GDAs (ALA, Its Isomers, and the Basics Part 2/3)

ALA’s main mechanism of action deals with its ability to regulate and help better control blood sugar. Porasuphatana et al looked at the glycemic and oxidative status of patients with type 2 diabetes mellitus following oral administration of alpha-lipoic acid in a randomized double-blinded placebo-controlled study. They had thirty eight outpatients with type 2 DM were recruited and randomly assigned to either placebo or treatment in various doses of ALA (300, 600, 900, and 1200 mg/day) for 6 months. Following the treatment, all subjects were evaluated for glucose status and oxidative biomarkers. Results showed that fasting blood glucose, HbA1c trended to decrease in a dose-dependent manner. Increase of urinary PGF2α-Isoprostanes (F2α-IsoP) was noted in placebo but not ALA-treated groups, indicating possible suppressing action of ALA on lipid peroxidation in DM subjects. 8-Hydroxy-2′-deoxyguanosine (8-OHdG) levels, however, were similar in both placebo and ALA groups as well as urinary microalbumin and serum creatinine. Safety evaluation was monitored and treatment was found to be well tolerated despite some minor side effects. Results from this study reflected the benefits of ALA in glucose status with slight efficiency on oxidative stress-related deterioration in DM patients (4.) Seeing that dosages as low as 300 and as high as 1200mgs of ALA were beneficial in reducing blood glucose levels shows promise, but this was merely one study and its not quite enough information for us to make an informed decision. This obviously means we need more data. For that we look to another study whose purpose was too examine the effects of alpha-lipoic acid (ALA) treatment over a period of 2 months on fasting blood glucose (FBG), insulin resistance (IR), and glutathione peroxidase (GH-Px) activity in type 2 diabetes (T2DM) patients. This study took place in Motahari Clinic, Shiraz, Iran, which is affiliated to Shiraz University of Medical Sciences from May to October 2006. Type 2 DM patients (n=57) were divided into 2 groups to receive either ALA (300 mg daily) or placebo by systematic randomization, and were followed-up for 8 weeks. After an overnight fasting and 2 hours after breakfast, patients’ blood samples were drawn and tested for FBG, 2 hours PPG, serum insulin level, and GH-Px activity. The result of the study showed a significant decrease in FBG and PPG levels, IR-Homeostasis Model Assessment (IR-HOMA index) and GH-Px level in the ALA group. The comparison of differences between FBG and IR at the beginning and at the end of study in the ALA treated group and the placebo group were also significant. This study supports the use of ALA as an antioxidant in the care of diabetic patients (5.)

Returning back briefly to Shay et al, we can see further on LA in correlation to its insulin pathway and how it handles glucose (3.) The interaction of LA and intracellular signaling is perceived to account for LA’s beneficial effects observed at 24 hours post-administration, a time point that is much delayed from the plasma LA Tmax of ~1 hour. This temporal difference is interesting in light of the rapid metabolism of LA and suggests a different mode of action versus other stimuli that LA mimics. For example, in cultured cells, insulin induced glucose uptake after 10 min. and a maximal effect after 30 min., while LA required 1 hour to induce its maximal effect on glucose uptake, which could be achieved by insulin in half the time. This delay is even evident when comparing the phosphorylation of Akt on Ser473 as induced by insulin versus LA [95]. Such a delay suggests that the effect of LA on glucose handling is not direct but necessitates the activation of additional mediator(s), and also supports the notion that LA or DHLA modulates the IR/PI3K/Akt pathway at different levels (6, 7.)

References

1. Dietary lipoic acid supplementation can mimic or block the effect of dietary restriction on life span. Brian J. Merry, Austin J. Kirk, Malcolm H. Goyns. Mech Ageing Dev. 2008 (https://www.ncbi.nlm.nih.gov/pubmed/18486188)
2. Antioxidant and prooxidant activities of alpha-lipoic acid and dihydrolipoic acid. Hadi Moini, Lester Packer, Nils-Erik L. Saris. Toxicol Appl Pharmacol. 2002 (https://www.ncbi.nlm.nih.gov/pubmed/12127266)
3. Alpha-lipoic acid as a dietary supplement: Molecular mechanisms and therapeutic potential. Shay, K. P., Moreau, R. F., Smith, E. J., Smith, A. R., & Hagen, T. M. (2009) http://doi.org/10.1016/j.bbagen.2009.07.026 (https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2756298/)
4. Glycemic and oxidative status of patients with type 2 diabetes mellitus following oral administration of alpha-lipoic acid: a randomized double-blinded placebo-controlled study. Supatra Porasuphatana, Suthi Suddee, Atinuch Nartnampong, Julraht Konsil, Busakorn Harnwong, Adichai Santaweesuk. Asia Pac J Clin Nutr. 2012 (https://www.ncbi.nlm.nih.gov/pubmed/22374556)
5. Effect of alpha-lipoic acid on blood glucose, insulin resistance and glutathione peroxidase of type 2 diabetic patients. Hasti Ansar, Zohreh Mazloom, Fatemeh Kazemi, Najmeh Hejazi. Saudi Med J. 2011 (https://www.ncbi.nlm.nih.gov/pubmed/21666939)
6. Multiple roles of phosphatidylinositol 3-kinase in regulation of glucose transport, amino acid transport, and glucose transporters in L6 skeletal muscle cells. Tsakiridis T, McDowell HE, Walker T, Downes CP, Hundal HS, Vranic M, Klip A. 1995. (https://www.ncbi.nlm.nih.gov/pubmed/7664650)
7. Engagement of the insulin-sensitive pathway in the stimulation of glucose transport by alpha-lipoic acid in 3T3-L1 adipocytes. Yaworsky K, Somwar R, Ramlal T, Tritschler HJ, Klip A. 2000. (https://www.ncbi.nlm.nih.gov/pubmed/10768090)
8. Effect of α-lipoic acid and exercise training on cardiovascular disease risk in obesity with impaired glucose tolerance. Andrea M McNeilly, Gareth W Davison, Marie H Murphy, Nida Nadeem, Tom Trinick, Ellie Duly, Anna Novials, Jane McEneny. Lipids Health Dis. 2011 (https://www.ncbi.nlm.nih.gov/pubmed/22107734)
9. Effects of alpha-lipoic acid supplementation on inflammation, oxidative stress, and serum lipid profile levels in patients with end-stage renal disease on hemodialysis. Tannaz Khabbazi, Reza Mahdavi, Javid Safa, Parvin Pour-Abdollahi. J Ren Nutr. 2012 (https://www.ncbi.nlm.nih.gov/pubmed/21908204)
10. The metabolism of dl-(1,6-14C)lipoic acid in the rat. E. H. Harrison, D. B. McCormick. Arch Biochem Biophys. 1974 (https://www.ncbi.nlm.nih.gov/pubmed/4598618)