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Background/Objectives. The comorbidity of osteoarthritis and type 2 diabetes mellitus poses a complex clinical challenge, complicating patient management due to overlapping pathophysiological mechanisms. This research aims to analyze the exacerbation of clinical symptoms and biochemical markers in patients with OA and T2DM compared to those with OA alone. Methods . We employed various assessment methods to evaluate inflammation, oxidative stress, and glycemic control in both cohorts. This study includes the administration of alpha-lipoic acid (ALA) to patients with comorbid OA and T2DM, monitoring its effects on joint function, inflammatory markers, oxidative stress levels, and glycemic control. Results. The findings indicate that T2DM significantly worsens clinical symptoms and biochemical markers in OA patients. Those with both conditions exhibited elevated indicators of inflammation and oxidative stress compared to OA-only patients. Additionally, correlations among metabolic, psychological, and inflammatory factors were identified. Body mass index emerged as a potential predictor for the deterioration of evaluated parameters. The analysis revealed that ALA administration led to statistically significant improvements in WOMAC pain scores, the Lequesne Algofunctional Index, and the AIMS-P compared to the control group. Conclusions. Further research into ALA's effects on OA progression in patients with comorbidities is essential for developing personalized treatment approaches.

Growing clinical evidence shows that sulfonylurea therapy for patients with type 2 diabetic mellitus (T2DM) contributes to progressive worsening of their liver. The present study presents hepatotoxicity induced by gliclazide, a second-generation sulfonylurea, and alpha-lipoic acid (ALA) as a novel and promising drug for T2DM treatment. Normal human liver cells (HL-7702) were incubated with high-glucose DMEM in the presence or absence of gliclazide and ALA for 72 h, and cell viability and death were measured by flow cytometry. Next, Sprague-Dawley rats were subjected to 12 h of fasting, and fasting blood glucose was measured. The rats were randomized into four groups: HC (healthy control; n = 7), T2DM (diabetic rats without treatment; n = 9), GLC (diabetic rats with 15 mg/kg gliclazide treatment; n = 7) and GLC+ALA (diabetic rats with gliclazide and 60 mg/kg ALA treatment; n = 7). T2DM was induced by a bolus administration of 110 mg/kg nicotinamide and 55 mg/kg streptozotocin intraperitoneally. The experimental protocol lasted for 6 weeks after which the animals were sacrificed and pancreas, liver and blood samples were collected for biochemical, histological and molecular analyses. Compared to healthy control (HC) group, exposure of HL-7702 cells to high glucose induced significant cell death by 19 % (p < 0.001), which was exacerbated with gliclazide treatment by 29 % (p < 0.0001) but markedly reduced by 6 % to near HC value following ALA treatment. In vivo, GLC-treated rats had severe liver damage characterized by increased hepatocellular vacuolation, and significant expression of ED-1, iNOS and caspase-3 as well as markedly high levels of liver enzymes (aspartate aminotransferase, alanine aminotransferase and alkaline phosphatase compared to T2DM rats. Interestingly, ALA administration prevented these pathological changes and protected the diabetic liver to levels comparable to HC rats. ALA showed hepatoprotective effect against gliclazide-induced hepatotoxicity by suppressing inflammation and apoptosis while activating antioxidant pathway in the diabetic liver. Abbreviations: ALA, Alpha-lipoic acid; ALT, Alanine aminotransferase; ALP, Alkaline phosphatase; AMPK, Adenosine monophosphate-activated protein kinase; AST, Aspartate aminotransferase; ATP, Adenosine triphosphate; DMEM, Dulbecco's Modified Eagle Medium; EDTA, ethylenediaminetetraacetic acid; FBG, Fasting blood glucose; FBS, Fetal bovine serum; GLC, Gliclazide; GLUT4, Glucose transporter type 4; GSH, Glutathione; H&E, Hematoxylin/Eosin; HbA1c, Glycosylated haemoglobin A1c; HC, Healthy control; HG, Hyperglycemic group; HOMA-β, Homeostasis model assessment of β-cell function; IL-1β, Interleukin-1β; IL-6, Interleukin-6; iNOS, Inducible nitric oxide synthase; K ATP , ATP-dependent potassium channels; MDA, Malondialdehyde; MPTP, Mitochondrial permeability transition pore; NO, Nitric oxide; P/S, Penicillin/streptomycin; PAS, Periodic acid-Schiff; RIA, Radioimmunoassay; ROS, Reactive oxygen species; SOD, Superoxide dismutase; T2DM, Type 2 diabetes mellitus; TBARS, Thiobarbituric acid reactive substances; TNF-α, Tumor necrosis factor-alpha., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier Inc. All rights reserved.)

This study aims to characterize the bone-protecting effects of Alpha-lipoic acid (ALA), a potent antioxidant, against the detrimental effects of the coexistence of type 2 diabetes mellitus (T2DM) and postmenopausal osteoporosis (POP) and identify the possible mechanisms with particular reference to its modulation of YAP/Glut4 pathway. The T2DM and POP coexisting model was induced in mice by high fat diet (HFD) + Streptozocin (STZ) + ovariectomy (OVX). The mice in the treatment groups were given ALA for 10 weeks. In the in vitro study, MC3T3-E1 cells were induced with 500 μM methylglyoxal for 24 h with or without pretreatment with ALA for 24 h. The oxidative and antioxidative biomarkers, bone microarchitecture, histo-morphology, and related protein expression of apoptosis, osteogenic differentiation and the YAP/Glut4 pathway were detected. The results showed ALA could improve glucose tolerance, inhibit oxidative stress and apoptosis and alleviate bone loss. Further study by siRNA technology revealed that the YAP/Glut4 pathway was implicated in the pathogenesis of bone loss due to the coexistence of T2DM and POP. Taken together, the present study has demonstrated for the first time that ALA exerts potent protective effects against bone loss in T2DM and POP coexisting conditions by modulating the YAP/Glut4 pathway., (© 2024. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

Aim: This Bayesian network meta-analysis of randomized controlled trials assessed the effect of adjuvant periodontal treatment in both periodontal and HbA1c outcomes in adult individuals with type 2 diabetes (T2DM)., Materials and Methods: A systematic search was done up to February 2023 comparing sub-gingival debridement (SD) in combination with local or systemic adjuvant treatment with SD alone for individuals with T2DM. The primary outcomes were changes in absolute HbA1c levels and full-mouth probing depth reported at 3- to 6-month post-treatment., Results: Seventy-two eligible publications evaluating 27 adjuvant treatments were retrieved. The combination of SD and systemic antibiotic metronidazole or SD and antioxidant alpha lipoic acid provided, respectively, 1.4% (95% credible interval [CrI] 0.48; 2.20) and 2.4% (95% CrI 1.50; 3.30) more significant improvement on HbA1c levels, and 0.89 mm (95% CrI 0.23; 1.50) and 0.92 mm (95% CrI 0.02; 0.92) greater periodontal probing depth reductions. Other adjuvant treatments provided added benefit to the periodontal outcomes without discernible effects on HbA1c., Conclusions: Adjuvant use of metronidazole or alpha lipoic acid was the best adjunct option to provide clinically meaningful HbA1c levels and probing depth reductions. However, no strong recommendation can be drawn due to the scarcity of studies for each adjuvant treatment and the low certainty of the resultant evidence., (© 2024 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.)

For investigating the impact of miR-146a rs2910164 polymorphism on the therapeutic efficacy of lipoic acid therapy in patients with type 2 diabetes mellitus (T2DM) peripheral neuropathy (DPN). 106 T2DM-DPN patients in our hospital from Jan. 2020- 2022 were selected. The probe detection method was utilized to determine the polymorphism of the miR-146a rs2910164 gene in peripheral blood. All patients were treated with zinc sulfate for 3 weeks period. According to the treatment effect, 37 patients who were ineffective in treatment will be divided into an ineffective group, and 79 patients who were effective in treatment will be divided into an effective group. The condition of miR-146a gene peptides was analyzed after treatment in both groups. The motor nerve conduction velocity (MNCV), sensory nerve conduction velocity (SNCV), and Toronto Clinical Scoring System (TCSS) scores of the median nerve and common peroneal nerve with different genotypes were compared between the 2 sets. The genotype frequencies of alleles G, GG, and GC in the valid group were lower than those in the invalid group; After treatment, MNCV and SNCV of CC genotype median nerve and common peroneal nerve in DPN patients were higher than those before treatment; The TCSS scores of the three genotypes less than post-treatment. The above results showed statistically significant differences (P<0.05). Lipoic acid is influenced by the miR-146a polymorphism gene in the treatment of T2DM-DPN patients, with the CC genotype having a lower susceptibility and the best clinical treatment effect.

Background: This systematic review explores the most current evidence regarding the mechanisms of neuropathic pain in patients with different types of diabetes and how this pain affects different functional and structural components of the neuroanatomical pain pathways. The review also seeks to provide guidelines for the best approach and treatment for patients experiencing this type of pain. The objective is to determine the effectiveness of alpha-lipoic acid (ALA) in improving functional and symptomatic outcomes in patients with diabetes mellitus type I and type II., Objective: To determine the effectiveness of alpha-lipoic acid (ALA) in improving functional and symptomatic outcomes in patients with diabetes mellitus type I and type II., Methods: We systematically search MEDLINE (via PubMed), EMBASE, SCOPUS, the Cochrane Central Register of Controlled Trials, the Cumulative Index to Nursing and Allied Health Literature, and Web of Science databases., Results: The findings of this review show that different forms of ALA do not present statistically significant changes for any of the scales included, including total symptom score (standardized mean difference [SMD] = -3.59, confidence interval [CI] = -4.16 to -3.02, and P < .00001), neuropathy impairment score (SMD = -1.42, CI = -3.68 to 0.84, and P = .22), and neuropathy symptom checklist (SMD = -0.09, CI = -0.15 to -0.02, and P = .01)., Conclusion: In comparison to the use of a placebo, the findings suggest that ALA does not exhibit significant differences in terms of pain reduction and different functional scales. Moreover, no specific dosages are identified to support the use of ALA for the reduction of neuropathic pain., Competing Interests: The authors have no conflicts of interest to disclose., (Copyright © 2023 the Author(s). Published by Wolters Kluwer Health, Inc.)

Polycystic ovary syndrome (PCOS) is among the most common female endocrinopathies, affecting about 4-25% of women of reproductive age. Women affected by PCOS have an increased risk of developing metabolic syndrome, type 2 diabetes mellitus, cardiovascular diseases, and endometrial cancer. Given the pivotal role of insulin resistance (IR) in the pathogenesis of PCOS, in the last years, many insulin-sensitizing factors have been proposed for PCOS treatment. The first insulin sensitizer recommended by evidence-based guidelines for the assessment and treatment of PCOS was metformin, but the burden of side effects is responsible for treatment discontinuation in many patients. Inositols have insulin-mimetic properties and contribute to decreasing postprandial blood glucose, acting by different pathways. ALA is a natural amphipathic compound with a very strong anti-inflammatory and antioxidant effect and a very noteworthy role in the improvement of insulin metabolic pathway. Given the multiple effects of ALA, a therapeutic strategy based on the synergy between inositols and ALA has been recently proposed by many groups with the aim of improving insulin resistance, reducing androgen levels, and ameliorating reproductive outcomes in PCOS patients. The purpose of this study is to review the existing literature and to evaluate the existing data showing the efficacy and the limitation of a treatment strategy based on this promising molecule. ALA is a valid therapeutic strategy applicable in the treatment of PCOS patients: Its multiple actions, including antinflammatory, antioxidant, and insulin-sensitizing, may be of utmost importance in the treatment of a very complex syndrome. Specifically, the combination of MYO plus ALA creates a synergistic effect that improves insulin resistance in PCOS patients, especially in obese/overweight patients with T2DM familiarity. Moreover, ALA treatment also exerts beneficial effects on endocrine patterns, especially if combined with MYO, improving menstrual regularity and ovulation rhythm. The purpose of our study is to review the existing literature and to evaluate the data showing the efficacy and the limitations of a treatment strategy based on this promising molecule.

Previous studies have shown mitochondrial dysfunction in various acute kidney injuries and chronic kidney diseases. Lipoic acid exerts potent effects on oxidant stress and modulation of mitochondrial function in damaged organ. In this study we investigated whether alpha lipoamide (ALM), a derivative of lipoic acid, exerted a renal protective effect in a type 2 diabetes mellitus mouse model. 9-week-old db/db mice were treated with ALM (50 mg·kg -1 ·d -1 , i.g) for 8 weeks. We showed that ALM administration did not affect blood glucose levels in db/db mice, but restored renal function and significantly improved fibrosis of kidneys. We demonstrated that ALM administration significantly ameliorated mitochondrial dysfunction and tubulointerstitial fibrotic lesions, along with increased expression of CDX2 and CFTR and decreased expression of β-catenin and Snail in kidneys of db/db mice. Similar protective effects were observed in rat renal tubular epithelial cell line NRK-52E cultured in high-glucose medium following treatment with ALM (200 μM). The protective mechanisms of ALM in diabetic kidney disease (DKD) were further explored: Autodock Vina software predicted that ALM could activate RXRα protein by forming stable hydrogen bonds. PROMO Database predicted that RXRα could bind the promoter sequences of CDX2 gene. Knockdown of RXRα expression in NRK-52E cells under normal glucose condition suppressed CDX2 expression and promoted phenotypic changes in renal tubular epithelial cells. However, RXRα overexpression increased CDX2 expression which in turn inhibited high glucose-mediated renal tubular epithelial cell injury. Therefore, we reveal the protective effect of ALM on DKD and its possible potential targets: ALM ameliorates mitochondrial dysfunction and regulates the CDX2/CFTR/β-catenin signaling axis through upregulation and activation of RXRα. Schematic figure illustrating that ALM alleviates diabetic kidney disease by improving mitochondrial function and upregulation and activation of RXRα, which in turn upregulated CDX2 to exert an inhibitory effect on β-catenin activation and nuclear translocation. RTEC renal tubular epithelial cell. ROS Reactive oxygen species. RXRα Retinoid X receptor-α. Mfn1 Mitofusin 1. Drp1 dynamic-related protein 1. MDA malondialdehyde. 4-HNE 4-hydroxynonenal. T-SOD Total-superoxide dismutase. CDX2 Caudal-type homeobox transcription factor 2. CFTR Cystic fibrosis transmembrane conductance regulator. EMT epithelial mesenchymal transition. α-SMA Alpha-smooth muscle actin. ECM extracellular matrix. DKD diabetic kidney disease. Schematic figure was drawn by Figdraw ( www.figdraw.com )., (© 2022. The Author(s), under exclusive licence to Shanghai Institute of Materia Medica, Chinese Academy of Sciences and Chinese Pharmacological Society.)

Introduction: Alpha-lipoic acid (ALA) is a licensed drug for the treatment of diabetic neuropathy. We recently reported that it also improves diabetic cardiomyopathy (DCM) in type 2 diabetes mellitus (T2DM). In this study, we present evidence supporting our hypothesis that the cardioprotective effect of ALA is via upregulation of cardiac hydrogen sulfide (H 2 S)-synthesizing enzymes., Methods: Following 12 h of overnight fasting, T2DM was induced in 23 out of 30 male Sprague-Dawley rats by intraperitoneal administration of nicotinamide (110 mg/kg) followed by streptozotocin (55 mg/kg) while the rest served as healthy control (HC). T2DM rats then received either oral administration of ALA (60 mg/kg/day; n = 7) or 40 mg/kg/day DL-propargylglycine (PAG, an endogenous H 2 S inhibitor; n = 7) intraperitoneally for 6 weeks after which all rats were sacrificed and samples collected for analysis. Untreated T2DM rats served as diabetic control (DCM; n = 9)., Results: T2DM resulted in weight loss, islet destruction, reduced pancreatic β-cell function and hyperglycemia. Histologically, DCM rats showed significant myocardial damage evidenced by myocardial degeneration, cardiomyocyte vacuolation and apoptosis, cardiac fibrosis and inflammation, which positively correlated with elevated levels of cardiac damage markers compared to HC rats (p < 0.001). These pathological alterations worsened significantly in PAG-treated rats (p < 0.05). However, ALA treatment restored normoinsulemia, normoglycemia, prevented DCM, and improved lipid and antioxidant status. Mechanistically, ALA significantly upregulated the expression of cardiac H 2 S-synthesizing enzymes and increased plasma H 2 S concentration compared to DCM rats (p < 0.001)., Conclusion: ALA preserves myocardial integrity in T2DM likely by maintaining the expression of cardiac H 2 S-synthezing enzymes and increasing plasma H 2 S level., (Copyright © 2022 The Authors. Published by Elsevier Inc. All rights reserved.)

Introduction: We previously reported that alpha-lipoic acid (ALA) supplementation protects against progression of diabetic kidney disease (DKD). In this study, we aim to investigate whether the mechanism of renal protection by ALA involves renal cystathionine γ-lyase/hydrogen sulfide (CSE/H 2 S) system in type 2 diabetes mellitus (T2DM)., Methods: Thirty-seven male Sprague-Dawley rats underwent 12 h of overnight fasting. To induce T2DM, 30 of these rats received intraperitoneal administration of nicotinamide (110 mg/kg) and streptozotocin (55 mg/kg). T2DM rats then received either oral administration of ALA (60 mg/kg/day) or intraperitoneal administration of 40 mg/kg/day DL-propargylglycine (PAG, a CSE inhibitor) or both for 6 weeks after which rats were sacrificed and samples collected for analysis. Untreated diabetic and non-diabetic rats served as diabetic and healthy controls respectively., Results: T2DM was characterized by reduced pancreatic β-cell function and hyperglycemia. Histologically, untreated diabetic rats showed significantly damaged pancreatic islets, glomerular and tubular injury, with elevated levels of renal function markers compared to healthy control rats (p < 0.001). These pathological changes worsened significantly following PAG administration (p < 0.05). While some renal protection was observed in ALA+PAG rats, ALA administration in untreated diabetic rats provided superior protection comparable to healthy control rats, with improved antioxidant status, lipid profile and reduced inflammation. Mechanistically, ALA significantly activated renal CSE/H 2 S system in diabetic rats, which was markedly suppressed in PAG-treated rats (p < 0.001)., Conclusion: Our data suggest that ALA protects against DKD development and progression by activating renal CSE/H 2 S pathway. Hence, CSE/H 2 S pathway may represent a therapeutic target in the treatment or prevention of DKD in diabetic patients., Competing Interests: Conflict of interest statement The authors declare that they have no competing interests, (Copyright © 2022 The Authors. Published by Elsevier Masson SAS.. All rights reserved.)

Purpose: The purpose of this study is to investigate the effects of the treatment with eye-drops based on a combination of antioxidant and mucomimetic molecules, namely 0.1% alpha-lipoic acid (ALA) and 0.3% hydroxy-propyl-methylcellulose (HPMC) on the ocular surface of diabetic patients with dry eye symptoms., Methods: Seventy patients, 42 M and 28 F, aged from 50 to79 years (mean 62.1 ± 10.5), affected by type II diabetes mellitus, were enrolled and divided in two groups treated for 2 months as follows: Group 1 (35 patients), received topical ALA/HPMC three times a day, Group 2 (35 patients) received topical HPMC (0.3%) alone, three times a day. The main outcome measures were: Ocular Surface Disease Index (OSDI), tear film break-up time (TBUT), corneal fluorescein staining, Schirmer I test, corneal sensitivity. An examination of tear film morphology with confocal microscopy was carried out in a subset of patients of each group at baseline and after two months. Statistical analysis was performed with t -test for the parametric data and Mann-Whitney U-test or chi-squared test for the nonparametric data., Results: Both treatments resulted in significant improvements of BUT, OSDI and tear film morphology, although the improvements observed in group 1 showed a higher trend than what observed for group 2. Moreover, only in group 1 a significant improvement was visible for corneal staining, and no significant improvements were observed in any group for Schirmer I and sensitivity., Conclusions: These results confirmed the efficacy of HPMC in the treatment of diabetic dry eye and indicated that the addition of a strong self-regenerating antioxidant like ALA may give a distinctive advantage for the healing of corneal defects (as evidenced by corneal staining), beside improving HPMC efficacy on three other parameters (BUT, OSDI score, tear morphology). Therefore, the addition of a strong antioxidant like ALA can be helpful in preventing or treating ocular surface defects in diabetic patients, in which the oxidative damage is predominant., Competing Interests: DR is a full time employee of Fidia Pharmaceuticals, the company selling the product Tioretin under analysis in this study. The other authors declare no conflict of interest., (© 2022 The Author(s). Published by IMR Press.)

Background/aims: Correlation between type 2 diabetes and other abnormalities such as obesity with redox balance disturbance was analyzed in many reports. Nonetheless, antioxidants impact on parameters accompanying these conditions is still unknown. Currently the role of redox imbalance in the adipose tissue has gained a lot of attention., Methods: We investigated the impact of α-lipoic acid (ALA) on plasma glucose and insulin concentrations, oxidative stress and inflammation parameters in the subcutaneous (SAT) and visceral (VAT) adipose tissue of high fat diet-fed (HFD) rats. Male Wistar rats were randomly divided into three groups (n = 6) - control diet (CTRL), HFD and HFD with α-lipoic acid (HFD+ALA)., Results: HFD increased body weight, plasma insulin and glucose as well as leads to oxidative stress parameters in the adipose tissue. ALA supplementation reduced body weight and oxidative stress parameters more effectively in the visceral than subcutaneous adipose tissue of insulin resistant rats., Conclusion: Insulin resistance led to increased enzymatic and non-enzymatic antioxidant systems, protein and lipid glycoxidation, nitrosative stress, and selected inflammatory parameters more in VAT than in SAT of insulin resistant rats. Moreover, ALA inhibited HFD consequences mainly in VAT mostly through glutathione (GSH) biosynthesis., Competing Interests: The authors declare that no conflicts of interest exist., (© Copyright by the Author(s). Published by Cell Physiol Biochem Press.)

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., (Copyright © 2022 The Authors. Published by Elsevier Masson SAS.. All rights reserved.)

Aim: To evaluate if therapy with a nutraceutical combination of alpha lipoic acid, Vitis vinifera L. and Ginkgo biloba (Blunorm forte ® ) can be helpful and be synergic with Avanafil., Methods: The trial included 123 males with type 2 diabetic mellitus and with erectile dysfunction (ED), aged ≥18 years. Patients were divided in four different arms: 1 st arm: placebo during the three months of treatment and before sexual act; 2 nd arm: placebo for three months and Avanafil: 1 tablet, 200 mg, 15-30 minutes before sexual act; 3 rd arm: Blunorm forte: 1 tablet, 40 minutes before the meal (breakfast) during the three months and Avanafil: 1 tablet, 200 mg, 15-30 minutes before sexual act; 4 th arm: Blunorm forte: 1 tablet, 40 minutes before the meal (breakfast and dinner) during the three months and placebo 15-30 minutes before sexual act., Results: A significant reduction of fasting plasma glucose, and homeostasis model assessment-insulin resistance index were recorded both in Avanafil + Blunorm forte and with Blunorm forte. Metalloproteinases-2, and -9 were reduced in the Avanafil + Blunorm forte group. High sensitivity-C-reactive protein was decreased by both Avanafil, and Avanafil + Blunorm forte group. No variations were recorded with the other treatments. The group treated with Blunorm forte and Avanafil reached a higher International Index of Erectile Function (IIEF) score after 3 months of therapy compared to baseline and placebo and compared to Avanafil and Blunorm forte taken alone., Conclusion: Blunorm forte ® can be helpful and synergic with Avanafil in increasing sexual performance compared to placebo., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2022 Derosa, D’Angelo, Preti and Maffioli.)

The research determined the role of α -lipoic acid (ALA) in reducing the brain manifestations of insulin resistance. The mechanism of ALA action is mainly based on its ability to "scavenge" oxygen free radicals and stimulate biosynthesis of reduced glutathione (GSH), considered the most critical brain antioxidant. Although the protective effect of ALA is widely documented in various diseases, there are still no studies assessing the influence of ALA on brain metabolism in the context of insulin resistance and type 2 diabetes. The experiment was conducted on male Wistar rats fed a high-fat diet for ten weeks with intragastric administration of ALA for four weeks. We are the first to demonstrate that ALA improves the function of enzymatic and nonenzymatic brain antioxidant systems, but the protective effects of ALA were mainly observed in the hypothalamus of insulin-resistant rats. Indeed, ALA caused a significant increase in superoxide dismutase, catalase, peroxidase, and glutathione reductase activities, as well as GSH concentration and redox potential ([GSH] 2 /[GSSG]) in the hypothalamus of HFD-fed rats. A consequence of antioxidant barrier enhancement by ALA is the reduction of oxidation, glycation, and nitration of brain proteins, lipids, and DNA. The protective effects of ALA result from hypothalamic activation of the transcription factor Nrf2 and inhibition of NF- κ B. In the hypothalamus of insulin-resistant rats, we demonstrated reduced levels of oxidation (AOPP) and glycation (AGE) protein products, 4-hydroxynoneal, 8-isoprostanes, and 3-nitrotyrosine and, in the cerebral cortex, lower levels of 8-hydroxydeoxyguanosine and peroxynitrite. In addition, we demonstrated that ALA decreases levels of proinflammatory TNF- α but also increases the synthesis of anti-inflammatory IL-10 in the hypothalamus of insulin-resistant rats. ALA also prevents neuronal apoptosis, confirming its multidirectional effects within the brain. Interestingly, we have shown no correlation between brain and serum/plasma oxidative stress biomarkers, indicating the different nature of redox imbalance at the central and systemic levels. To summarize, ALA improves antioxidant balance and diminishes oxidative/glycative stress, protein nitrosative damage, inflammation, and apoptosis, mainly in the hypothalamus of insulin-resistant rats. Further studies are needed to determine the molecular mechanism of ALA action within the brain., Competing Interests: There is no conflict of interests., (Copyright © 2022 Mateusz Maciejczyk et al.)

Objective: The aim: To study the possibilities of alpha-lipoic acid (ALA) to control the parameters of carbohydrate metabolism., Patients and Methods: Materials and methods: We examined 80 people with type 2 DM and coronary heart disease who suffered non-Q-myocardial infarction (non-Q-MI). All patients at the time of inclusion in the study received oral hypoglycemic agents, ACE inhibitor, β-blocker, statin and antiplatelet agent. 600 mg of ALA per day for 4 months was added to this treatment. After checking the patients for compliance with the criteria, they were divided into the main and experimental groups. The dosage of alpha-lipoic acid was determined for each of the groups. The results of the treatment were analyzed by determining the mean and standard deviations., Results: Results: At the end of the observation period, a significant decrease in the level of fasting glucose (FG) by 11.6% was found, which corresponded to the average size of the clinical effect. The values of glycosylated hemoglobin (HbA1c) and the insulin resistance index HOMA (HOMA-IR) showed only a tendency to decrease on the background of treatment. The effect of ALA on postprandial glycemia (PPG) and insulin levels was not detected in this study., Conclusion: Conclusions: An additional 4-month dose of ALA in addition to baseline therapy showed a moderate effect on the decrease in FG concentration in the absence of significant dynamics in other parameters of glycemic control in the examined patients.

Elevated oxidative stress is a common denominator between pathways implicated in the pathogenesis of diabetes mellitus and diabetes complications, prompting the use of antioxidant compounds in diabetes therapy. Alpha-lipoic acid (ALA), has been investigated for its role as a potent antioxidant in diabetes treatment and the results from clinical trials indicate improved glucose metabolism, reduced oxidative stress, improved endothelial dysfunction, a decline in platelet reactivity and moderate improvements to weight loss yet conflicting data regarding insulin metabolism. ALA inhibits nuclear factor kappa B (NFkB), chelates divalent transient metal ions and induces the expression of adenosine monophosphate-activated protein kinase (AMPK). This narrative review explores the results from clinical trials investigating the role of ALA in the treatment of diabetes mellitus.

Objectives: Progranulin (PGRN) is a secreted growth factor that helps to regulate neuronal survival by blocking tumor necrosis factor-alpha (TNFα) receptors. The antioxidant alpha-lipoic acid (ALA) is used in diabetic neuropathy to improve nerve conduction and relieve neuropathic pain, but its effects on PGRN levels have not yet been elucidated., Methods: In this prospective study, 54 patients with type 2 diabetes and peripheral neuropathy received 600 mg of ALA daily for 6 months. Twenty-four patients with diabetes without neuropathy were also included in the study. Serum PGRN and TNFα levels were determined using enzyme-linked immunosorbent assays. In addition, current perception threshold (CPT) testing was used to assess sensory neuropathy., Results: After ALA treatment, serum PGRN levels were significantly increased and CPT values were significantly improved. Furthermore, there were significant positive correlations among TNFα, ICAM-1, and PGRN levels both before and after ALA treatment. A significant negative correlation was observed between the improvements in CPT and the PGRN levels. Furthermore, ICAM-1 levels were an independent predictor of PGRN levels., Conclusions: Changes in serum PGRN levels indicate that ALA treatment may have beneficial effects on endothelial function and neuronal inflammation.

Background: The pathogenesis of diabetic peripheral neuropathy is more complex and it is not yet clear, but studies have shown that microangiopathy and oxidative stress responses are closely related to their pathogenesis. At present, the treatment of improving microcirculation and antioxidant stress is mainly used in clinical. Alprostadil is a commonly used vasodilator, and alpha lipoic acid is an antioxidant, which can effectively reduce oxidative stress responses and delay the progression of diabetes mellitus and its complications. However, there is a lack of evidence-based medical evidence for alprostadil combined with alpha lipoic acid in the treatment of diabetic peripheral neuropathy, and this article aims to understand the clinical effectiveness and safety of alprostadil combined with alpha lipoic acid in the treatment of diabetic peripheral neuropath by a meta-analysis of published randomized controlled trials., Methods: In this study, we obtain the relevant literature by retrieving 8 electronic databases, including PubMed, EMBASE, Web of Science, the Cochrane Library, CBM, CNKI, VIP, and WanFang Database. Retrieving a randomized controlled study of alprostadil combined with alpha lipoic acid in the treatment of diabetic peripheral neuropath, while the language of the literature is restricted and it only includes Chinese and English literature. For the publication of literature, the time is from the beginning of the database to August 31, 2020. In the English database, using the retrieval method of subject word combined free word. The two researchers read the titles and abstracts of all the literature independently based on the inclusion and exclusion criteria. If it cannot be determined whether the literature is included by reading the title and abstract, then download and read the full text of the literature. If there is a dispute between the two researchers about the literature, so it should discuss the dispute with the third researcher in order to reach a conclusion. Using the bias risk assessment tool of randomized controlled trials in Cochrane systematic review to evaluate the bias risk of the included literature; Using RevMan 5.3 software to conduct statistical analysis; Using funnel plot analysis to analyze the situation of literature publication bias., Results: This study will provide a high-quality evidence on the effects of hydrolyzed protein formula milk on gastrointestinal diseases and physical development of premature infants., Conclusion: This study will draw reliable evidence-based medical evidence for alprostadil combined with Alpha lipoic acid in the treatment of diabetic peripheral neuropathy, thus providing help for the clinical treatment of diabetic peripheral neuropathy., Registration Number: Open Science Framework (OSF), registration number: DOI 10.17605/OSF.IO/7S46G.

A number of aging-related disorders (ARD) have been related to oxidative stress (OS) and mitochondrial dysfunction (MDF) in a well-established body of literature. Most studies focused on cardiovascular disorders (CVD), type 2 diabetes (T2D), and neurodegenerative disorders. Counteracting OS and MDF has been envisaged to improve the clinical management of ARD, and major roles have been assigned to three mitochondrial cofactors, also termed mitochondrial nutrients (MNs), i.e., α-lipoic acid (ALA), Coenzyme Q10 (CoQ10), and carnitine (CARN). These cofactors exert essential-and distinct-roles in mitochondrial machineries, along with strong antioxidant properties. Clinical trials have mostly relied on the use of only one MN to ARD-affected patients as, e.g., in the case of CoQ10 in CVD, or of ALA in T2D, possibly with the addition of other antioxidants. Only a few clinical and pre-clinical studies reported on the administration of two MNs, with beneficial outcomes, while no available studies reported on the combined administration of three MNs. Based on the literature also from pre-clinical studies, the present review is to recommend the design of clinical trials based on combinations of the three MNs.

Patients with combined coronary heart disease and diabetes mellitus make up a growing segment of the population and require a comprehensive treatment approach. Patients with concurrent diabetes mellitus and coronary heart disease have a worse projection. Under these conditions, the incidence of recurrent myocardial infarction, early disability due to complications, and the risk of coronary death are increased. Therefore, the priority task is to find ways to optimize drug treatment of this category of patients, taking into account the impact of drugs on the pathogenetic links of coronary heart disease progression and the development of cardiovascular complications. One hundred twelve people were examined in the research. The patients had type 2 diabetes with a history of non-Q-myocardial infarction receiving oral antidiabetic therapy and basic therapy, including an ACE inhibitor, a β-blocker, a statin, and an antiplatelet agent. Analysis of the investigated parameters in the leading group after receiving alpha-lipoic acid for 4 months showed a significant decrease in the concentration of C-Reactive Protein, IL-6 and TNF-α. According to the results of our research, taking alpha-lipoic acid for 4 months in patients with type 2 diabetes who underwent non-Q-myocardial infarction reduced the activity of systemic inflammation and did not significantly affect the content of anti-inflammatory IL-10 in patients. In light of the above, it is of interest to administer alpha-lipoic acid to these patients, considering the positive effects of the agent such as antioxidant properties, vasorelaxation, positive metabolic profile, as well as an anti-inflammatory potential., (©Carol Davila University Press.)

Alpha-lipoic acid (ALA) has been used as a dietary supplement at different doses in patients with diabetes mellitus type 2 (T2DM) due to its antioxidant, anti-inflammatory, and hypoglycemic effects. However, the reports on the effects of ALA are controversial. For this reason, the purpose of the present study was to determine the effect of 600 mg/day of ALA on the markers of oxidative stress (OxS) and inflammation and RAGE in older adults with T2DM. A quasiexperimental study was carried out with a sample of 135 sedentary subjects (98 women and 37 men) with a mean age of 64 ± 1 years, who all had T2DM. The sample was divided into three groups: (i) experimental group (EG) with 50 subjects, (ii) placebo group (PG) with 50 subjects, and control group (CG) with 35 subjects. We obtained the following measurements in all subjects (pre- and posttreatment): glycosylated hemoglobin (HbA1c), receptor for advanced glycation end products (RAGE), 8-isoprostane, superoxide dismutase (SOD), glutathione peroxidase (GPx), total antioxidant status (TAS), and inflammatory (CRP, TNF- α , IL-6, IL-8, and IL-10) markers. Regarding the effect of ALA on HbA1c, a decrease was observed in the EG (baseline 8.9 ± 0.2 vs. posttreatment 8.6 ± 0.3) and the PG (baseline 8.8 ± 0.2 vs. posttreatment 8.4 ± 0.3) compared to the CG (baseline 8.8 ± 0.3 vs. six months 9.1 ± 0.3) although the difference was not statistically significant ( p < 0.05). There was a statistically significant decrease ( p < 0.05) in the blood concentration of 8-isoprostane in the EG and PG with respect to the CG (EG: baseline 100 ± 3 vs. posttreatment 57 ± 3, PG: baseline 106 ± 7 vs. posttreatment 77 ± 5, and CG: baseline 94 ± 10 vs. six months 107 ± 11 pg/mL). Likewise, a statistically significant decrease ( p < 0.05) in the concentration of the RAGE was found in the EG (baseline 1636 ± 88 vs. posttreatment 1144 ± 68) and the PG (baseline 1506 ± 97 vs. posttreatment 1016 ± 82) compared to CG (baseline 1407 ± 112 vs. six months 1506 ± 128). A statistically significant decrease was also observed in all markers of inflammation and in the activity of SOD and GPx in the CG with respect to the EG and PG. Our findings suggest that the administration of ALA at a dose of 600 mg/day for six months has a similar effect to that of placebo on oxidative stress, inflammation, and RAGE in older adults with T2DM. Therefore, higher doses of ALA should be tried to have this effect. This trial is registered with trial registration number ISRCTN13159380.

Type 2 diabetes mellitus (T2DM) is evolving to an epidemic of the modern world. T2DM is associated with a number of pathological complications, including cardiovascular disease that is mostly promoted by the increased oxidative stress in type 2 diabetic patients. We performed a randomized double-blind placebo-controlled trial to investigate the effectiveness of an individualized oral supplementation with α-lipoic acid (ALA), carnosine, and thiamine. For that purpose, 82 obese type 2 diabetic patients were randomly assigned to 2 groups, and were either supplemented daily with 7 mg ALA/kg body weight, 6 mg carnosine/kg body weight, and 1 mg thiamine/kg body weight or placebo for 8 weeks. An array of biochemical tests including the estimation of oxidative stress and platelet aggregation were performed at baseline and at follow-up. Moreover, the antiplatelet activity of each of the supplement's components was determined ex vivo at human and washed rabbit platelets. Glucose and HbA 1c levels were significantly reduced after supplementation (135.7 ± 19.5 mg/dL vs. 126.5 ± 16.8 mg/dL and 8.3% ± 0.3% vs. 6.03% ± 0.58%, respectively, P < .05); however, insulin was significantly increased (3.6 ± 0.7 μIU/mL vs. 6.8 ± 0.2 μIU/mL, P < .05). The patients treated with the supplement recorded higher follow-up values for HOMA-IR and HOMA-β, and a significant drop in serum hydroperoxide level. Only ALA inhibited platelets aggregation ex vivo through ADP, platelet activating factor, arachidonic acid, epinephrine, collagen, and thrombin pathways. Daily supplementation with an individualized ALA, carnosine, and thiamine supplement effectively reduced glucose concentration in type 2 diabetic patients, probably by increasing insulin production from the pancreas. In addition to that, the reduction of oxidative stress and inhibition of platelet aggregation could potentially provide greater cardiovascular protection. Further studies are needed to fine-tune the supplementation dose-response effects in T2DM patients.

Objective: We investigated the clinical value of alprostadil combined with the α-lipoic acid in treating type 2 diabetes mellitus with erectile dysfunction (DMED)., Patients and Methods: We selected a total of 76 cases of patients who were admitted to endocrinology department of our hospital from June 2014 to June 2015 and diagnosed as DMED, and the average age was (46.7 ± 7.2) years old, average course of diabetes mellitus was (6.2 ± 2.8) years and average body mass index was (25.4 ± 1.3) kg/m2. 40 cases were randomly divided in the observation group while 36 cases were divided in the control group. They received blood glucose control therapy. The patients in the observation group received 60 mg alprostadil hydrochloride and 600 mg α-lipoic acid added into 250 mL normal saline, intravenous drip once per day for 2 weeks. The patients in the control group took tadalafil 5 mg orally, once per night for 2 weeks as a course of treatment. There were no cases of loss., Results: The effective rate of treatment in observation group is significantly higher than that in the control group (95.0% vs. 80.5%, p < 0.05). The score of IIEF-5, EHGS and the FMD value of brachial artery of the observation group after the operation were significantly higher than that of the control group (p < 0.05). The adverse reaction rate in the observation group was lower than that in the control group (7.5% vs. 13.9%, p < 0.05)., Conclusions: Alprostadil combined with α-lipoic acid can improve DMED patients' vascular endothelial function and erection hardness to treat erectile dysfunction with less adverse effects and better safety.

Aims: We aimed to analyze the impact of baseline factors on the efficacy of α-lipoic acid (ALA) over 4 years in the NATHAN 1 trial., Methods: This was a post-hoc analysis of the NATHAN 1 trial, a 4-year randomized study including 460 diabetic patients with mild-to-moderate polyneuropathy using ALA 600 mg qd or placebo. Amongst others, efficacy measures were the Neuropathy Impairment Score of the lower limbs (NIS-LL) and heart rate during deep breathing (HRDB)., Results: Improvement and prevention of progression of NIS-LL (ΔNIS-LL≥2 points) with ALA vs. placebo after 4 years was predicted by higher age, lower BMI, male sex, normal blood pressure, history of cardiovascular disease (CVD), insulin treatment, longer duration of diabetes and neuropathy, and higher neuropathy stage. Participants treated with ALA who received ACE inhibitors showed a better outcome in HRDB after 4 years., Conclusions: Better outcome in neuropathic impairments following 4-year treatment with α-lipoic acid was predicted by normal BMI and blood pressure and higher burden due to CVD, diabetes, and neuropathy, while improvement in cardiac autonomic function was predicted by ACE inhibitor treatment. Thus, optimal control of CVD risk factors could contribute to improved efficacy of α-lipoic acid in patients with higher disease burden., (Copyright © 2016 Elsevier Inc. All rights reserved.)

We have previously demonstrated that treating diabetic rats with enalapril, an angiotensin converting enzyme (ACE) inhibitor, α-lipoic acid, an antioxidant, or menhaden oil, a natural source of omega-3 fatty acids can partially improve diabetic peripheral neuropathy. In this study we sought to determine the efficacy of combining these three treatments on vascular and neural complications in a high fat fed low dose streptozotocin treated rat, a model of type 2 diabetes. Rats were fed a high fat diet for 8 weeks followed by a 30 mg/kg dose of streptozotocin. Eight weeks after the onset of hyperglycemia diabetic rats were treated with a combination of enalapril, α-lipoic acid and menhaden oil. Diabetic rats not receiving treatment were continued on the high fat diet. Glucose clearance was impaired in diabetic rats and significantly improved with treatment. Diabetes caused steatosis, elevated serum lipid levels, slowing of motor and sensory nerve conduction, thermal hypoalgesia, reduction in intraepidermal nerve fiber profiles, decrease in cornea sub-basal nerve fiber length and corneal sensitivity and impairment in vascular relaxation to acetylcholine and calcitonin gene-related peptide in epineurial arterioles of the sciatic nerve. Treating diabetic rats with the combination of enalapril, α-lipoic acid and menhaden oil reversed all these deficits to near control levels except for motor nerve conduction velocity which was also significantly improved compared to diabetic rats but remained significantly decreased compared to control rats. These studies suggest that a combination therapeutic approach may be most effective for treating vascular and neural complications of type 2 diabetes., (Published by Elsevier B.V.)

Type 2 diabetes is a common metabolic disorder characterized by resistance to the actions of insulin to stimulate skeletal muscle glucose disposal. In light of the staggering financial/human cost of type 2 diabetes, there is considerable need for safe and effective agents that can be used to prevent and/or adjunctively treat the disease. Available evidence suggests that a number of natural supplements, including cinnamon, biotin, fenugreek, ginseng, banaba, and alpha-lipoic acid, have the potential to reduce the risk for type 2 diabetes in the large at-risk population. The evidence also suggests that, when used adjunctively, these natural products are likely to help clinicians achieve optimal glycemic control, improve long-term prognosis, and/or minimize the need for insulin therapy in type 2 diabetics. More research, particularly well-designed, long-term human clinical trials, is certainly needed to accurately define the value and place of these supplements in diabetes prevention and management.

Effective treatment of diabetic sensorimotor polyneuropathy remains a challenge. To assess the efficacy and safety of α-lipoic acid (ALA) over 20 weeks, we conducted a multicenter randomized withdrawal open-label study, in which 45 patients with type 2 diabetes and symptomatic polyneuropathy were initially treated with ALA (600 mg tid) for 4 weeks (phase 1). Subsequently, responders were randomized to receive ALA (600 mg qd; n = 16) or to ALA withdrawal (n = 17) for 16 weeks (phase 2). During phase 1, the Total Symptom Score (TSS) decreased from 8.9 ± 1.8 points to 3.46 ± 2.0 points. During phase 2, TSS improved from 3.7 ± 1.9 points to 2.5 ± 2.5 points in the ALA treated group (p < 0.05) and remained unchanged in the ALA withdrawal group. The use of analgesic rescue medication was higher in the ALA withdrawal group than ALA treated group (p < 0.05). In conclusion, in type 2 diabetic patients with symptomatic polyneuropathy who responded to initial 4-week high-dose (600 mg tid) administration of ALA, subsequent treatment with ALA (600 mg qd) over 16 weeks improved neuropathic symptoms, whereas ALA withdrawal was associated with a higher use of rescue analgesic drugs. This trial is registered with ClinicalTrials.gov Identifier: NCT02439879.

Presence of comorbidity in patients--that is essential hypertension and type 2 diabetes is associated with early progression of target organs affection and cardiovascular complications. Hyperinsulinemia and insulin resistance are some of the factors that determine the frequency of cardiovascular complications in type 2 diabetes. According to some authors, endothelial dysfunction is a link between insulin resistance and cardiovascular diseases. To investigate severity of endothelial dysfunction in patients with essential hypertension and type 2 diabetes and its correction by using a complex treatment α-lipoic acid we have examined 84 patients with essential hypertension stage II and type 2 diabetes in a moderate condition before and after 6 months treatment. The patients were divided into two groups: the first one consisted of the patients who received only basic therapy, and another one consisted of those patients who in addition to basic therapy received also α-lipoic acid in tablets at a dose of 600 mg/day. After the investigation it was discovered that changes in the vascular wall in patients with essential hypertension and type 2 diabetes are characterized by increase of intima-media thickness and pulse wave velocity in the carotid arteries and abdominal aorta, decrease of endothelium-dependent vasodilation degree and increase of the levels of proinflammatory cytokines. Under the influence of the mentioned complex therapy in these patients it was found some improvement of metabolic homeostasis and correction of endothelial dysfunction. The effect on the structural and functional state of great vessels and proinflammatory cytokines, gained due to additional prescription of α-lipoic acid to the patients with essential hypertension and type 2 diabetes, was more considerable that the one which was shown in the group of patients who received only standard therapy.

Objective: This study aims to evaluate the efficacy and safety of α-lipoic acid in the treatment of aged type 2 diabetes mellitus (T2DM) complicated with acute cerebral infarction., Patients and Methods: 90 patients were randomly divided into two groups, on the basis of conventional treatment. The experiment group was administrated with α-lipoic acid, while only Vitamin C for the control group, for 3 consecutive weeks. Before and after the experiment, superoxide dismutase (SOD), glutathione peroxidase (GSH-Px) and malondialdehyde (MDA) levels were measured and scored with the NIHSS (National Institutes of Health Stroke Scale), and the changes of blood glucose, insulin function and other indicators were observed., Results: After the treatment, the plasma SOD and GSH-Px levels increased, while MDA decreased (p < 0.05), with statistical significance when compared with the control group (p < 0.01). NIHSS score, blood glucose, blood lipids and HOMA-IA of the experiment group decreased significantly (p < 0.01); and no significant adverse reactions were found in both groups., Conclusions: α-lipoic acid was safe and effective in the treatment of aged T2DM complicated with acute cerebral infarction, significantly reducing the patient's oxidative stress, blood glucose and lipid levels and being able to improve islet function.

Background: Short-term continuous subcutaneous insulin infusion (CSII) in patients with newly diagnosed type 2 diabetes has been proved effective in improving metabolic control and β-cell function, thus inducing long-term drug-free remission. A randomized controlled trial was conducted to investigate whether CSII in combination with rosiglitazone, metformin, or α-lipoic acid separately brings about extra benefits., Patients and Methods: One hundred sixty patients with newly diagnosed type 2 diabetes were randomized to one of four treatment groups: CSII alone, CSII in combination with rosiglitazone or metformin for 3 months, or CSII with α-lipoic acid intravenous infusion for 2 weeks. Duration of CSII treatment was identical in the four groups. Glucose and lipid profiles, homeostasis model assessment (HOMA) indices, acute insulin response (AIR), intramyocellular lipid (IMCL) level, and malondialdehyde level were compared before and after intervention., Results: The near-normoglycemia rate at the third month in CSII alone and that in combination with rosiglitazone, metformin, or α-lipoic acid was 72.5%, 87.5%, 90%, and 75%, respectively (metformin group vs. CSII alone, P=0.045). The metformin group achieved euglycemia in a shorter time (2.6 ± 1.3 vs. 3.7 ± 1.8 days, P=0.020) with less daily insulin dosage and was more powerful in lowering total cholesterol, increasing AIR and HOMA β-cell function, whereas reduction of IMCL in the soleus was more obvious in the rosiglitazone group but not in the metformin group. The efficacy of combination with α-lipoic acid was similar to that of CSII alone., Conclusions: Short-term CSII in combination with rosiglitazone or metformin is superior to CSII alone, yet the efficacy of the two differs in some way, whereas that with α-lipoic acid might not have an additive effect.

Objective: To evaluate the effect of alpha-lipoic acid (LA) combined with transient intensive insulin therapy on adipokine level in patients with type 2 diabetic perineuropathy (DPN)., Methods: Totally 120 type 2 DPN patients who were receiving transient intensive insulin treatment were equally and randomly divided into LA group and methycobal group (which was set as the control group). The treatment lasted two weeks. The levels of biochemical indicators and adipokine were measured before treament and two weeks after treament., Results: After treatment with insulin, serum blood-fasting glucose(FBG), tumor necrosis factor-Α(TNFΑ), and hypersensitive C-reactive protein (HSCRP)were significantly decreased in both LA group and methycobal group(all P <0.05), while adiponectin (APN) significantly increased (both P <0.05). Compared with the methycobal group,the level of APN was significantly higher and those of TNFΑ and HSCRP were significantly lower in LA group(all P <0.05).Leptin showed no significant change before and after treatment(all P >0.05)., Conclusion: Transient intensive insulin therapy with LA treatment can regulate adpokine and enhance the anti-inflammatory effect of insulin in type 2 DPN patients.

To evaluate the protective effects of α-lipoic acid on the kidneys of Goto-Kakisaki (GK) diabetic rats, ten GK diabetic rats were randomly divided into a diabetic control group and a lipoic acid-treated diabetic group with α-lipoic acid 35 mg·Kg-1 intraperitoneal injections. Four healthy Wistar rats served as normal controls. Malonaldehyde (MDA), ascorbic acid (vitamin C), vitamin E, glutathione (GSH) and superoxide dismutase (SOD) levels in renal homogenate, and urine protein excretion were measured. The expression of mRNA for NF-κB, NADPH oxidase subunits p22phox and p47phox in renal tissue was examined by realtime PCR. Pathological changes in renal tissue were evaluated by light and electron microscopy. There were significant increases in urine protein excretion, MDA levels and the expression of mRNA of NF-κB, p22phox and p47phox, and significant decreases in GSH, SOD, vitamin C and vitamin E levels in the diabetic control group compared with the normal control group. Pathological changes of renal tissue were more progressive in the diabetic control group than in the normal control group. All the parameters above were improved in the α-lipoic acid-treated diabetic group. Oxidative stress is increased in the kidney of type 2 diabetic GK rats. It is associated with the progression of diabetic nephropathy. α-lipoic acid can protect renal function in diabetic rats via its antioxidant activity.

Eighty-one patients with diabetes mellitus type 2 (DM) and cardiovascular autonomic neuropathy were studied. The combined treatment with ω-3 PUFA, benfotiamine, and α-lipoic acid resulted in significant positive changes in total cholesterol, triacylglycerol, LDL and HDL cholesterol levels. The efficacy of this treatment was not associated with the improved compensation of DM but was a result of the direct influence of pharmacological agents on the metabolic rate studied.

Unlabelled: Erectile dysfunction (ED) is the inability to develop and/or maintain an erection that is sufficient for satisfactory sexual intercourse. The prevalence of erectile dysfunction in diabetic men is 28-75%, this percentage rising with patient's age and duration of diabetes. The AIM of the present study was to investigate erectile dysfunction and quality of life in patients with type 2 diabetes mellitus (T2DM) after treating them with transdermal testosterone or with alpha-lipoic acid., Materials and Methods: The effect of a 12-week treatment with transdermal testosterone or alpha-lipoic acid on the erectile function and quality of life of 45 men with ED and T2DM was studied in a randomized, prospective, open clinical, comparative study. The parameters we measured in the patients were body weight and body mass index (BMI); the albumin, lipids, HbA1C, testosterone (T), sex hormone-binding globulin (SHBG), follicle stimulating hormone (FSH), luteinizing hormone (LH) and microalbuminuria levels; the International Index of Erectile Function (IIEF) and Health related quality of life (SF-36) questionnaires were completed to evaluate ED and quality of life before and after 12 weeks of treatment with alpha-lipoic acid (600 mg, parenterally, for 7 days, followed by 600 mg received per os) or with transdermal testosterone in a dose of 50 mg daily., Results: Testosterone treatment decreased BMI significantly (p < 0.01), increased testosterone concentrations (p < 0.01) and raised the SHBG levels (p < 0.05), improved the glycemic control and lipid profile (total cholesterol, p < 0.05; HDL cholesterol, p < 0.05; triglycerides, p < 0.05). The patients treated with alpha-lipoic acid had their BMI (p < 0.01), HbA1C (p < 0.01), total cholesterol (p < 0.01), HDL-cholesterol (p < 0.01) and triglycerides (p < 0.01) significantly reduced. The indicators for ED in both groups were also statistically significantly improved. There was improvement for all patients' self-assessment score for "physical functioning" (p = 0.001), for "role limitations due to physical health" (p < 0.001) and for "general health perception" (p = 0.021)., Conclusions: Transdermal testosterone and alpha-lipoic acid have a tangible beneficial effect on erectile dysfunction and on metabolic disorders in T2DM patients and can be used to treat such patients.

Introduction: Diabetes mellitus is a metabolic, chronic and incurable disease which reduces span and quality of life. Over 50% of diabetic patients have clinical manifestations of diabetic neuropathy., Aim: To show a positive influence of alpha lipoic acid on clinically manifested diabetic neuropathy symptoms as well as the effect of alpha lipoic acid in patients glycaemic control., Material and Methods: Testing has been conducted in Cantonal Hospital"Irfan Ljubijankic MD" in Bihac and included 20 diabetes type 2 patients who were diagnosed with clinically manifested diabetic neuropathy. All the patients' conditions were evaluated by: medical history, clinical parameters, detailed internal examination, laboratory analyses for glycaemic control assessment and mono filament test. They were treated with oral anti-diabetics and insulin as well as with alpha lipoic acid preparation in duration of four months. They were divided into two groups, with good (HbA1c < 7%) and poor (HbAc > or = 7%) glycaemic control. Medical control has been conducted four months after the research started., Results: Twenty patients took part in the research, 7 male and 13 female. The average age of the patients was 58.6 in the first and 55.6 years in the second group. The average patients' disease duration was 13.4 +/- 6.6 years in the first and 11.2 +/- 5.4 years in the second group. The difference in gender, average age and disease duration in both groups statistically is not significant (p < or = 0.05). The number of negative points after the therapy has been reduced for 56.4% in the first and 43.1% for the second group (p < or = 0.05). Prior to the treatment, all the patients in both groups had paresthesia. At medical checkup, there were 40% less patients in the first group and 10% in the second one (p < or = 0.01). The difference is statistically significant (p < or = 0.05) in night pain occurrence between two groups of patients after alpha lipoic acid treatment (40% more patients had night pain in the second group after the treatment). The same number of patients in both groups, 40% had muscle atrophy and difficulty in walking. At medical checkup, 30% in first group and 20% less patients had discomforts (p > or = 0.05). Regression of subjective sensations in both groups of patients after alpha lipoic acid treatment has been noted., Conclusion: Alfa lipoic acid is an effective drug in the treatment of diabetic distal sensory-motor neuropathy and its therapeutic effect is more effective in patients with good glycaemic control.

Background: We sought to determine whether a combination of angiotensin-converting enzyme inhibitors (ACEIs) and the nutraceutical α-lipoic acid (ALA) regulates blood pressure, endothelial function, and proteinuria in diabetic patients with Stage I hypertension., Methods: A total of 40 diabetic patients with Stage I hypertension were treated in a crossover double-blinded manner. Patients were administered quinapril ([QUI] 40 mg/d) for 8 weeks or QUI + ALA (600 mg/d) for 8 weeks. Measurements included blood pressure, 24-hour collection of urinary albumin, and endothelial-dependent flow-mediated dilation (FMD)., Results: There was a change of metabolic parameters in both study groups after 8 weeks of therapy. In comparison to baseline, the 24-hour urinary albumin significantly decreased by 30% in the QUI group (P = .018, time comparison) and 53% in QUI + ALA group (P < .005, time and group comparison). Also, when compared with baseline, FMD significantly increased by 58% in QUI group (P < .005, time comparison) and by 116% in QUI + ALA group (P < .005, time and group comparison). Systolic and diastolic blood pressure reduced significantly by 10% with QUI treatment. There was no further blood pressure reduction when patients were administered both QUI and ALA., Conclusions: In diabetic patients with hypertension, QUI reduces blood pressure, proteinuria, and improves endothelial function. Moreover, this effect is strongly potentiated with a combination of QUI and ALA. These results may attenuate the progression of vascular pathophysiology seen in patients with a combination of diabetes and hypertension.

Background: This study assessed the effect of a systemic oral treatment with antioxidants (AOs) in preretinopathic diabetes (PRD) patients, through the evaluation of oxidative stress in plasma and changes in the full-field electroretinogram (ERG)., Methods: Thirty-two PRD subjects with good metabolic control were recruited. Patients were randomized in two groups, one of which received oral AO treatment with α-lipoic acid at 400 mg/day in association with genistein and vitamins, whereas the other group received a placebo. Free radicals and the AO barrier were evaluated in plasma with the Free Radical Analytical System 4 instrument (H&D srl, Parma, Italy), and the same day the electrophysiological response was measured by ERG. These analyses were performed at enrollment and after 30 days of treatment., Results: Statistically significant increases of plasma AO levels and ERG oscillatory potential values were observed in the group treated with AO, but not in the control group., Conclusions: Results of this preliminary study suggest that an oral treatment with AOs in PRD subjects may have a protective effect on retinal cells, as detected by ERG analysis, through the strengthening of the plasma AO barrier.

Despite well-controlled blood glucose levels, diabetic complications still inevitably take place via several mechanisms including excessive generation of free radicals in patients who suffer from diabetes mellitus (DM). A randomized double-blind placebo-controlled clinical trial to investigate the effectiveness of oral supplementation of DL-alpha-lipoic acid (ALA) on glycemic and oxidative status in DM patients was conducted. Thirty eight outpatients with type 2 DM were recruited and randomly assigned to either placebo or treatment in various doses of ALA (300, 600, 900, and 1200 mg/day) for 6 months. Following the treatment, all subjects were evaluated for glucose status and oxidative biomarkers. Results showed that fasting blood glucose, HbA1c trended to decrease in a dose-dependent manner. Increase of urinary PGF2α-Isoprostanes (F2α-IsoP) was noted in placebo but not ALA-treated groups, indicating possible suppressing action of ALA on lipid peroxidation in DM subjects. 8-Hydroxy-2'-deoxyguanosine (8-OHdG) levels, however, were similar in both placebo and ALA groups as well as urinary microalbumin and serum creatinine. Safety evaluation was monitored and treatment was found to be well tolerated despite some minor side effects. Results from this study reflected the benefits of ALA in glucose status with slight efficiency on oxidative stress-related deterioration in DM patients.

Objective: To examine the effects of alpha-lipoic acid (ALA) treatment over a period of 2 months on fasting blood glucose (FBG), insulin resistance (IR), and glutathione peroxidase (GH-Px) activity in type 2 diabetes (T2DM) patients., Methods: This study took place in Motahari Clinic, Shiraz, Iran, which is affiliated to Shiraz University of Medical Sciences from May to October 2006. Type 2 DM patients (n=57) were divided into 2 groups to receive either ALA (300 mg daily) or placebo by systematic randomization, and were followed-up for 8 weeks. After an overnight fasting and 2 hours after breakfast, patients' blood samples were drawn and tested for FBG, 2 hours PPG, serum insulin level, and GH-Px activity., Results: The result of the study showed a significant decrease in FBG and PPG levels, IR-Homeostasis Model Assessment (IR-HOMA index) and GH-Px level in the ALA group. The comparison of differences between FBG and IR at the beginning and at the end of study in the ALA treated group and the placebo group were also significant., Conclusion: This study supports the use of ALA as an antioxidant in the care of diabetic patients.

Antioxidants probably play an important role in the etiology of type 2 diabetes (DM2). This study evaluated the effects of supplementation with lipoic acid (LA) and α-tocopherol on the lipid profile and insulin sensitivity of DM2 patients. A randomized, double-blind, placebo-controlled trial involving 102 DM2 patients divided into four groups to receive daily supplementation for 4 months with: 600 mg LA (n = 26); 800 mg α-tocopherol (n = 25); 800 mg α-tocopherol + 600 mg LA (n = 25); placebo (n = 26). Plasma α-tocopherol, lipid profile, glucose, insulin, and the HOMA index were determined before and after supplementation. Differences within and between groups were compared by ANOVA using Bonferroni correction. Student's t-test was used to compare means of two independent variables. The vitamin E/total cholesterol ratio improved significantly in patients supplemented with vitamin E+LA and vitamin E alone (p ≤ 0.001). There were improvements of the lipid fractions in the groups receiving LA and vitamin E alone or in combination, and on the HOMA index in the LA group, but not significant. The results suggest that LA and vitamin E supplementation alone or in combination did not affect the lipid profile or insulin sensitivity of DM2 patients., (Copyright © 2011 Elsevier Ireland Ltd. All rights reserved.)

Objective: The aim of this study was to investigate the effect of alpha-lipoic acid (ALA) treatment on endothelium-dependent and -independent vasodilatation, assessed by forearm blood flow (FBF), in patients with type 2 diabetes mellitus., Research Design and Methods: A total of 30 subjects with type 2 diabetes were included in this randomized, controlled, double-blinded, parallel group study. FBF responses to intra-arterial acetylcholine (ACh) and glycerol trinitrate (GTN) were measured before and after 21 days of intravenous treatment with 600 mg alpha-lipoic acid or placebo., Results: FBF responses were comparable at baseline. After treatment, FBF reactivity to ACh and GTN was unchanged in subjects receiving placebo. By contrast, ALA treatment increased endothelium-dependent vasodilatation to ACh (P < 0.05) but not to GTN compared with baseline., Conclusions: Intravenous ALA treatment improves endothelium-dependent vasodilatation in patients with type 2 diabetes, in the absence of effects on forearm vasomotor function. If this salutary action translates into vascular risk reduction remains to be established.

Type 2 Diabetes Mellitus (T2DM) which is characterised by insulin resistance, is closely linked to the triad of glucolipotoxicity, inflammation and oxidative stress. Increased adiposity, leading to increased free fatty acids (FFAs), contributes to insulin resistance by disrupting the signal transduction pathway of insulin mediated glucose disposal, and causes impaired insulin secretion. Hyperglycaemia and dyslipidaemia driven oxidative stress resulting from enhanced free-radical formation and/or defects in antioxidant defence is implicated in the pathogenesis of diabetic neuropathy (DN). This and other inflammatory pathways account for a complex network of interacting metabolic factors responsible for causing diabetes and her complications. There is growing evidence that Alpha Lipoic Acid (ALA) has beneficial effects on the treatment of T2DM and some of its complications. It represents an attractive pharmacological target in the treatment of T2DM by modulating the signal transduction pathways in insulin resistance and antagonizing the oxidative and inflammatory stresses, which are major players in the pathogenesis of this disorder. A potent anti-oxidant and free radical scavenger, ALA also targets cellular signal transduction pathways which increases glucose uptake and utilization, thus providing specific targeted therapy in the treatment of insulin resistance and diabetic neuropathy. Apart from the rare risk of Insulin Autoimmune Syndrome (IAS), ALA has shown to be relatively safe, even in patients with renal and liver failure. This review focuses and summarises the molecular mechanisms of T2DM, and underlines the therapeutic value of ALA in this globally significant disease.

The authors have studied structural functional peculiarities of the left ventricle in patients with type 2 diabetes mellitus, dependent on the presence of cardiovascular form of diabetic autonomic neuropathy and dynamics of the studied parameters in patients with type 2 diabetes mellitus complicated with cardiovascular form of diabetic autonomic neuropathy treated with alpha-lipoic acid. The study included 82 patients with type 2 diabetes mellitus. The study has shown that the development of cardiovascular form of diabetic autonomic neuropathy results in dilatation and hypertrophy of the left ventricle walls, increase of its weight and impairment of diastolic function of the left ventricle manifesting itself by a decrease of early filling phase and an increase of myocardial hardness, as well as a decrease of cardiac rhythm variability and increase of QT-interval. Use of alpha-lipoic acid in complex treatment of diabetic autonomic neuropathy contributes to more effective influencing on diastolic function of the left ventricle and electrophysiological properties of the myocardium.

Objective: To evaluate the effect of alpha-lipoic acid (ALA) on diabetic peripheral neuropathy (DPN)., Methods: 95 type 2 diabetic patients complicated with DPN were randomly divided into 2 groups: treatment group (n = 52), receiving ALA 600 mg/d in normal saline 250 ml given by intravenous drip infusion once a day for 14 days; and control group (n = 43), administered with radix salviae 20 ml by intravenous drip infusion once a day for 14 days. Before and 7 and 14 days after the management fasting glucose (FPG), fasting insulin (FINS), supersensitive C reactive protein (sCRP), and HbA1c were measured, and total symptom score (TSS) and Michigan neuropathy screening instrument (MNSI) were used to evaluate the nervous symptoms., Results: 50 cases of the treatment group and 43 control cases completed the study. Compared with the control group, the TSS of the treatment group reduced significantly after 1 week, but the MNSI score did not change significantly. The TSS 7d after ALA administration of the treatment group was significantly lower than that before the ALA treatment in the same group and that of the control group 7 days after the radix salviae infusion as well (both P < 0.05). The TSS and MNSI score 14 days after the management of the treatment group were significantly lower than those of the control group (both P < 0.01). The symptom scores of numbness, sting sensation, and burning sensation reduced significantly 2-weeks after ALA treatment, but there were no significant differences in these symptoms after the management in the control group. The total gratification rate of the treatment group was 90% (45/50), significantly higher than hat of the control group (13.95%, 6/43, P < 0.01). One patient of the 50 patients receiving ALA treatment felt chest distress 2 days after ALA administration, but the symptom was improved in the same day after the velocity of intravenous drip was slowed down, and no other adverse effects were found in these two groups., Conclusion: ALA effectively improves the sensitive symptoms of DPN patients and is safe for most of the patients.

Aims: Multiple pathogenic pathways are involved in diabetic neuropathy and diverse treatments have been tried without success. The aim of this study was to assess the effect of alpha-lipoic acid on skin blood flow in patients with diabetic neuropathy., Methods: We measured skin blood flow in 13 control subjects and 19 patients with diabetic neuropathy using the laser Doppler blood flow technique. Skin blood flow and the extent of skin blood flow changes were compared before and after diabetic patients received 600 mg/day alpha-lipoic acid intravenously for 14 days., Results: Although no significant differences in absolute values of skin blood flow or in the extent of changes were noted, symptoms were reduced after alpha-lipoic acid treatment., Conclusions: This study suggests that alpha-lipoic acid, a potent antioxidant, improves symptoms of diabetic neuropathy. Larger studies are needed to determine whether improvements in skin blood flow also occur in patients with diabetic neuropathy.

Objective: Diabetic endotheliopathy is the result of hyperglycemia and the production of oxygen-free radicals. In vitro and in vivo data have shown beneficial effects of dexlipotam (DEX), a tromethamine salt of R(+)-alpha-lipoic acid, on oxidative stress in hyperglycemic states, but no data are available on the effects of this agent on endothelial function. The purpose of this pilot study was to evaluate the impact of DEX on endothelial function in patients with type 2 diabetes (DM2) and to estimate the safety and tolerability of DEX., Material and Methods: DEX 960 mg and DEX 1,920 mg were investigated in DM2 patients over a period of 4 weeks using a randomized, placebo- (PLA) controlled, double-blinded study with 3 parallel groups. The marker of arterial function after 4-week therapy with DEX was the maximum percentage change versus baseline in the flow-mediated dilation of the brachial artery (FMD) after reperfusion., Results: A total of 114 diabetic patients were randomized to the three study groups. DEX was safe and well tolerated. Dyspepsia appeared to be the most relevant side effect of DEX treatment. Systolic (p = 0.078) and diastolic blood pressure (p = 0.059) tended to be lower in patients treated with DEX at a dose of 1,920 mg. There were no significant differences in FMD between the placebo- and the DEX-treated groups. In patients with poorer glucose control (HbA1c > 6.5% Hb), FMD increased significantly after 4-week treatment with DEX: PLA -1.51 +/- 2.98%, DEX 960 mg +1.22 +/- 3.22, p = 0.027, DEX 1,920 mg +1.47 +/- 3.78, p= 0.012. The magnitude of the mean change compared to placebo was 2.73% (DEX 920) and 2.98% (DEX 1,920) in patients with HbAlc > 7.5% Hb (DEX 960, p = 0.007, DEX 1,920, p = 0.032). The effects of treatment were usually statistically significant in subgroups with more severe vascular stress (longer duration of disease, pretreatment history, higher LDL-C, higher blood pressure)., Conclusion: DEX therapy appears to reduce endothelial dysfunction in DM2, especially in men with long history of DM2 and having poor glucose control. These findings will be useful in patient selection in future prospective clinical trials with drugs to treat vascular stress.