Diabetic Neuropathy: Pathogenesis and Treatment with Alpha-Lipoic Acid
James Meschino DC, MS, ND
Overview: hyperglycemia-induced ischemic and auto-oxidative lipid peroxidation is suggested to cause diabetic neuropathy
Interrelated Pathogenic Mechanisms In Diabetic Neuropathy:
- Hyperglycemia inhibits nitric oxide synthesis, resulting in impaired microvascular tone, reduced nerve blood flow, and endoneurial hypoxia. Endoneurial hypoxia is secondary to a reduction in nerve blood flow and increased endoneurial vascular resistance. Much of the endoneurial microvascular damage and hypoxia is due to nitric oxide inactivation.
- The hypoxic nerve can continue to function on glucose alone under anoxic circumstances via anaerobic glycolysis. Hyperglycemia increases nerve cell glycolysis and leads to increased flux of the polyol pathway, mediated by aldose reductase and sorbitol dehydrogenase, leading to accumulation of sorbitol and depletion of myo-inositol. Nevertheless, sorbitol per se is non-toxic and it seems likely that mechanisms other than nerve sorbitol accumulation cause neuropathy.
- Reduction of myo-inositol is associated with reduced Na+-K+-ATPase activity. Myo-inositol is a key plasma membrane phospholipid, signaling agent and preserves the function of Na+-K+-ATPase activity. Reduced Na+-K+-ATPase activity is shown to decrease amino acid uptake by cells, which impairs protein synthesis required to renew important neuronal structures (e.g. microtubules) as well as peptides and neurotransmitters. It also reduces intracellular potassium and may increase intracellular sodium, which have detrimental effects on cell function.
- Hyperglycemia also activates protein kinase (PKC), which promotes synthesis of diacylglycerol (DAG) The increased activity of PKC may impair endoneurial blood flow.
- The increased availability of glucose in diabetes induces enhanced production of AGEs. This process is defined as auto-oxidative glycosylation and is considered the major cause of increased ROS production among diabetic subjects. Accumulation of advanced glycation end products (AGEs) that exert their damaging effects by binding to specific receptors on the surface of neurons. Binding of AGEs to their receptors causes oxidative stress and activates nuclear factor-κB (NF-κB). Hyperglycemia-induced oxidative stress induces programmed cell death of nerves, which contributes to the pathology of diabetic neuropathy. Note that specific antioxidants and over expression of antioxidant enzymes can inhibit NF-κB activation
- As diabetes has been associated with increased production and/or decreased clearance of ROS, oxidative stress has been suggested to contribute to defective nerve blood supply and endoneurial oxidative damage.
- Increased nerve lipid peroxidation in vivo. The most reliable index of increased oxidative stress is reduction in GSH – a common finding in diabetic and other types of nerve damage.
- Alterations in mitogen-activated protein kinases (MAPKs) results in a signaling cascade involved in the pathogenesis of peripheral diabetic neuropathy.
- Abnormal Ca2+ homeostasis and signaling
Acetyl-L Carnitine and Alpha Lipoic Acid
- Supplementation with acetyl-L-carnitine corrects perturbations of neural Na+-K+-ATPase, myo-inositol, and nitric oxide. It also improves nerve fiber regeneration and alleviates symptoms, particularly pain in patients with established diabetic neuropathy.
- Alpha-lipoic acid seems to normalize endoneurial Na+-K+-ATPase activity in experimental diabetic nerves. As observed in retinal cells, the improved Na+-K+-ATPase activity could improve myo-inositol uptake by the Na+–myo-inositol co-transporter.
- Alpha-lipoic acid has an effect on glucose uptake, thereby increasing polyol pathway activity. It is also known to increase oxidative phophorylation by up-regulating pyruvate dehydrogenase and alpha-ketoglutarate dehydrogenase enzymes, enabling cells to generate more ATP energy for normal function and repair
- A study found reduced frequency of apoptosis in diabetic animals that were treated with the antioxidant taurine.
- The role of oxidative stress in nerve damage has been extensively studied in experimental diabetes and in diabetic subjects. Motor nerve and sensory nerve conduction velocities are the principal endpoints in studying the therapeutic effectiveness of alpha-lipoic acid on nerve function. Alpha-lipoic acid has been shown to improve motor nerve conduction velocity in experimental diabetic neuropathy and protect peripheral nerves from ischemia in rats.
- Treatment with alpha-lipoic acid increases reduced glutathione (GSH) in vivo and in vitro.
- GSH is an important endogenous antioxidant. Alpha-lipoic acid is a powerful lipophilic free radical scavenger of peripheral nerve both in vitro and in vivo. Treatment with alpha-lipoic acid increases GSH in vivo and in vitro. GSH is an important endogenous antioxidant, and together with lipoic acid, it seems to play a predominant role in the redox-dependent mechanisms of various cellular targets. As diabetes has been associated with increased production and/or decreased clearance of ROS, oxidative stress has been suggested to contribute to defective nerve blood supply and endoneurial oxidative damage.
- In addition to its role as a key cellular antioxidant, Alpha-lipoic acid has additional actions such as stimulating nerve growth factor and promoting fiber regeneration.
Oral Treatment with Alpha-lipoic Acid
Alpha-lipoic acid has been an approved treatment for diabetic neuropathy and other diabetic co-morbidities in Germany since 1966.
- Five week study showed improved neuropathic symptoms and deficits in 187 patients with diabetic symmetrical polyneuropathy. An oral dose of 600 mg once daily seems to provide the optimum risk-to-benefit ratio in the SYDNEY 2 trial. The adverse effects (mainly nausea) with the 1,200 mg dose daily occurred in 21% of patients, somewhat higher than that observed in the ALADIN I (15%) and ALADIN II study (7%), with the same dose of alpha-lipoic acid.
- In the seven-month ALADIN III trial, 509 subjects received either 600 mg of alpha-lipoic acid or placebo. While no significant difference was noted in subjective symptom evaluation among the groups, treatment with alpha-lipoic acid was associated with improved nerve function.
- In the ISLAND Study, 300 mg of alpha-lipoic acid was applied as monotherapy and in combination with 150 mg imbesartan daily. There was a significant increase in endothelium-dependent flow-mediated vasodilation of the brachial artery, by 44% and 75% respectively, compared with placebo treatment after four weeks. This effect was accompanied by reductions in plasma levels of interleukin-6 and plasminogen activator-1, suggesting that alpha-lipoic acid may improve endothelial dysfunction via anti-inflammatory and antithrombotic mechanisms
- Other studies have reported good results in diabetic neuropathy using a daily dosage of 600 mg, three times daily
- Alpha-lipoic acid has also been shown to down-regulate the expression of cell-adhesion molecules ICAM-1 and VCAM-1 in a dose-dependent manner. These observations might be of preventive and/or therapeutic benefit in arteriosclerosis and other inflammatory disorders.
- Clinical and postmarketing surveillance studies have revealed a highly favorable safety profile of the alpha-lipoic acid.
Vallianou, N, Evangelopoulos and Koutalas. Alpha-lipoic Aaid and diabetic neuropathy. Rev Diabet Stud. 2009 Winter; 6(4): 230–236. Published online 2010 February 10. doi: 10.1900/RDS.2009.6.230