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SPORT SCIENTIST
Banned
Uses of Supplemental Alpha Lipoic Acid - A Thesis on glucose disposal
CONTENTS:
1. INTRODUCTION
2. USES OF SUPPLEMENTAL ALPHA LIPOIC ACID
Glucose disposal - ANIMAL/HUMAN STUDIES
3. TOLERANCE AND SAFETY
4. POSSIBLE FUTURE RESEARCH
5. SUMMARY
1.INTRODUCTION
Alpha -Lipoic acid is known by various chemical names including thioctic acid, 1,2-dithiolane-3-pentanoic acid and 1,2-dithiolane-3-valeric acid. It was discovered in 1937 as a growth factor for potatoes by Snell et al (Snell et al. 1937) In the 1950's Reed and co-workers (Reed et al. 1951) isolated and characterised the compound. Although initially described as a vitamin, alpha lipoic acid was later discovered to be synthesized by plants and animals (Rosenburg et al. 1959).
The chemical structure of lipoic acid dictates that the oxidative decarboxylation of pyruvate into acetyl-CoA and alpha-ketoglutarate into succinyl CoA, respectively occurs. Thus lipoate possesses a central position in metabolism, regulating carbon flow into the Krebs cycle, which respectively results in the the production of ATP (Patel et al. 1990). Octanoate is the immediate precursor to this 8 carbon fatty chain (ALA), with cysteine utilized as a source of sulfur (Dupre et al. 1980). The mitachondrion is the site of de novo alpha lipoic acid synthesis and function (Moini et al. 2002)
Alpha lipoic acid is an exceptional antioxidant, scavenging the oxides, hydrogen peroxide, singlet oxygen, hydroxyl radicals, nitric oxide radicals, hypochlorous acid and peroxynitrate (Parker et al. 1995). Alpha-lipoic acid has excellent absorptiona nd is highly bioavailiable. The alpha lipoic acid / dihydrolipoic acid redox pair act efficiently in the quenching of free radicals, and in metal chelation. It also has an amphiphilic character having preferential interactions with other anti oxidants, and also modulating gene expression. Due to the fulfillment of these criteria, alpa-lipoic acid has been termed an "ideal oxidant"
2. USES OF SUPPLEMENTAL ALPHA LIPOIC ACID
i) Glucose disposal
Alpha-lipoic acid has potent insulin-mimetic characteristics. It directly activates tyrosine and serine/thyronine kinases of the insulin signaling pathway in both skeletal and adipo-cytes, which stimulates glucose uptake (Haugaard et al. 1970). Increasing evidence suggests that insulin resistance may be associated with increased oxidative stress and that supplementation with antioxidants may be beneficial (Ceriello 2002). Obese rats were used to determine the effects of acute and chronic treatments with R-,S-Lipoic acid on glucose transport in skeletal muscle(Jacob et al. 1996) Alpha lipoic acid markedly increased net glucose uptake into muscle from lean (insulin sensitive) and obese (insulin resistant) rats (Streeper et al. 1997).
Acute treatment with R-lipoic acid increased insulin-mediated glucose transport by 64% , where as the S form showed no significant effect. Chronic R-lipoic acid administration reduced plasma insulin and free fatty acids. Further, R-lipoic acid improved insulin stimulated glycogen synthesis and glucose oxidation. The level of GLUT-4 transport protein was unaffected by chronic treatment with R-lipoic acid, but was reduced by S-lipoic acid. Thus glucose disposal is promoted by the R- but not the S-enametor of alpha lipoic acid
The effects of supplemental alpha lipoic acid were also studied by (Khamaisi et al. 1997). When administered in vivo, alpha lipoic acid , reduced blood glucose in hypoglycemictic rats. The independent effects of exercise training and alphalipoic acid supplementation on glucose transport in the skeletal muscle of obese rats has recently been studied (Saengsirisuwan et al. 2001), in which during an oral glucose tolerance test , exercise training alone or in combination with R-kipoic acid (30mg/kg/d for 6 weeks) resulted in a significant decrease in glucose (26-32%) and insulin (29-30%) responses compared with sedantary rats. R-lipoic acid alone reduced the glucose insulin index by 19% This is an indicator of increased insulin sensitivity, which was reduced a further 48-52% when combined with exercise. Exercise or lipoic acid supplementation individually increased insulin-mediated glucose transport by 44-57% in the soleus muscle. Supplementing alpha lipoic acid improved glucose transport by decreasing protein carbonyls levela, whereas exercise training incresed GLUT-4 protein contents. Thus, lipoic acid interacts additively with endurance exercise training to improve insulin action in insulin-resistant skeletal muscle.
HUMAN STUDIES
Studies on the use of R-, S- lipoic acid on insulin stimulated glucose disposal have been carried out in patients with type 2 diabetes. Acute intravenous administration of 1000mg of alpha-lipoic acid significantly improved insulin-stimulated glucose disposal as assessed by the glucose clamp technique (Jacob et al. 1996). Improved insulin stimulated glucose uptake of similar magnitude, 55% of treated compared to 265 of controls, also was found in 20 non insulin dependent diabetics after 10d of 500mg injections of lipoic acid (Jacob et al. 1999).
Oral administration of alpha-lipoic acid supplements (1200mg/d) to lean and obese diabetics decreased both serum lactate and pyruvate and improved insulin sensitivity after 4 weeks of treatment (Jacob et al. 1997). In a multi-centre trial, a 4 week oral treatment with alpha-lipoic acid increased insulin stimulated glucose disposal (63% of treated compared with 25% of placebo group) in patients with type 2 diabetes (Jacob et al. 1999). Interestingly, insulin stimulated glucose utilization was optimal at a dose of 600mg/d; increased doseages (1200 and 1800mg/d) had no additional beneficial effect on insulin sensitivity in these adult diabetics. These promising findings outlining the benefits of alpha-lipoic acid supplementation glucose disposal await confirmation in a large-scale randomized controlled trial.
TOLERANCE AND SAFETY
Although neither animal nor human studies to date have shown serious side effects with the administration of alpha-lipoic acid, there is a dearth of information availiable on this subject. Packer et al. (1979) stated that the LD50 is approximately 400-500mg/kg bodyweight following i.v. aministartion in rats 400-500mg/kg after oral administration in dogs. There is no evidence ofcarcinogenic or teratogenesic effects, but pregnant womwn are advised not to injest supplemental alpha-lipoic acid until more data is availiable. A daily dose of 1800mg alpha-lipoic acid was tolerated by diabetic adults for 7 months without advese effects 9Ziegler et al.1999). In humans, side effects include allergic skin reactions and possible hypoglycemia in diabetic patients as a consequence of improved glucose utilization with very high doses of alpha-lipoic acid (Packer et al. 1995)
RECOMENDATIONS FOR FUTURE RESEARCH
There is a criticla need to expand the fod composition database in order to include alpha-lipoic acid, with only a very limited number of foods having been analysed for their ALA content. This information will serve as a tool in enabling dieticians to determine the amount of ALA obtained from the diet. Another challenge is to determine whether improvements in glucose metabolism already demonstrated in animal models can be achieved, wholly or in part in humans. Similar to other food components that are present in very low concentrations in foods and are speculated to be antidiabetogenic, such as chromium, alpha-lipoic acid may be a nutriceutical when provided in adequate amounts in the diet.
SUMMARY
Alpha-lipoic acid and its reduced form, dihydrolipoic acid, are unique and vital antioxidants. They quench a variet of ROS, inhibit reactive oxygen and spare other antioxidants. Experimental as well as clinical trials highlight the potential usefulness of alpha-lipoic acid as a promoter of glucose utilization independent of GLUT-4 and a theraputic agent to ameliorate adverse effects of diabetes on cataract formation and neuropathy.
Although enriching the alpha-lipoic acid content of diets boosts antioxidant capacities in liver and skeletal muscles of rodents, similar studies have not been performed in humans. Thus, there is no specific evidence that supplemental alpha-lipoic acid enhances physical or sport performance in humans, despite promising findings in rodent models. Until convincing data from food fortification or supplementation trials with alpha-lipoic acid are availiable, it is merely speculative that this natural antioxidant promotes physical function and performance in humans. The antioxidant properties of alpha-lipoic acid and its interaction with other key antioxidants such as vitamin E, ascorate and glutathione will provide numerous opportunities for future research activity in human health promotion, reduction of disease symptoms and exercise performance and blood sugar maintaimance related fields.
REFERENCES
-email me if you would like these
CONTENTS:
1. INTRODUCTION
2. USES OF SUPPLEMENTAL ALPHA LIPOIC ACID
Glucose disposal - ANIMAL/HUMAN STUDIES
3. TOLERANCE AND SAFETY
4. POSSIBLE FUTURE RESEARCH
5. SUMMARY
1.INTRODUCTION
Alpha -Lipoic acid is known by various chemical names including thioctic acid, 1,2-dithiolane-3-pentanoic acid and 1,2-dithiolane-3-valeric acid. It was discovered in 1937 as a growth factor for potatoes by Snell et al (Snell et al. 1937) In the 1950's Reed and co-workers (Reed et al. 1951) isolated and characterised the compound. Although initially described as a vitamin, alpha lipoic acid was later discovered to be synthesized by plants and animals (Rosenburg et al. 1959).
The chemical structure of lipoic acid dictates that the oxidative decarboxylation of pyruvate into acetyl-CoA and alpha-ketoglutarate into succinyl CoA, respectively occurs. Thus lipoate possesses a central position in metabolism, regulating carbon flow into the Krebs cycle, which respectively results in the the production of ATP (Patel et al. 1990). Octanoate is the immediate precursor to this 8 carbon fatty chain (ALA), with cysteine utilized as a source of sulfur (Dupre et al. 1980). The mitachondrion is the site of de novo alpha lipoic acid synthesis and function (Moini et al. 2002)
Alpha lipoic acid is an exceptional antioxidant, scavenging the oxides, hydrogen peroxide, singlet oxygen, hydroxyl radicals, nitric oxide radicals, hypochlorous acid and peroxynitrate (Parker et al. 1995). Alpha-lipoic acid has excellent absorptiona nd is highly bioavailiable. The alpha lipoic acid / dihydrolipoic acid redox pair act efficiently in the quenching of free radicals, and in metal chelation. It also has an amphiphilic character having preferential interactions with other anti oxidants, and also modulating gene expression. Due to the fulfillment of these criteria, alpa-lipoic acid has been termed an "ideal oxidant"
2. USES OF SUPPLEMENTAL ALPHA LIPOIC ACID
i) Glucose disposal
Alpha-lipoic acid has potent insulin-mimetic characteristics. It directly activates tyrosine and serine/thyronine kinases of the insulin signaling pathway in both skeletal and adipo-cytes, which stimulates glucose uptake (Haugaard et al. 1970). Increasing evidence suggests that insulin resistance may be associated with increased oxidative stress and that supplementation with antioxidants may be beneficial (Ceriello 2002). Obese rats were used to determine the effects of acute and chronic treatments with R-,S-Lipoic acid on glucose transport in skeletal muscle(Jacob et al. 1996) Alpha lipoic acid markedly increased net glucose uptake into muscle from lean (insulin sensitive) and obese (insulin resistant) rats (Streeper et al. 1997).
Acute treatment with R-lipoic acid increased insulin-mediated glucose transport by 64% , where as the S form showed no significant effect. Chronic R-lipoic acid administration reduced plasma insulin and free fatty acids. Further, R-lipoic acid improved insulin stimulated glycogen synthesis and glucose oxidation. The level of GLUT-4 transport protein was unaffected by chronic treatment with R-lipoic acid, but was reduced by S-lipoic acid. Thus glucose disposal is promoted by the R- but not the S-enametor of alpha lipoic acid
The effects of supplemental alpha lipoic acid were also studied by (Khamaisi et al. 1997). When administered in vivo, alpha lipoic acid , reduced blood glucose in hypoglycemictic rats. The independent effects of exercise training and alphalipoic acid supplementation on glucose transport in the skeletal muscle of obese rats has recently been studied (Saengsirisuwan et al. 2001), in which during an oral glucose tolerance test , exercise training alone or in combination with R-kipoic acid (30mg/kg/d for 6 weeks) resulted in a significant decrease in glucose (26-32%) and insulin (29-30%) responses compared with sedantary rats. R-lipoic acid alone reduced the glucose insulin index by 19% This is an indicator of increased insulin sensitivity, which was reduced a further 48-52% when combined with exercise. Exercise or lipoic acid supplementation individually increased insulin-mediated glucose transport by 44-57% in the soleus muscle. Supplementing alpha lipoic acid improved glucose transport by decreasing protein carbonyls levela, whereas exercise training incresed GLUT-4 protein contents. Thus, lipoic acid interacts additively with endurance exercise training to improve insulin action in insulin-resistant skeletal muscle.
HUMAN STUDIES
Studies on the use of R-, S- lipoic acid on insulin stimulated glucose disposal have been carried out in patients with type 2 diabetes. Acute intravenous administration of 1000mg of alpha-lipoic acid significantly improved insulin-stimulated glucose disposal as assessed by the glucose clamp technique (Jacob et al. 1996). Improved insulin stimulated glucose uptake of similar magnitude, 55% of treated compared to 265 of controls, also was found in 20 non insulin dependent diabetics after 10d of 500mg injections of lipoic acid (Jacob et al. 1999).
Oral administration of alpha-lipoic acid supplements (1200mg/d) to lean and obese diabetics decreased both serum lactate and pyruvate and improved insulin sensitivity after 4 weeks of treatment (Jacob et al. 1997). In a multi-centre trial, a 4 week oral treatment with alpha-lipoic acid increased insulin stimulated glucose disposal (63% of treated compared with 25% of placebo group) in patients with type 2 diabetes (Jacob et al. 1999). Interestingly, insulin stimulated glucose utilization was optimal at a dose of 600mg/d; increased doseages (1200 and 1800mg/d) had no additional beneficial effect on insulin sensitivity in these adult diabetics. These promising findings outlining the benefits of alpha-lipoic acid supplementation glucose disposal await confirmation in a large-scale randomized controlled trial.
TOLERANCE AND SAFETY
Although neither animal nor human studies to date have shown serious side effects with the administration of alpha-lipoic acid, there is a dearth of information availiable on this subject. Packer et al. (1979) stated that the LD50 is approximately 400-500mg/kg bodyweight following i.v. aministartion in rats 400-500mg/kg after oral administration in dogs. There is no evidence ofcarcinogenic or teratogenesic effects, but pregnant womwn are advised not to injest supplemental alpha-lipoic acid until more data is availiable. A daily dose of 1800mg alpha-lipoic acid was tolerated by diabetic adults for 7 months without advese effects 9Ziegler et al.1999). In humans, side effects include allergic skin reactions and possible hypoglycemia in diabetic patients as a consequence of improved glucose utilization with very high doses of alpha-lipoic acid (Packer et al. 1995)
RECOMENDATIONS FOR FUTURE RESEARCH
There is a criticla need to expand the fod composition database in order to include alpha-lipoic acid, with only a very limited number of foods having been analysed for their ALA content. This information will serve as a tool in enabling dieticians to determine the amount of ALA obtained from the diet. Another challenge is to determine whether improvements in glucose metabolism already demonstrated in animal models can be achieved, wholly or in part in humans. Similar to other food components that are present in very low concentrations in foods and are speculated to be antidiabetogenic, such as chromium, alpha-lipoic acid may be a nutriceutical when provided in adequate amounts in the diet.
SUMMARY
Alpha-lipoic acid and its reduced form, dihydrolipoic acid, are unique and vital antioxidants. They quench a variet of ROS, inhibit reactive oxygen and spare other antioxidants. Experimental as well as clinical trials highlight the potential usefulness of alpha-lipoic acid as a promoter of glucose utilization independent of GLUT-4 and a theraputic agent to ameliorate adverse effects of diabetes on cataract formation and neuropathy.
Although enriching the alpha-lipoic acid content of diets boosts antioxidant capacities in liver and skeletal muscles of rodents, similar studies have not been performed in humans. Thus, there is no specific evidence that supplemental alpha-lipoic acid enhances physical or sport performance in humans, despite promising findings in rodent models. Until convincing data from food fortification or supplementation trials with alpha-lipoic acid are availiable, it is merely speculative that this natural antioxidant promotes physical function and performance in humans. The antioxidant properties of alpha-lipoic acid and its interaction with other key antioxidants such as vitamin E, ascorate and glutathione will provide numerous opportunities for future research activity in human health promotion, reduction of disease symptoms and exercise performance and blood sugar maintaimance related fields.
REFERENCES
-email me if you would like these
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