Diabetes & Metabolism Journal

Original Articles

The Effect of alpha-Lipoic Acid on Proteinuria and Renal TGFbeta Expression in Obese Type 2 Diabetic Rat Model.: Seok Woo Kang, Seong Jin Lee, Dong Sun Kim, Tae Wha Kim; Korean Diabetes J. 2008;32(1):21-29. Published online February 1, 2008; DOI: https://doi.org/10.4093/kdj.2008.32.1.21

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BACKGROUND
It is well known that renal TGFbeta expression is related to the development of diabetic nephropathy. Alpha-lipoic acid (ALA), a potent antioxidant and cofactor of mitochondrial respiratory enzymes, can improve the insulin resistance and the vascular endothelial dysfunction, and suppresses the development of diabetic vascular complications. This study was undertaken to investigate whether ALA could reduce urinary protein excretion and renal TGFbeta protein expression in obese type 2 diabetes mellitus animal model, Otsuka Long-Evans Tokushima Fatty (OLETF) rat. METHODS: Obese 30 male OLETF rats were randomly divided to 3 groups at the age of 30 weeks. The rats in the Control group fed normal rat chow while the rats in the ALA group were fed with rat chow containing ALA (0.5% of food weight). Ten rats in the Pair-fed group were fed with normal rat chow, but were given the same amount of food as consumed by the ALA group. During 5 weeks of ALA feeding, food intake and body weight were checked in metabolic chamber. Blood glucose levels, HbA1c and urinary protein excretion were measured at 30 weeks and 35 weeks of age, and renal TGFbeta protein expression at 35 weeks of age was measured by Western blot and represented by relative unit (RU). Immunohistochemical staining for TGFbeta protein in renal tissue was also examined at 35 weeks of age. RESULTS: Food intake, body weight, blood glucose levels, HbA1c and urinary protein excretion among the Control, ALA and Pair-fed groups at 30 weeks of age were not different. At 35 weeks of age, food intake was significantly decreased in the ALA group than the Control group (Control group vs. ALA group, 27.7 +/- 1.1 g/day vs. 22.4 +/- 1.4 g/day, P < 0.001), and body weight was significantly decreased in the ALA group than the Control and Pair-fed groups (Control group: 694.4 +/- 10.3 g, ALA group: 600.4 +/- 7.4 g, Pair-fed group: 685.4 +/- 11.6 g, P < 0.001). Blood glucose levels were significantly decreased in the ALA group than the Control and Pair-fed groups (Control group: 157.7 +/- 4.6 mg/dL, ALA group: 130.7 +/- 4.8 mg/dL, Pair-fed group: 153.7 +/- 3.3 mg/dL, P < 0.001) although blood glucose levels from 30 weeks to 34 weeks of age and HbA1c at 35 weeks of age were not different among the groups. Urinary protein excretion and renal TGFbeta protein expression were significantly decreased in the ALA group than the Control and Pair-fed groups (urinary protein excretion, Control group: 5.033 +/- 0.254 mg/mgCr, ALA group: 3.633 +/- 0.303 mg/mgCr, Pair-fed group: 4.977 +/- 0.339 mg/mgCr, P < 0.001; renal TGFbeta protein expression, Control group: 7.09 +/- 0.17 RU, ALA group: 4.14 +/- 0.26 RU, Pair-fed group: 7.00 +/- 0.29 RU, P < 0.001). In the ALA group at 35 weeks of age, urinary protein excretion and renal TGFbeta protein expression were positively related in the Control, ALA and Pair-fed groups (Control group, r = 0.847, P = 0.002; ALA group, r = 0.954, P < 0.001; Pair-fed group, r = 0.858, P = 0.002). TGFbeta staining in glomeruli was observed in all groups but was decreased in the ALA group at 35 weeks of age. CONCLUSION: These results suggest that ALA may prevent the increase of food intake, body weight, blood glucose, urinary protein excretion and renal TGFbeta protein expression in obese type 2 diabetic rat model. The effect of ALA on diabetic nephropathy presented as proteinuria and renal TGFbeta expression in diabetic patients needs to be further clarified.

Citations

Citations to this article as recorded by

Dietary alpha-lipoic acid boosts growth, immune-antioxidant traits, behavior, and transcriptomes of antioxidant, apoptosis, and immune-related genes to combat cold stress in Nile tilapia (Oreochromis niloticus)
Amany Behairy, Hanan A. Ghetas, Noura A. Abd-Allah, Walaa El-Houseiny, Ahmed H. Arisha, Mohamed M. M. Metwally, Basma A. Elshafey, Adham A. Al-Sagheer, Engy M. M. Mohamed
Aquaculture International.2024; 32(4): 4061. CrossRef

The Effect of Alpha-Lipoic Acid on the Protection of Epidermal Nerve Fibers and Microcapillaries in the Streptozotocin-Induced Diabetic Rats.: Ming Han Piao, Heung Yong Jin, Sun Kyung Song, Seun Mi Kang, So Young Kim, Ji Hyun Park, Hong Sun Baek, Tae Sun Park; Korean Diabetes J. 2007;31(6):488-497. Published online November 1, 2007; DOI: https://doi.org/10.4093/jkda.2007.31.6.488

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Abstract PDF: BACKGROUND
Diabetic neuropathy is associated with risk factors for macrovascular diseases and other microvascular complications. Alpha-lipoic acid (ALA) administration has been reported to improve metabolic abnormalities and ameliorate peripheral polyneuropathy in diabetic patients. In addition, ALA improves endoneurial nutritive neural blood flow and nerve conduction velocity in diabetic rats. But it is not clear whether ALA has a preservation effect on microvasculature in addition to the effect on intraepidermal nerve fibers (IENFs). We investigated the effect of ALA on intraepidermal nerve fiber density (numbers/mm) and cutaneous capillary length in streptozotocin-induced diabetic rats. METHODS: The rats were randomly divided into 3 groups: diabetes without diet control, diabetes with diet control, and diabetes with ALA treatment. Diabetes was induced by a single intraperitoneal injection of streptozotocin (60 mg/kg) and the effect of ALA treatment was assessed by IENF immunostained with protein gene product 9.5 and by quantification of total cutaneous capillary length with mouse anti-rat reca-1 immunostaining. RESULTS: The value of IENF density significantly increased in ALA treatment group compared with other groups (P < 0.05). Quantification of microvascularity was also significantly increased in ALA treatment group compared with other groups (P < 0.05). CONCLUSION: The results of this study suggest that ALA administration in diabetic rats may be beneficial in the prevention of peripheral neuropathy associated with improvement of microvascularity. And the symptomatic amelioration after ALA treatment may be attributed to this morphological improvement.

The Effects of Alpha-Lipoic Acid on Epidermal Nerve Preservation in the Diabetic Neuropathy of OLETF Rats.: Ming Han Piao, Ji Hyun Park, Hong Sun Baek, Tae Sun Park; Korean Diabetes J. 2006;30(3):170-176. Published online May 1, 2006; DOI: https://doi.org/10.4093/jkda.2006.30.3.170

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Abstract PDF: BACKGROUND
Alpha-Lipoic acid (ALA) administration has been reported to ameliorate some of symptoms of peripheral polyneuropathy in diabetic patients and to improve endoneurial nutritive neural blood flow and nerve conduction velocity in diabetic rats. But it is not clear whether ALA has the preservation effect on epidermal nerve fibers (ENFs) density. METHODS: We tested the efficacy of ALA in preserving current perception thresholds (CPTs) and ENFs (numbers/mm) in OLETF (Otsuka Long-Evans Tokushima Fatty) rats, an animal model of type 2 diabetes, which were fed with sucrose until diabetes mellitus developed. Thereafter, one group of OLETF rats was fed with ALA and the other was not for 40 weeks. Diabetic rats were administered with ALA (80 mg/kg of body weight/day) by oral feeding for 40 weeks. The effect of ALA treatment on ENFs preservation was assessed by protein gene product 9.5 immunostaining. Quantification of neuropathic symptoms on the dorsum of hind paws of rat was measured by CPT test every 4 weeks. RESULTS: Numbers of ENF significantly decreased in OLETF rats fed without ALA compared with OLETF rats fed with ALA (P < 0.01). The thresholds at 2000, 250 and 5 Hz in OLETF rats fed with ALA did not increased and OLETF rats without ALA significantly increased at 80 weeks (P < 0.01). CONCLUSION: These observations suggest that administrations of ALA may be useful for preserving ENFs and CPTs in OLETF rats dorsum of hind paws skin.

Randomized Controlled Trial

The Comparison of Efficacy with alpha-lipoic Acid Treatment Methods in Diabetic Polyneuropathy.: Hyejin Lee, Kyung Wan Min, Kyung Ah Han; Korean Diabetes J. 2006;30(2):112-121. Published online March 1, 2006; DOI: https://doi.org/10.4093/jkda.2006.30.2.112

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Abstract PDF: BACKGROUND
Diabetic neuropathy represents a major health problem, as it is responsible for substantial morbidity, increased mortality, and impaired quality of life. Antioxidant treatment has been shown to prevent nerve dysfunction, providing a rationale for a potential therapeutic value in diabetic patients. The safety and efficacy of alpha-lipoic acid (ALA) given intravenously were proved in many studies, but the oral treatment remains to be established. Therefore we compare the efficacy and safety of ALA given intravenously followed by oral treatment and given only orally. METHODS: 45 outpatients were randomly assigned to sequential treatment with ALA intravenously for 2 weeks, followed by orally for 10 weeks (group 1, n = 21); ALA orally for 12 weeks (group 2, n = 24). The primary end point was change of the sum score of severity and duration of total symptom score (TSS). HbA1c and safety parameters were determined at baseline and after 12 weeks. RESULTS: The TSS was significantly decreased from baseline to 2 week and 12 week in both groups. But no significant differences between the two groups were noted at 2 week and 12 week. There were no significant changes in HbA1c and safety parameters between baseline and 12 week. The rate of adverse events were 47.6% in group 1 and 12.5% in group 2. CONCLUSION: We conclude that both methods of ALA treatment are effective to improve the symptoms of diabetic polyneuropathy, and the safety was probably superior in oral treatment method

Original Articles

Effect of 12-week Oral Treatment with alpha-lipoic acid on the Nerve Conduction in Symptomatic Diabetic Neuropathy.: Tae Seo Sohn, Jung Min Lee, Sang Ah Chang, Hyun Shik Son, Bong Youn Cha, Ho Young Son, Kwang Woo Lee, Sung Ku Kang; Korean Diabetes J. 2005;29(6):533-539. Published online November 1, 2005

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Abstract PDF: BACKGROUND
Diabetic peripheral neuropathy is multifactorial disorder arising from hyperglycemia and insulin deficiency. It has been suggested that oxidative stress resulting from enhanced free-radical formation and defects in antioxidant defence plays a major role among the putative pathogenic mechanisms of diabetic neuropathy. As alpha-lipoic acid, a natural antioxidant, has been suggested to improve symptoms of diabetic neuropathy, we assessed the efficacy of alpha-lipoic acid on neuropathic symptoms and peripheral nerve conduction in patients with type 2 diabetes mellitus with symptomatic polyneuropathy. METHODS: A cohort of 30 type 2 diabetic patients with symptomatic polyneuropathy received a daily dose of 600 mg alpha-lipoic acid, and was followed for 3 months. Neuropathic symptoms (pain, burning, paraesthesiae, and numbness) of the feet were scored at monthly interval and summarized as a Total Symptom Score (TSS). Nerve conduction study was done before and after 3 month treatment of alpha-lipoic acid. RESULTS: Treatment of alpha-lipoic acid given 600 mg per oral for 12 weeks improved the symptoms of diabetic polyneuropathy. Effects of alpha-lipoic acid on nerve conduction study were that in the motor nerve, the amplitudes of median nerve and tibial nerve and the conduction velocity of tibial nerve improved after 12 weeks treatment. In the sensory nerve, the conduction velocities of median nerve, ulnar nerve, and sural nerve improved after 12 weeks. CONCLUSION: alpha-Lipoic acid was effective in the treatment of diabetic peripheral polyneuropathy improving both clinical manifestations and nerve conduction. The improvement of clinical manifestations may be due to improved conduction velocity of sensory fibers.

Alpha-Lipoic acid Inhibits TNF-alpha-Induced Fractalkine Expression in Rat aortic Smooth Muscle Cells.: Keun Gyu Park, Hye Soon Kim, Seong Yeol Ryu, Chang Wook Nam, Byung Kyu Chae, Eui Dal Jung, Jung Guk Kim, Bo Wan Kim, In Kyu Lee; Korean Diabetes J. 2005;29(5):409-417. Published online September 1, 2005

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Abstract PDF: BACKGOUND: The induction of vascular inflammation via the proinflammatory cytokine/ nuclear factor (NF)-kappaB pathway is one of the key mechanisms in the development and progression of atherosclerosis. Accumulating evidence suggests a recently identified chemokine, fractalkine, is involved in arterial inflammation and atherogenesis; however, few studies have examined the effects of pharmacological agents on this process. The purposes of this study were to determine if alpha-lipoic acid (ALA) inhibits the expression of tumor necrosis factor (TNF)-alpha-stimulated fractalkine in vascular smooth muscle cells(VSMCs). METHODS: Rat VSMCs were isolated and cultured. Northern and Western blot analyses were performed to evaluate the effects of ALA on the expression of TNF-alpha-stimulated fractalkine in VSMCs. A gel shift assay was performed to examine the mechanism by which ALA inhibits the expression of fractalkine. RESULTS: TNF-alpha markedly induced the expression of fractalkine in primary cultured VSMCs. ALA inhibited the expression of TNF-alpha-stimulated fractalkine in cultured VSMCs. The result of the gel shift assay suggested the inhibitory effects of AS-6 on the expression of TNF-alpha-stimulated fractalkine were mediated via the NF-kappaB pathway. CONCLUSION: This study has shown that ALA has anti-inflammatory effects on VSMCs, which are mediated by the inhibitoin, at least in part, of the NF-kappaB dependent inflammatory signal-stimulated expression of fractalkine. Our data suggest the possibility that antioxidants, such as ALA, inhibit the NF-kappaB pathway, which may be used to prevent the development and progression of atherosclerosis.

Effect of Peroxisome Proliferator Activated Receptor-gamma Agonist, Angiotensin II Receptor Blocker and alpha-lipoic Acid on Renal VEGF Expression in Diabetic Nephropathy.: Jang Hyun Koh, Yeon Lee, Mi Jin Kim, Young Goo Shin, Eun Young Lee, Choon Hee Chung; Korean Diabetes J. 2004;28(5):367-376. Published online October 1, 2004

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Abstract PDF: BACKGROUND
Diabetic nephropathy is one of the most serious complications in diabetes mellitus, and it is the leading cause of end stage renal disease. It has been reported that angiotensin converting enzyme inhibitor (ACEi) reduces the vascular endothelial growth factor (VEGF) expression, and so it plays an important role in reducing the renal damage. Peroxisome proliferator activated receptor-gamma (PPAR-gamma) agonist is known to reduce insulin resistance in type 2 diabetic patients. In the previous study, PPAR-gamma agonist was shown to lower VEGF expression in the retina, but it increased the plasma VEGF level. Alpha-lipoic acid (alpha-LA), which is an antioxidant, lowers the increased level of VEGF in retina as well. The precise role of PPAR-gamma agonist and alpha-LA on renal VEGF expression in diabetic nephropathy is still uncertain. We studied the effect of PPAR-gamma agonist, angiotensin II receptor blocker (ATIIRB) and alpha-LA on the renal VEGF expression in diabetic rats. METHODS: We used 60 Sprague-Dawley male rats, those were 8 weeks old and weighted about 300 g each as the study subjects. Among them, 48 rats were chosen and injected with streptozotocin (70 mg/kg) into peritoneal cavity to induce diabetes mellitus. The rast were than divided into 5 groups. Group I was a normal control group (n=12), group II was diabetic control group (n=12), group III was diabetic group that was given with PPAR-gamma agonist (n=12), group IV was the diabetic group that was given ATIIRB (n=12), and group V was the diabetic rats that were given alpha-LA (n=12). We measured their body weight, blood glucose levels, 24 hour urine protein and albumin levels at the baseline, the 8th and the 16th weeks of the experiment. On the 16th weeks of our experiment we extracted the kidneys to measure the glomerular volume, the optical density of the VEGF staining and VEGF mRNA expression. RESULTS: At the beginning of the study, the 5 groups all showed similar 24 hour urine albumin levels. At the 8th week, group II showed an increased urine albumin level of 143.4 +/- 117.2 mg/day; this was greater than that of group IV (60.7+/-30.6 mg/day) (p<0.05). The glomerular volume and optical densities of VEGF expression were significantly reduced in group III, IV and V compared to group II. For group IV and V, the renal VEGF mRNA expression was significantly lower than that of group II, but group III showed no significant difference. from group II. CONCLUSION: Angiotensin II receptor blocker delayed the progression of diabetic nephropathy. PPAR-gamma agonist and alpha-lipoic acid did not have any protective effect against the progression of diabetic nephropathy in spite of the decreased VEGF expression noted in this study.

The Effect of Alpha-lipoic Acid on Endothelial Dysfunction in Postmenopausal Uncomplicated Type 2 Diabetes.: Ho Chan Cho, Sang Jun Lee, Mi Jung Kim, Hye Sun Kim, Tae Sung Yun, Sung Jae Kim, Sang Hyon Kim, Seung Ho Hur, Kyo Chul Moon, Jae Hoon Bae, In Kyu Lee; Korean Diabetes J. 2002;26(4):242-252. Published online August 1, 2002

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Abstract PDF: BACKGROUND
Recently, increased oxidative stress has been proposed as a major cause of vascular complications of patients with diabetes mellitus. Increased generation of oxygen free radicals in patients with diabetes mellitus could deplete cellular antioxidants and inactivate endothelial dependent vasodilating factor (EDRF), such as nitric oxide (NO). The purpose of this study was to evaluate whether the antioxidant alpha-lipoic acid (ALA) is effective in endothelial dysfunction of brachial artery, which induced by increased oxidative stress in postmenopausal diabetic women using high resolution ultrasound technique and initial reaction time (IRT) measurement. METHODS: We enrolled 11 menopausal women (mean age, 56.5+/-5.1 years) with uncomplicated type 2 diabetes. All patients were taking 1200 mg of ALA (Thioctacid(R), Bukwang, Korea). We measured of superoxide anion (O2-) in neutrophils as a marker of oxidative stress. Flow-mediated dilation (FMD) was measured using a high-resolution ultrasound. RESULTS: After treatment of ALA, fasting blood glucose was decreased significantly, the endothelium-dependent vasodilation of the brachial artery was increased, and O2- production was also decreased significantly. CONCLUSION: These results show that short term ALA treatment could improve the endothelial dysfunction in patients with type 2 diabetes mellitus. This improvement might be related with the antioxidants effect of ALA.

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