Title: Beneficial effects of alpha-lipoic acid in diabetes and its complications
Key words: thioctic acid, mitochondrial complexes, diabetes, reductive, oxidative, DHLA, glucose, glycolysis, lactate, pyruvate, antioxidants, blood sugar, hyperglycaemia, albuminuria, neuropathy, Vitamin C, Vitamin E, glutathione, free radicals, apoptosis
Date: May 2001
Category: Specific conditions
Author: Pam Brown/Ian Davies
Beneficial effects of alpha-lipoic acid in diabetes and its complications
a-lipoic acid (thioctic acid) is a co-factor in mitochondrial complexes involved in oxidative decarboxylation. It is recycled easily between its oxidised form and reduced form (dihydrolipoic acid (DHLA)), in the presence of NADH or NADPH by three separate enzymes (glutathione reductase, thioredoxin reductase and lipoamide dehydrogenase)1. In vivo a -lipoic acid/DHLA is bound in the mitochondria, but it can function in lipid and aqueous tissues and cross the blood brain barrier, so its beneficial effects are available throughout the body. Diabetes results in high reductive and oxidative stress, both of which can be helped by effects of a -lipoic acid/DHLA2.
In vitro effects of lipoic acid and beneficial effects in diabetes
Glucose disposal and utilisation
In vitro studies have shown thata -lipoic acid /DHLA improves glucose disposal by improving insulin sensitivity, increasing glucose uptake by recruitment of GLUT transporters and increasing glycolysis; these have been shown in vivo3. Hyperglycaemia in diabetes results in reductive stress (high NADH/NAD+ ratio), inhibition of glycolysis and fatty acid metabolism and increase in intracellular reactive oxygen species. Lipoic acid uses NADH as a co-factor for its reduction to DHLA, thus lowering this ratio, increasing glycolysis and fatty acid metabolism2 and decreasing ROS.
Clinical studies in type 2 diabetes with 1200mg/day orally decreased lactate and pyruvate4; other studies have shown improved glucose utilisation with IV lipoic acid. Lipoic acid and DHLA scavenge free radicals, recycle other antioxidants, and increase the levels of intracellular glutathione thus decreasing free radical formation, and cellular damage2. In the diabetic patient this results in improved blood sugar control as well as delaying complications.
Antioxidant effects/regeneration other antioxidants
a-lipoic acid is a potent antioxidant1 and can scavenge ROS such as hydroxyl radicals, hydrogen peroxide and singlet oxygen5. Lipoate/DHLA can also chelate transition metals preventing hydroxyl radical production5.
Hyperglycemia in diabetes is associated with generation of ROS and elevated oxidative stress which is thought to play a role in development of late diabetic complications. Lipoic acid significantly improves the imbalance between oxidative stress and depleted antioxidant defences despite poor glycemic control and albuminuria6.
ROS cause cumulative damage to nerve cells resulting in peripheral nerve ischaemia/hypoxia and peripheral and cardiac neuropathy7. Antioxidant effects of a -lipoic acid are likely to be beneficial in preventing or treating diabetic neuropathy and possibly other diabetic complications7. Beneficial effects have been shown in clinical studies for intravenous a -lipoic acid 600mg/day IV (ALADIN study) 8 and 1800mg/day9 orally over 3 weeks in symptomatic peripheral diabetic neuropathy and alleviation of pain was achieved with as little as 200mg/day. Oral treatment with 800mg/day for several months may improve cardiac autonomic dysfunction10.
Vitamin C and E levels and erythrocyte glutathione are sub-normal in diabetes11. DHLA12,13 and glutathione14 have been shown in vitro to be capable of regenerating vitamin C, which can then recycle vitamin E12,13. Administration of a -lipoic acid to Vitamin E deficient mice15 or vitamin C/E deficient guinea pigs prevented signs of deficiency. DHLA can also regenerate intracellular glutathione, by reducing extracellular cystine to cysteine which is taken up into the cell much faster, resulting in increased glutathione synthesis1. Glutathione then has an important antioxidant role within the cell.
Inhibition NF kappaB activation
NF-kappaB can be activated in response to a wide range of stimuli, including the intracellular oxidative stress associated with poor glycemic control in diabetes11. a -lipoic acid/DHLA decreases or inhibits this5.
Prevention of protein glycation reactions
Formation of advanced glycation end products (AGEs) due to elevated nonenzymatic glycation of proteins, lipids and nucleic acids is increased in patients with diabetes and results in oxidative stress and radical generation9. a -lipoic acid/DHLA can bind to proteins such as albumen preventing glycation reactions5.
a-lipoic acid/DHLA in vitro also protects against glutamate cytotoxicity and prevent apoptosis, but it is not clear whether these are important in diabetes or its complications.