R-alpha-lipoic-acid and energetic metabolism

The prevalence and effects that obesity can cause on the human body and health are a big concern in the health care system. It is currently estimated that 1.9 billion adults are overweight, and almost 600 million people of productive age suffer from obesity. The increased weight is often associated with high mortality risk. This condition is also linked to insulin resistance, deranged blood glucose levels, an augmented central and visceral adiposity, and overall increased risk of developing chronic disease.

Over the passing of years, new treatment guidelines proposed with the foundation of large studies like ACCORD, ATP-III, and ADVANCE have been the blueprint for most medical clinicians. However, the increased risk of hypoglycemia, low compliance, and secondary effects such as sexual dysfunction and gut permeability associated with aggressive medication treatment have turned heads to a more natural or physiologic treatment. Nevertheless, most of these protocol treatments use supplementation that involves more than one component to acquire health benefits. Besides, most of the studies and interventions are applied in a mild to moderate condition state.

R-alpha-lipoic-acid

Alpha-lipoic acid is a compound that contains sulfur carbons in its structure, and it is present in all cells. ALA has 2 enantiomeric forms, R- and S- a-LA, but only the R-a-LA form is endogenously synthesized. Also, R-ALA has a wide variety of roles in energetic metabolism:

Metabolic function:

A substrate as acyl-CoA is needed for the citric acid cycle to produce energy in the metabolic process. Nevertheless, pyruvate from glycolysis has to pass through the enzyme pyruvate dehydrogenase for this to be possible. This enzyme is commonly known as pyruvate dehydrogenase complex and its composed of three enzymes E1, E2, and E3. Where ALA serves as a cofactor of E2, without this acyl- CoA could not be synthesized. Besides, enzymatic complexes like branched-chain -keto acid dehydrogenase complex (BCKDC) and -ketoglutarate dehydrogenase complex are composed of the same 3 subunits, ALA being the main cofactor of E2.

• Metabolic regulation

Enzyme complexes like pyruvate dehydrogenase and a-keto dehydrogenase function like rate-limiting mechanisms, regulating allosteric pathways by substrates and products.

In lower PDC activity in peripheral tissues, there would be an increase in gluconeogenic substrates, resulting in hyperglycemia. On the other hand, reduced activity in branched-chain -keto acid dehydrogenase complex (BCKDC) can result in the appearance of maple syrup urine disease, which is accompanied by neurological impairment and brain damage. Furthermore, the increased levels of BCAA result in epilepsy and growth retardation due to the decreased protein synthesis.

Redox system and ALA:

ALA has a thiolane ring reduced to dihydrolipoic acid (DHLA) via NADH and NADPH-dependent pathways. The DHLA is released into the extracellular space to increase cysteine transport and GSH levels in the cells. Therefore, the increased DHLA and GSH levels could decrease reactive oxygen species levels or alter protein function and activity.

Lastly, this increment of GSH and DHLA levels has protective effects against ROS. Consequently, R-ALA is linked to antioxidant effects that contribute to an improvement of endothelial function.

Medical applications of R-ALA

• Diabetes:

R-ALA is commonly found as an over-the-counter nutritional supplementation. However, the medical interventions performed with R-ALA are numerous and well supported. In literature, R-ALA’s supplementation can restore the mitochondrial potential and ATP content in vascular smooth muscle.

Studies made in overweight Korean subjects suggest that with an intervention of 1800mg/day for 20 weeks of R-ALA and a restricted diet of 600 kcal, there is an improved energy expenditure due to an increased ATP generation. This anti-obesity effect of R-ALA in humans may be explained by previous reports that hypothalamic AMP-activated protein kinase (AMPK) activity is suppressed by R-ALA in rodents, leading to reduced food intake and enhanced energy expenditure.

Another study intervened with type 2 diabetes mellitus patients with 600mg of R-ALA per day resulting in improved glucose uptake. Furthermore, insulin sensitivity was associated with an improved translocation of GLUT4 in skeletal muscle and adipose tissue. Other important results in this study were: the prevention of increased cholesterol levels, less atherosclerotic lesions, protection of b-cells.

• Vascular dysfunction:

Nitric oxide is produced by vascular endothelial cells as an endothelial-dependent relaxing factor, and it contributes greatly to vasodilatation. R-ALA contributes mainly as a cofactor for eNOS (endothelial nitric oxide synthase). Also, the improvement of endothelial function due to NO is related to reducing white blood cell adhesion, coagulation, and abnormal vascular smooth muscle cell proliferation.

• Obesity and overweight

A meta-analysis review that included 12 human studies that intervened patients with 300mg- 1800mg/day R-ALA supplementation showed no significant effect in reducing body weight (1.27kg compared to the placebo group). Besides, when the BMI was compared between R-ALA and control groups, a -0.40kg/m² resulted from the intervened group.

Even if the results may seem small, there is cofounding evidence that R-ALA’s supplementation reduces weight and BMI compared with placebo groups. However, R-ALA’s effects have been proven to be dose-dependent and could be achieved without diet modification. The higher dose has yet to be reported, and studies report that patients had no side-effects.

The use and supplementation of R-alpha-lipoic-acid is extensively used to reduce metabolic impairments caused by an increased inflammatory and oxidative stress. However, the benign-side effects of R-ALA have proven to be replicable in different settings. In addition, R-ALA’s modulation of metabolic, anti-inflammatory and antioxidant pathways in the cornerstone of the medical application of this supplement. – Ana Paola Rodríguez Arciniega. Master’s in clinical nutrition

SMOOTH(ie) genes:

References:

Park, Sungmi, et al. “Physiological effect and therapeutic application of alpha-lipoic acid.” Current medicinal chemistry 21.32 (2014): 3636-3645.

Kucukgoncu, Suat, et al. “Alpha‐lipoic acid (ALA) as a supplementation for weight loss: results from a meta‐analysis of randomized controlled trials.” Obesity Reviews 18.5 (2017): 594-601.

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