levels, which were increased in diabetes, were not significantly altered by alpha-lipoic acid treatment. Normal rats treated with a high dose of alpha-lipoic acid (50 mg/kg) survived but diabetic rats on similar treatment died during the course of the experiment. The activity of glutathione peroxidase was increased in livers of normal rats treated with alpha-lipoic acid, but decreased in diabetic rats after alpha-lipoic acid treatment. Hepatic catalase activity was decreased in both normal and diabetic rats after alpha-lipoic acid treatment. Concentrations of reduced glutathione and glutathione disulfide in liver were increased after alpha-lipoic acid treatment of normal rats, but were not altered in diabetics. In kidney, glutathione peroxidase activity was elevated in diabetic rats, and in both normal and diabetic animals after alpha-lipoic acid treatment. Superoxide dismutase activity in heart was decreased in diabetic rats but normalized after treatment with alpha-lipoic acid; other cardiac enzyme activities were not influenced by either diabetes or antioxidant treatment. These results suggest that after 14 days of treatment with an appropriate pharmacological dose, alpha-lipoic acid may reduce oxidative stress in STZ-induced diabetic rats, perhaps by modulating the thiol status of the cells.
Article
Diabetic nephropathy is characterized by excessive deposition of extracellular matrix (ECM) in the kidney. TGF-beta1 has been identified as the key mediator of ECM accumulation in diabetic kidney. High glucose induces TGF-beta1 in glomerular mesangial and tubular epithelial cells and in diabetic kidney. Antioxidants inhibit high glucose-induced TGF-beta1 and ECM expression in glomerular mesangial and tubular epithelial cells and ameliorate features of diabetic nephropathy, suggesting that oxidative stress plays an important role in diabetic renal injury. High glucose induces intracellular reactive oxygen species (ROS) in mesangial and tubular epithelial cells. High glucose-induced ROS in mesangial cells can be effectively blocked by inhibition of protein kinase C (PKC), NADPH oxidase, and mitochondrial electron transfer chain complex I, suggesting that PKC, NADPH oxidase, and mitochondrial metabolism all play a role in high glucose-induced ROS generation. Advanced glycation end products, TGF-beta1, and angiotensin II can also induce ROS generation and may amplify high glucose-activated signaling in diabetic kidney. Both high glucose and ROS activate signal transduction cascade (PKC, mitogen-activated protein kinases, and janus kinase/signal transducers and activators of transcription) and transcription factors (nuclear factor-kappaB, activated protein-1, and specificity protein 1) and upregulate TGF-beta1 and ECM genes and proteins. These observations suggest that ROS act as intracellular messengers and integral glucose signaling molecules in diabetic kidney. Future studies elucidating various other target molecules activated by ROS in renal cells cultured under high glucose or in diabetic kidney will allow a better understanding of the final cellular responses to high glucose.
Article
It is widely accepted that proteinuria reduction is an appropriate therapeutic goal in chronic proteinuric kidney disease. Based on large randomized controlled clinical trials (RCT), ACE inhibitor (ACEI) and angiotensin receptor blocker (ARB) therapy have emerged as the most important antiproteinuric and renal protective interventions. However, there are numerous other interventions that have been shown to be antiproteinuric and, therefore, likely to be renoprotective. Unfortunately testing each of these antiproteinuric therapies in RCT is not feasible. The nephrologist has two choices: restrict antiproteinuric therapies to those shown to be effective in RCT or expand the use of antiproteinuric therapies to include those that, although unproven, are plausibly effective and prudent to use. The goal of this work is to provide the documentation needed for the nephrologist to choose between these strategies. This work describes 25 separate interventions that are either antiproteinuric or may block injurious mechanisms of proteinuria. Each intervention is assigned a level of recommendation (Level 1 is the highest; Level 3 is the lowest) according to the strength of the evidence supporting its antiproteinuric and renoprotective efficacy. Pathophysiologic mechanisms possibly involved are also discussed. The number of interventions at each level of recommendation are: Level 1, n = 7; Level 2, n = 9; Level 3, n = 9. Our experience indicates that we can achieve in most patients the majority of Level 1 and many of the Level 2 and 3 recommendations. We suggest that, until better information becomes available, a broad-based, multiple-risk factor intervention to reduce proteinuria can be justified in those with progressive nephropathies. This work is intended primarily for clinical nephrologists; therefore, each antiproteinuria intervention is described in practical detail.
Article
Diabetes is the leading cause of ESRD because diabetic nephropathy develops in 30 to 40% of patients. Diabetic nephropathy does not develop in the absence of hyperglycemia, even in the presence of a genetic predisposition. Multigenetic predisposition contributes in the development of diabetic nephropathy, thus supporting that many factors are involved in the pathogenesis of the disease. Hyperglycemia induces renal damage directly or through hemodynamic modifications. It induces activation of protein kinase C, increased production of advanced glycosylation end products, and diacylglycerol synthesis. In addition, it is responsible for hemodynamic alterations such as glomerular hyperfiltration, shear stress, and microalbuminuria. These alterations contribute to an abnormal stimulation of resident renal cells that produce more TGF-beta1. This growth factor upregulates GLUT-1, which induces an increased intracellular glucose transport and D-glucose uptake. TGF-beta1 causes augmented extracellular matrix protein deposition (collagen types I, IV, V, and VI; fibronectin, and laminin) at the glomerular level, thus inducing mesangial expansion and glomerular basement membrane thickening. However, low enzymatic degradation of extracellular matrix contributes to an excessive accumulation. Because hyperglycemia is the principal factor responsible for structural alterations at the renal level, glycemic control remains the main target of the therapy, whereas pancreas transplantation is the best approach for reducing the renal lesions.
Article
Diabetic vascular complication is a leading cause of end-stage renal failure, acquired blindness, a variety of neuropathies and accelerated atherosclerosis, which could account for disabilities and high mortality rates in patients with diabetes. Recent large prospective clinical studies have shown that intensive glucose control reduces effectively microvascular complications among patients with diabetes, and insulin resistance and postprandial hyperglycemia seem to be involved in diabetic macrovascular complications. Chronic hyperglycemia is a major initiator of diabetic vascular complications. Indeed, high glucose, via various mechanisms such as increased production of advanced glycation end products, activation of protein kinase C, stimulation of the polyol pathway and enhanced reactive oxygen species generation, regulates vascular inflammation, altered gene expression of growth factors and cytokines, and platelet and macrophage activation, thus playing a central role in the development and progression of diabetic vascular complications. This article summarizes the molecular mechanisms of diabetic vascular complications and the potential therapeutic interventions that may prevent these disorders even in the presence of hyperglycemia, control of which is often difficult with current therapeutic options.
Article
The present study investigates the antiglycating effect of alpha-lipoic acid (LA) in high fructose-fed rats in vivo and its potential to inhibit the process of glycation in vitro. In addition, the effect of LA on glucose utilisation in rat diaphragm was also studied. Rats fed a high fructose diet (60% total calories) were administered with 35 mg/kg b.w, lipoic acid (LA) intraperitoneally for 20 days. The effects of LA on plasma glucose, fructosamine, protein glycation and glycated haemoglobin in high fructose rats and on in vitro glycation were studied. In vitro utilization of glucose was carried out in normal rat diaphragm in the presence and absence of insulin in which LA was used as an additive. The contents of glucose, glycated protein, glycated haemoglobin and fructosamine were significantly lowered on LA administration to high fructose-fed rats. LA prevented in vitro glycation and the accumulation of advanced glycation end products. Further LA enhanced glucose utilization in the rat diaphragm. This effect was additive to that of insulin and did not interfere with the action of insulin. The findings provide evidence for the therapeutic utility of lipoic acid in diabetes and its complications.
Article
Amelioration of insulin resistance could improve both glycaemic control and cardiovascular risk factors in patients with type 2 diabetes mellitus. Alpha-lipoic acid has been shown to improve insulin action after parenteral administration. the aim of the study was to assess the effect of oral administration of alpha-lipoic acid on insulin sensitivity in patients with type 2 diabetes. twelve patients (mean+/-sD; age 52.9+/-9.9 yrs; body mass index 33.9+/-7.4 kg/m(2)) were treated with oral alpha-lipoic acid, 600 mg twice daily over a period of 4 weeks. twelve subjects with normal glucose tolerance served as a control group in terms of insulin sensitivity (Is). Is was measured by a 2h manual hyperinsulinaemic (insulin infusion rate-40 mU/m(2 )body surface area/min) euglycaemic (blood glucose kept at 5 mmol/l) clamp technique and expressed as a glucose disposal rate (M) and insulin sensitivity index (IsI). At the end of the treatment period, Is of diabetic patients was significantly increased: M from 3.202+/-1.898 to 5.951+/-2.705 mg/kg/min (mean+/-sD), p<0.01; and IsI from 4.706+/-2.666 to 7.673+/-3.559 mg/kg/min per mIU/l x 100 (mean+/-sD), p<0.05. the difference was not statistically significant between the Is of diabetic patients after alpha-lipoic acid therapy and control subjects. short-term oral alpha-lipoic acid treatment increases peripheral insulin sensitivity in patients with type 2 diabetes mellitus.
Article
Treatments of diabetic nephropathy (DN) delay the onset of end-stage renal disease. We report the results of safety/tolerability studies in patients with overt nephropathy and type 1/type 2 diabetes treated with pyridoxamine, a broad inhibitor of advanced glycation. The two 24-week studies were multicenter Phase 2 trials in patients under standard-of-care. In PYR-206, patients were randomized 1:1 and had baseline serum creatinine (bSCr) <or=2.0 mg/dl. In PYR-205/207, randomization was 2:1 and bSCr was <or=2.0 for PYR-205 and >or=2.0 but <or=3.5 mg/dl for PYR-207. Treated patients (122 active, 90 placebo) received 50 mg pyridoxamine twice daily in PYR-206; PYR-205/207 patients were escalated to 250 mg twice daily. Adverse events were balanced between the groups (p = NS). Slight imbalances, mainly in the PYR-205/207 groups, were noted in deaths (from diverse causes, p = NS) and serious adverse events (p = 0.05) that were attributed to pre-existing conditions. In a merged data set, pyridoxamine significantly reduced the change from baseline in serum creatinine (p < 0.03). In patients similar to the RENAAL/IDNT studies (bSCr >or=1.3 mg/dl, type 2 diabetes), a treatment effect was observed on the rise in serum creatinine (p = 0.007). No differences in urinary albumin excretion were seen. Urinary TGF-beta1 also tended to decrease with pyridoxamine (p = 0.049) as did the CML and CEL AGEs. These data provide a foundation for further evaluation of this AGE inhibitor in DN.
Article
The therapeutic potential of lipoic acid (LA) in diabetes and diabetic nephropathy treatment was elucidated. Alloxan diabetic rabbits were treated daily for three weeks with either 10 or 50 mg of LA per kg body weight (i.p.). The following parameters were measured: 1) serum glucose, urea, creatinine and hydroxyl free radical (HFR) levels; 2) blood glutathione redox state; 3) urine albumin concentration; 4) hepatic and renal HFR levels, GSH/GSSG ratios, cysteine contents and the activities of the enzymes of glutathione metabolism; and 5) the activity of renal NADPH oxidase. Histological studies of kidneys were also performed. The treatment of diabetic rabbits with 50 mg of LA resulted in lethal hypoglycaemia in 50% of animals studied. Although the low dose of LA did not change serum glucose concentration, it decreased serum urea and creatinine concentrations, attenuated diabetes-induced decline in GSH/GSSG ratio and abolished hydroxyl free radicals accumulation in serum, liver and kidney cortex. LA did not change the activities of the enzymes of glutathione metabolism, but it elevated hepatic content of cysteine, which limits the rate of glutathione biosynthesis. Moreover, LA lowered urine albumin concentration and attenuated glomerulopathy characteristic of diabetes. However, it did not affect diabetes-stimulated activity of renal NADPH oxidase. In view of these data, it is concluded that low doses of LA might be useful for the therapy of diabetes and diabetic nephropathy. Beneficial action of LA seems to result mainly from direct scavenging of HFR and restoring glutathione redox state due to elevation of intracellular cysteine levels.
Effect of Lipoic Acid and Pyridoxine on Nephropathy Int
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N. Noori et al.: Effect of Lipoic Acid and Pyridoxine on Nephropathy Int. J. Vitam. Nutr. Res. 83 (2) © 2013 Hans Huber Publishers, Hogrefe AG, Bern
Modi-fi cation of proteins in vitro by physiological levels of glucose
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Voziyan, P.A., Khalifah, R.G., Thibaudeau, C., Yildiz, A., Jacob, J., Serianni, A.S. et al. (2003) Modi-fi cation of proteins in vitro by physiological levels of glucose. J. Biol. Chem. 278, 46616 – 46624.
PhD Department of Clinical Nutrition & Dietetics Faculty of Nutrition Sciences and Food Technology National Nutrition and Food Technology Research Institute
  • Hadi Tabibi
Hadi Tabibi, PhD Department of Clinical Nutrition & Dietetics Faculty of Nutrition Sciences and Food Technology National Nutrition and Food Technology Research Institute 46, West Arghavan St. Farahzadi Blvd., Shahrak Qods P.O. Box: 19395 -4741, Tehran Islamic Republic of Iran hadtabibi@yahoo.com
Diabetes and Kidney Disease: Time to Act. International Diabetes Federation
International Diabetes Federation, International Society of Nephrology. (2003) Diabetes and Kidney Disease: Time to Act. International Diabetes Federation, Brussels.
Diabetic nephropathy: diagnosis, prevention, and treatment
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N. Noori et al.: Effect of Lipoic Acid and Pyridoxine on Nephropathy Int. J. Vitam. Nutr. Res. 83 (2) © 2013 Hans Huber Publishers, Hogrefe AG, Bern 3. Gross, J.L., Azevedo, M.J., Silveiro, S.P., Canani, L.H., Caramori, M.L. and Zelmanovitz, T. (2005) Diabetic nephropathy: diagnosis, prevention, and treatment. Diabetes Care 28, 164 -176.