A compound given as a dietary supplement to overweight but otherwise healthy people in a clinical trial caused many of the patients to slim down, research by Oregon State University and Oregon Health & Science University showed.
The research, published in the Journal of Nutrition, analyzed the effects of 24 weeks of daily, 600-milligram doses of lipoic acid supplementson 31 people, with a similarly sized control group receiving a placebo.
“The data clearly showed a loss in body weight and body fat in people taking lipoic acid supplements,” said Balz Frei, director emeritus of OSU’s Linus Pauling Institute and one of the scientists on the study.
“Particularly in women and in the heaviest participants.”
Produced by both plants and animals, lipoic acid sets up shop in cells’ mitochondria, where it’s normally attached to proteins involved in energy and amino acid metabolism.
A specialized, medium-chain fatty acid, it’s unique in having two sulfur atoms at one end of the chain, allowing for the transfer of electrons from other sources.
The body generally produces enough lipoic acid to supply the enzymes whose proper function requires it.
When taken as a dietary supplement, lipoic acid displays additional properties that might be unrelated to the function in the mitochondria.
They include the stimulation of glucose metabolism, antioxidant defenses and anti-inflammatory responses – making it a possible complementary treatment for people with diabetes, heart disease and age-related cognitive decline.
“Scientists have been researching the potential health benefits of lipoic acid supplements for decades, including how it might enhance healthy aging and mitigate cardiovascular disease,” said Alexander Michels, another Linus Pauling Institute scientist involved with the study.
“In both rodent models and small-scale human clinical trials, researchers at the LPI have demonstrated the beneficial effects of lipoic acid on oxidative stress, lipid metabolism and circadian rhythm.”
The OSU/OHSU project addressed two issues commonly ignored by previous human trials, said Tory Hagen, a professor of biochemistry and biophysics in the OSU College of Science and the study’s corresponding author.
“Many existing clinical studies using lipoic acid have focused on volunteers with pre-existing conditions like diabetes, making it difficult to determine if lipoic acid supplements simply act as a disease treatment or have other beneficial health effects,” said Hagen, principal investigator and Helen P. Rumbel Professor for Healthy Aging Research at the institute.
“Another issue is the formulation of the supplement. Many previous studies have used the S form of lipoic acid, which is a product of industrial synthesis and not found in nature. We only used the R form of lipoic acid—the form found in the body naturally.”
Contrary to what was expected by the researchers, decreased levels of triglycerides – a type of fat, or lipid, found in the blood – were not seen in all the participants taking lipoic acid.
“The effect of lipoic acid supplements on blood lipids was limited,” said Gerd Bobe, another LPI scientist who collaborated on the study. “But people who lost weight on lipoic acid also reduced their blood triglyceride levels – that effect was clear.”
Other effects of the lipoic acid supplements were measurable as well.
“By the end of the study, some markers of inflammation declined,” Hagen said. “The findings also suggest that lipoic acid supplementation provides a mild reduction in oxidative stress. It is not a perfect panacea, but our results show that lipoic acid supplements can be beneficial.”
Identifying which patients will benefit the most from lipoic acid supplementation, and how much they need, is important for both clinical and economic reasons, he added.
“Lipoic acid supplements are often quite expensive,” he said. “So understanding how we can maximize benefits with smaller amounts of the supplement is something we are interested in pursuing.”
Oxidative stress (OxS) is a biochemical imbalance that is propitiated by excessive production of reactive oxygen and nitrogen species, which provoke oxidative damage to biomolecules and cannot be counteracted by antioxidative systems.
This is an important factor that contributes to aging and the development of several diseases, including type 2 diabetes mellitus (T2DM) [1, 2].
For several decades, it has been shown that OxS and the chronic inflammatory process are involved in the physiopathological mechanisms of T2DM [3].
In this sense, the chronic hyperglycemia that is present in T2DM activates several unusual metabolic pathways in organisms, such as the sorbitol pathway (or that of aldose reductase), nonenzymatic protein glycosylation, glucose autooxidation, modification of protein kinase C activity, pseudohypoxia, lipoprotein-altered metabolism, and cytokine-associated alteration. All these pathways generate reactive oxygen species (ROS) and, consequently, OxS [4].
Likewise, several studies have shown that aging and/or T2DM increases the synthesis and secretion of cytokines, such as interleukin 6 (IL-6), tumor necrosis factor-alpha (TNF-α), and free radicals.
These are all recognized as factors that increase the risk of disease-related complications [4, 5]. In this regard, our research group showed that aging in the context of diabetes increases the production of OxS and causes inflammation [6].
For this reason, some therapeutic supplements have been proposed with antioxidant and anti-inflammatory properties, such as vitamins A, C, E; omega 3 and 6 fatty acids; coenzyme Q10; melatonin; and alpha-lipoic acid [7–9].
Alpha-lipoic acid (ALA) is an amphipathic substance, which is synthesized in the mitochondria of plants and animals from octanoic acid and cysteine as a sulfur donor through the reactions catalyzed by the enzyme lipoic acid synthase.
The participation of ALA in oxidative metabolism is essential. [7]
ALA chemically exists in two enantiomeric forms R and S although only the R isoform acts as a cofactor in the oxidant metabolism, since it binds through an amide bond to the amino group of the lysine residues.
This allows it to form a lipoamide, which is a cofactor of the enzymes, pyruvate dehydrogenase and α-ketoglutarate dehydrogenase [10, 11].
Several studies have demonstrated the antioxidant, anti-inflammatory, and hypoglycemic properties of ALA [12–15].
Furthermore, ALA has been shown to have a positive effect on the OxS linked with aging [16]. For this reason, the aim of the present study was to determine the effect of 600 mg/day of ALA on some markers of OxS and inflammation and RAGE in older adults with T2DM.
Discussion
Alpha-lipoic acid (ALA) is synthesized de novo in the body from fatty acid and cysteine in low quantities. Therefore, it is important to consume exogenous sources of ALA to have a therapeutic effect.
In this regard, it has been shown that ALA is found abundantly in animal tissues, being located mainly in THE viscera, such as THE heart, liver, and kidneys. However, it is also found in high concentrations in vegetables, such as broccoli, spinach, tomatoes, peas, potatoes, and rice bran [26, 27].
However, to fully utilize its antioxidant, anti-inflammatory, and hypoglycemic properties, a racemic mixture available in capsules was prepared from a commercial product provided by ProductosMedix®.
In this sense, it has been demonstrated that the gastrointestinal absorption of ALA depends on the timing of ingestion as there is a greater absorption of the compound if it is administered 30 minutes before or 2 hours after food intake.
It has also been shown that the absorption of ALA is enantioselective since the R isoform is absorbed more efficiently than S [28–30].
Several studies have shown a therapeutic effect of ALA with doses of 300–1800 mg per day administered for three months up to four years. In this regard, we decided to administer 600 mg per day of ALA for six months in the present study, which took the evidence of effectiveness and safety for the elderly population into consideration [31–39].
Among the beneficial health effects of taking ALA supplements, it has been observed that the administration of ALA is capable of promoting the synthesis of nitric oxide. In this regard, it has been proposed that ALA stimulates the PI3K/Akt signaling pathway, with Akt being responsible for the phosphorylation and subsequent activation of eNOS (NO synthase), an enzyme that catalyzes the conversion of L-arginine and O2 in citrulline with NO release [9]. This is a molecule that is responsible for regulating the elasticity of the walls of blood vessels and improving endothelial function, which results in a decrease in blood pressure. In addition, ALA reduces the levels of reactive oxygen species, which also favors endothelial function and subsequently lowers blood pressure [31]. However, no statistically significant differences were observed after treatment with ALA in our study. In this sense, our findings are similar to that reported in the systematic review published by Mohammadi et al., who found that the administration of ALA at doses of 300–1800 mg/day has no effect on arterial hypertension [40].
On the other hand, it has been observed that the administration of ALA decreases the body weight and, consequently, the BMI in both animals and humans. In this regard, although the precise mechanisms are unknown, it has been suggested that ALA participates in the modulation of some pathways that are involved in energy homeostasis, the synthesis and oxidation of lipids, and the elimination of cholesterol through the liver. One of these pathways involves the protein kinase being activated by adenosine monophosphate (AMPK). It is known that AMPK integrates both hormonal and nutrient signals in the hypothalamus, which gives it a functional role in behavior that is related to food consumption and energy expenditure. Likewise, it has been suggested that ALA has an anorectic effect, which is more evident during the first two weeks of supplementation and gradually dissipates over time [41, 42]. In this regard, no statistically significant differences were observed in the BMI after treatment with ALA in our study, which is in contrast to previously reported results as researchers found that the administration of ALA induces a moderate loss of body weight and a statistically significant decrease in the BMI.
However, this effect was observed with higher doses of ALA (1200 mg/day and 1800 mg/day) [42–44] compared to the 600 mg/day administered in our investigation.
Likewise, it is important to point out that time is another determining factor since the anorectic effect only occurs during the first weeks as mentioned above.
Regarding the effect of ALA on lipid metabolism, it has been pointed out that it reduces lipogenesis at the peripheral level by increasing the β-oxidation of fatty acids and improving the energy expenditure of the whole body [45, 46].
In this sense, a statistically significant increase in blood HDL concentration was observed in the EG after treatment () in our study although this increase was also observed in the PG, which suggests that the administration of ALA at a dose of 600 mg/day has an effect on HDL that is similar to placebo.
In this regard, similar findings were reported by Khabbazi et al. in a study conducted in patients with renal failure, who were given 600 mg/day of ALA for eight weeks [47].
In addition, Koh et al. did not observe statistically significant changes in the HDL blood concentration in obese adults, who consumed 1200 and 1800 mg/day of ALA for 20 weeks in comparison with the placebo group [48].
These results are in contrast to the statistically significant increase in HDL concentration found by Zhang et al. in obese patients given a dose of 600 mg/day of ALA for two weeks compared with a placebo group [46].
For this reason, the effect of ALA on the lipid profile remains controversial so its indication for these purposes would not be justified.
On the other hand, ALA has been shown to have a hypoglycemic effect since it improves the uptake and utilization of glucose by fat cells and skeletal muscle by inducing the translocation of glucose transporters (GLUT 1 and GLUT 4) from the Golgi complex to the cell membrane.
Likewise, ALA stimulates the activity of the insulin receptor and its substrates (IR and IRS1) as well as phosphoinositol-3-kinase (PI3K), promoting tyrosine phosphorylation in the IR and improving the glucose uptake that is dependent on PI3K.
Using the above-mentioned mechanisms, the ALA is capable of attenuating the formation of advanced glycation end products by reducing the concentration of circulating glucose and preventing it from reacting with proteins with a prolonged half-life, which subsequently decreases the expression of the AGE receptor (receptor for advanced glycation end products (RAGE)) in the cell membrane [9].
In the present study, no statistically significant differences were found in HbA1c (%) after treatment in the group that consumed ALA compared to the PG and CG (), with these results being consistent with what was observed in other studies [49, 50].
However, a hypoglycemic effect has also been reported with higher doses (1200–1800 mg/day) of ALA so it has been noted that the effect on HbA1c (%) depends on the dose [37, 38]. This may explain the negative results of our study.
With respect to the antioxidant capacity of ALA, it has been pointed out that it is a powerful redox pair that is capable of neutralizing different ROS. In addition, it has the ability to restore the reduced/oxidized glutathione ratio (GSH/GSSG) by either transferring electrons directly to the GSSG for reduction or increasing the synthesis of glutathione through improving the plasma uptake of cystine to subsequently reduce it to cysteine, which is the precursor of glutathione.
ALA is also able to regenerate the reduced forms of other antioxidants, such as vitamins C and E. Furthermore, ALA has the ability to chelate ionic metals and counteract their oxidizing effects, which gives it enormous antioxidant capacity [9].
Regarding the effect of ALA on the OxS markers, it has been reported that the administration of ALA at doses of 300–1200 mg/day for three to six months has a positive effect on different oxidative stress markers, such as MDA, SOD, GPx, PGF2α-isoprostane, and 8-hydroxy-2-deoxyguanosine [37, 51].
Negative results have also been observed, as shown in the following studies: Sola et al. did not find statistically significant differences in the concentration of 8-isoprostane in adult patients with metabolic syndrome after treatment with 300 mg of ALA for 4 weeks compared with the placebo group [32].
Likewise, Khabbazi et al., in a study conducted in patients with renal failure, who were given 600 mg/day of ALA for eight weeks, did not observe statistically significant changes in MDA and total antioxidant status levels [47]; Sharman et al., in a trial conducted in healthy adults, who were given 600 mg/day of ALA for seven days, also found no changes in the levels of MDA, SOD, GPx, and catalase [52]; and Ahmadi et al. also found no changes in MDA with the administration of 600 mg/day of ALA for two months in hemodialysis patients [53].
In our study, no statistically significant differences were observed in the blood concentration of 8-isoprostane between the EG and the PG (). On the other hand, GPx, SOD, and SOD/GPx also showed no statistically significant changes in EG compared to PG after treatment.
This may be due to the dose of ALA and/or the length of the follow-up of administration of the treatment, considering that ours was a population of older adults, so the degree of oxidative stress is greater due to the aging process associated to diabetes mellitus.
Regarding the anti-inflammatory properties of ALA, it has been indicated that it has the capacity to decrease the production of TNF-α, IL-1β, and IL-6 both in animal models and in humans.
ALA acts at the level of phosphorylation of the factor inhibitor protein κB (IKK) and prevents the activation and release of NF-κB, which also prevents its translocation to the nucleus and the subsequent transcription of genes that direct the synthesis of proinflammatory proteins (TNF-α, IL-1β, and IL-6) [46, 47].
In this regard, a decrease in the markers of chronic inflammation has been reported in diabetic patients treated with ALA at doses of 300–600 mg/day for 3–6 months [32, 46, 47].
In contrast, we observed a significant increase () in all proinflammatory parameters evaluated (CRP, TNF-α, IL-1β, IL-6, IL-8, and IL-10) in the GC after six months compared to the GE and GP in our study.
Consistent with our findings regarding the effect of ALA on the OxS markers, our results suggest that the administration of 600 mg/day of ALA has an anti-inflammatory effect that is similar to placebo.
The multiple regression analysis allows us to demonstrate the relationship of the concentration of ALA with the markers of OxS and chronic inflammation.
In this regard, although the correlation of ALA with TNF-α, IL-6, IL-1β, SOD, GPx, and 8-isoprostane was statistically significant, the effect of ALA was not sufficient to show statistically significant differences between the EG and PG in the blood concentration of these markers; therefore, our findings do not support the anti-inflammatory and antioxidant effect of ALA in older adults with type 2 diabetes mellitus with a dose of 600 mg/day of ALA for six months.
Conclusions
Our findings do not support the anti-inflammatory and antioxidant effect of ALA at a dose of 600 mg/day for six months in older adults with type 2 diabetes mellitus. In this regard, the exacerbating effect of diabetes mellitus and aging on oxidative stress and inflammation should be considered [6].
For this reason, the administration of doses of 1200–1800 mg/day of ALA could be useful to mitigate the oxidative stress and inflammation as well as to avoid the production of AGEs that occurs in T2DM in older adults, although the effectiveness of such higher doses must be verified through controlled clinical trials.
reference link : https://www.hindawi.com/journals/omcl/2019/3276958/
More information: Gerd Bobe et al, A Randomized Controlled Trial of Long-Term (R)-α-Lipoic Acid Supplementation Promotes Weight Loss in Overweight or Obese Adults without Altering Baseline Elevated Plasma Triglyceride Concentrations, The Journal of Nutrition (2020). DOI: 10.1093/jn/nxaa203
