How Does Alpha Lipoic Acid Improve Peripheral Neuropathy and Insulin Resistance - Essay Example

Alpha Lipoic Acid: What is it, and how does it improve peripheral neuropathy and insulin resistance Introduction Alpha lipoic acid (ALA) is a potent antioxidant and free-radical scavenger. It is both water and fat soluble and can regenerate endogenous antioxidants. ALA has been shown to both decrease blood sugar in diabetics as well as attenuate secondary conditions associated with diabetes. Research has shown that oral ALA supplementation improves insulin sensitivity in patients with type 2 diabetes (Boulton, 2005). Diabetes Mellitus Diabetes mellitus (DM) comprises a group of common metabolic disorders that share the phenotype of hyperglycemia. Several distinct types of DM exist and are caused by a complex interaction of genetics, environmental factors, and life-style choices. The metabolic dysregulation associated with DM causes secondary pathophysiologic changes in multiple organ systems that impose a tremendous burden on the individual with diabetes and on the health care system. The two broad categories of DM are designated type 1 and type 2. ALA has been shown to be useful in type 2 diabetes mellitus, and in order to understand the mechanism of action of ALA in control of DM and DM-associated complicating conditions, such as, neuropathy, it is important to understand the pathophysiologic and biochemical mechanism of these conditions (Boulton, 2005). Biochemical Changes in Diabetes Mellitus A prominent biochemical feature of type 2 DM is insulin resistance. This group of disorders is characterised by a pathogenic process that leads to hyperglycemia through variable degrees of insulin resistance, impaired insulin secretion, and increased glucose production. Type 2 DM is characterized by three pathophysiologic abnormalities: impaired insulin secretion, increasing peripheral insulin resistance, and excessive hepatic glucose production. Obesity, particularly visceral or central as evidenced by the hip-waist ratio, is very common in type 2 DM. Adipocytes secrete a number of biologic products, namely, leptin, TFN-alpha, free fatty acids, resistin, and adiponectin that modulate insulin secretion, insulin action, and body weight and may contribute to the insulin resistance. As expected, in the early stage of the disease, glucose tolerance remains normal despite insulin resistance since the pancreatic beta cells compensate by increasing the output of insulin. As insulin resistance and compensatory hyperinsulinemia progress, the pancreatic islets in certain individuals are unable to sustain the hyperinsulinemic state (Huebschmann et al., 2006). Diabetic Neuropathy Diabetic neuropathy occurs in approximately 50% of individuals with long-standing type 1 and type 2 DM. It may manifest as polyneuropathy, mononeuropathy, and/or autonomic neuropathy. As with other complications of DM, the development of neuropathy correlates with the duration of diabetes and glycemic control; both myelinated and unmyelinated nerve fibers are lost. Because the clinical features of diabetic neuropathy are similar to those of other neuropathies, the diagnosis of diabetic neuropathy should be made only after other possible etiologies are excluded (Boulton et al., 2004). The most common form of diabetic neuropathy is distal symmetric polyneuropathy. It most frequently presents with distal sensory loss. Hyperesthesia, paresthesia, and dysesthesia also occur. Any combination of these symptoms may develop as neuropathy progresses. Symptoms include a sensation of numbness, tingling, sharpness, or burning that begins in the feet and spreads proximally. Neuropathic pain develops in some of these individuals, occasionally preceded by improvement in their glycemic control. Pain typically involves the lower extremities, is usually present at rest, and worsens at night. Both an acute and a chronic form of painful diabetic neuropathy have been described. As diabetic neuropathy progresses, the pain subsides and eventually disappears, but a sensory deficit in the lower extremities persists. Physical examination reveals sensory loss, loss of ankle reflexes, and abnormal position sense (Boulton et al., 2004). ALA Alpha-lipoic acid, a potent antioxidant, also regenerates endogenous antioxidants, such as vitamin E, vitamin C, and glutathione. Alpha-lipoic acid is an endogenous coenzyme that acts in conjunction with pyrophosphatase in carbohydrate metabolism and synthesis of adenosine triphosphate (ATP). Supplemental alpha-lipoic acid exerts potent antioxidant activity and is well known for its usefulness as an intra- and extracellular free-radical scavenger and as a water- and fat-soluble antioxidant (Ziegler, 2004). Patients with type 2 diabetes who took alpha-lipoic acid daily experienced improved insulin resistance and glucose tolerance after several weeks of treatment in one study. Both single and short-term administrations of alpha-lipoic acid have produced increased insulin sensitivity; one study demonstrated an increased glucose clearance of nearly 50%. In another trial, daily infusions of 500 mg of alpha-lipoic acid over 10 days in patients with type 2 diabetes resulted in approximately a 30% increased glucose metabolized clearance. Studies such as these, as well as the known potent antioxidative-replenishing effects of alpha-lipoic acid, support using this supplement for treating metabolic syndrome. It is a wise choice for helping to normalize metabolism by enhancing insulin effectiveness and performing general antioxidation to address the pro-oxidative effects of the conditions comprising metabolic syndrome (Boulton, 2005). Many studies on patients with type 2 diabetes have shown that ALA increases insulin-dependent glucose disposal. Specifically, one study showed that the rate of metabolic clearance of glucose increased by 50% with ALA supplementation. ALA can also affect glucose uptake into skeletal muscle directly (Corbett, 2005). One study demonstrated that glucose uptake increased by 40%-300% in muscle cells after subjects were given ALA supplementation. Animal studies have shown that ALA stimulates adenosine monophosphate (AMP)-activated protein kinase in skeletal muscle, which regulates cellular energy metabolism as well as decreasing triglyceride accumulation (Livingstone and Davis, 2007). Skeletal-muscle triglyceride accumulation has been shown to contribute to insulin resistance. Similar studies have shown that ALA suppresses AMP-activated protein kinase in the hypothalamus, causing a decrease in food intake, increasing energy expenditure, and resulting in significant weight loss, which may be beneficial in controlling insulin resistance (Vincent et al., 2007). Chemistry Alpha-Lipoic acid chemically 1,2-dithiolane-3-pentanoic acid and named trivially as 6,8-thioctic acid, is a sulfur-containing cofactor found in most prokaryotic and eukaryotic microorganisms, as well as plant and animal tissue. It is best known as a requisite component of several multienzyme complexes that function in the oxidative decarboxylation of various alpha-keto acids and glycine, as well as the oxidative cleavage of 3-hydroxy-2-butanone to acetaldehyde and acetyl-coenzyme A (Ziegler et al., 2004). In its capacity as a cofactor, it is bound covalently in an amide linkage to the N6-amino group of a lysine residue on one of the proteins of the complex, producing a long tether which facilitates the direct channeling of intermediates among the various active sites located on different subunits. The key functional property of the lipoyl cofactor is its ability to undergo redox chemistry, interchanging between the cyclic disulfide and reduced dithiol forms. The disulfide form of the cofactor acts as an electron acceptor in each of the multienzyme complexes that employ it, becoming reduced by two-electrons during turnover. The reducing equivalents generated in each overall reaction are ultimately transferred to NAD, affording NADH and a proton (Vincent et al., 2007). Biochemistry Two cellular systems combine to protect cells against damaging effects of free radicals that are generated under normal metabolic conditions or in excess in pathological processes. Antioxidant enzymes, such as, superoxide dismutase, catalase eliminate free radicals by enzymatic reactions whereas low-molecular weight antioxidants such as, vitamin C, vitamin E, glutathione neutralize radicals by direct chemical interactions. Alpha-Lipoic acid, which belongs to the second group, is an endogenous cofactor for several 2-oxoacid dehydrogenase multienzyme complexes. it is covalently linked to a lysine residue of dihydrolipoamide acetyltransferase in the pyruvate dehydrogenase (PDH) complex to accept an acyl intermediate from the dehydrogenase components and transfer it to coenzyme-A (Obrosova et al., 2005). The resulting reduced form of LA, dihydrolipoic acid (DHLA), is then reoxidized by lipoamide dehydrogenase. Free LA is considered a therapeutically potent thiol antioxidant due to its reductive power. The low oxidation potential, -0.29 V of the reduced form of DHLA results from the two vicinal thiol groups within the molecule that enable efficient scavenging of free radicals, such as superoxide, hydroxyl, and peroxyl radicals. These interactions also contribute to the regeneration of other low-molecular weight antioxidants, such as vitamin C, glutathione, and vitamin E (Livingstone and Davis, 2007). In addition, the metal-chelating activity of LA also contributes to its antioxidative activity through the inhibition of metal ion-dependent formation of free radicals in cells. Another mechanism suggests that dihydrolipoamide dehydrogenase that reduces LA to DHLA consumes cellular NAD(P)H, which is an essential cofactor to several free radical-producing enzymes (Obrosova et al., 2004). Studies have shown that ALA can prevent the onset of diabetes. This model showed that ALA reduced body weight, protected pancreatic beta-cells from destruction, and reduced triglyceride accumulation in skeletal muscle and pancreatic islets. ALA has also been shown to exhibit antiglycating effects. In diabetic experimental subjects, ALA showed a significant decrease in glucose, glycated protein, glycated hemoglobin, and fructosamine. A study was performed in individuals with symptomatic diabetic polyneuropathy and oral ALA supplementation. The results indicated that oral ALA in doses of 600 mg, 1,200 mg, and 1,800 mg per day was effective in reducing neuropathic symptoms of diabetic distal symmetric polyneuropathy at five weeks evaluation (Corbett, 2005). Physiologic Effects The regulation of glucose homeostasis in the intact organism is mediated by the coordinated functions of several organ systems. The liver is the primary site of glucose production from the glycogenolytic and gluconeogenic processes whereas the skeletal muscle, which comprises 40% of the body weight of humans and most other mammalian species, is the predominant site of glucose disposal following a meal or during an exercise bout (Dobrowsky et al., 2005). Interventions that improve whole-body insulin resistance and insulin resistance of skeletal muscle glucose transport include exercise training or caloric restriction leading to a loss of visceral fat mass, and treatment with a variety of pharmaceutical or nutriceutical compounds. Because they possess reactive sulfhydryl groups, a-lipoic acid and its reduced form, dihydrolipoic acid, can function as potent antioxidants, scavenging several reactive oxygen and nitrogen species and also acting to chelate transition metals (Ziegler et al., 2004). Acute and chronic treatment with the antioxidant a-lipoic acid can induce beneficial metabolic effects in a variety of animal models characterized by insulin resistance of skeletal muscle glucose transport and metabolism. In general, these studies have shown that treatment with alpha-lipoic acid enhances whole-body glucose tolerance and insulin sensitivity due to an improvement in the action of insulin to stimulate the disposal of glucose in skeletal muscle. In addition, in some models, it has been shown that alpha-lipoic acid can suppress hepatic glucose production, which would also contribute to this improved glucoregulation (Ziegler, 2008). Therapeutic Effects Several studies have also demonstrated that specific conjugates of alpha-lipoic acid can be effective in enhancing glucose tolerance and insulin action in conditions of insulin resistance associated with both type-1 diabetes and prediabetes. Racemic alpha-lipoic acid has been used in Germany in the treatment of diabetic polyneuropathy for many years. Because a-lipoic acid has been reported to have a number of potentially beneficial effects in both prevention and treatment of free-radical mediated diseases, numerous preclinical and clinical trials especially for the therapy of type-2 diabetes-induced diabetic polyneuropathy have been conducted (Ziegler et al., 2006). The efficacy of alpha-lipoic acid treatment on neuropathic disorders has been contradictorily discussed because the results of the individual trials varied and a conclusive interpretation is difficult. Alpha-lipoic acid used for the management of diabetic neuropathy will likely be administered on a long-term basis. Exogenous LA supplementation has been reported to decrease ischemia-reperfusion injury in peripheral nerves. In addition, LA supplement has been shown to reduce cellular injury caused by antioxidant deficiency (Ziegler, 2008). Conclusion Diabetic peripheral neuropathy affects more than half of the patients with type 2 diabetes. In many cases even severe neuropathic deficits are asymptomatic, whereas in others these may be extremely debilitating. It has been suggested that vasculopathy mediated by peroxynitrite radicals in the setting of hyperglycation of the nerves resulting from metabolic abnormalities associated with diabetes and associated oxidative stress leads to neuropathy of diabetes. Given its unique chemical and biochemical properties, alpha-lipoic acid, as evidenced in literature would control obesity and insulin resistance in type 2 diabetics. Moreover studies show, intravenously administered alpha-lipoic acid may be beneficial in symptomatic relief and reversal of diabetic neuropathy. Reference Boulton, AJM., Malik, RA., Arezzo, JC., and Sosenko, JM., (2004). Diabetic Somatic Neuropathies. Diabetes Care; 27: 1458 - 1486. Boulton, AJM., (2005). Management of Diabetic Peripheral Neuropathy. Clin. Diabetes; 23: 9 - 15. Corbett, CF., (2005). Practical Management of Patients With Painful Diabetic Neuropathy. The Diabetes Educator; 31: 523 - 540. Dobrowsky, RT., Rouen, S., and Yu, C., (2005). Altered Neurotrophism in Diabetic Neuropathy: Spelunking the Caves of Peripheral Nerve. J. Pharmacol. Exp. Ther.; 313: 485 - 491. Huebschmann, AG., Regensteiner, JG., Vlassara, H., and Reusch, JEB., (2006). Diabetes and Advanced Glycoxidation End Products. Diabetes Care; 29: 1420 - 1432. Livingstone, C. and Davis, J., (2007). Review: Targeting therapeutics against glutathione depletion in diabetes and its complications. 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