Unanswered Questions With (R)-Lipoic Acid and (S)-Lipoic Acid

I don't completely understand this article (it's very complicated), but one thing they say is that lipoylation of the different components of the pyruvate dehydrogenase complex (PDHC) produces these extremely complicated effects on the regulation of the PDHC. It's important to remember that the thiamine diphosphate-dependent step is the rate-limiting step, and, to the extent that exogenous lipoic acid could compete for thiamine uptake into cells or have a similar effect, lipoic acid's effects sound more uncertain to me. I think one has to ask why lipoic acid can lower blood sugar, have these hypoglycemic effects, and have "antioxidant" effects. Its antioxidant effects could be due to condition-specific inhibition (an increase in the "throttling back," as these authors describe it, of the overall PDHC activity by the E1a kinase) of the PDHC. The inhibition of other thiamine-dependent enzyme complexes can have "antioxidant" effects under certain circumstances, and so can a lot of things. But what's the mechanism of the antioxidant effect or the hypoglycemic effect? This article makes it sound like maximal lipoylation of the different sites (the PDHC is really complex and has 16 subunits composed of subunits or some large number of subunits like that) tends to help inhibit the PDHC activity.

I know lipoic acid sometimes reduces lactic acidosis in people who can't synthesize it (it's synthesized in vivo from octanoic acid), but racemic lipoic acid was shown to cause biotin deficiency in animals. And there's the whole issue with the (R)-form being the natural enantiomer. Racemic mixtures of (R,S)-lipoic acid are still being sold, and the (R)-enantiomer is the natural enantiomer. The (S)-form could potentially cause issues, and researchers have expressed some concerns about it. The amount of biotin that would be required to prevent deficiency from these massive dosage forms of lipoic acid would be, seemingly, impossible to take. I'm just saying that proteins are lipoylated by endogenously-biosynthesized (R)-lipoate (it's apparently synthesized while it's attached to the proteins, not in free form), and maybe the proteins are meant to be "underlipoylated" under some conditions. I'll try to read some more articles on the mechanistic effects of exogenous, free lipoic acid, but some studies show it enhances AMPK activation (and others show inhibition). It seems strange to me, and it could have inhibitory effects on something like the PDHC and be beneficial to people with diabetes but...not necessarily have "purely desirable" effects in a person without diabetes. Here's the article:

http://www.jbc.org/cgi/content/full/271/2/653 (Sundari Ravindran et al., 1996) (pubmed: http://www.ncbi.nlm.nih.gov/pubmed/8557670?dopt=Abstract)