THE POTENTIAL ROLE OF α-LIPOIC ACID IN THE MANAGEMENT OF DIABETES MELLITUS: POSSIBLE MOLECULAR MECHANISM
ABSTRACT: Αlpha –lipoic acid
(LA) is synthesized in the liver and other tissues. In its physiological role,
it acts as a co-factor in a multi-enzyme dehydrogenase complex, which generates
acetyl-CoA and succinyl-CoA from pyruvate and
α-ketoglutarate respectively. Acetyl-CoA and succinyl-CoA are two
important compounds participating in the Krebs cycle present in
mitochondria. Thus, LA is an essential
compound in the generation of ATP in mitochondria. Hyperglycemia in diabetes
mellitus (DM) can result in the generation of reactive oxygen species (ROS) by
way of a process called glycoxidation. ROS can damage important cell components
such as membrane lipids, proteins and DNA. This cell damaging action of ROS has
been implicated in the development of diabetic complications such as
macro-angiopathy (atherosclerosis), micro-angiopathy (retinopathy,
nephropathy), neuropathy and cataract. ROS can also damage β-pancreatic cells resulting in a decrease in
insulin secretion. There is also evidence that ROS can cause insulin resistance,
although its exact molecular mechanism remains to be elucidated LA and its
reduced form: dihydrolipoic acid (DHLA) do not appear to be present in the
unbound state under normal conditions but are bound as lipoamide and dihydrolipoamide
to a lysine residue present in dihydrolipoyl-transacetylase, one of the 3
subunits forming the multi-enzyme dehydrogenase complex. However, after dietary
supplementation, both forms appear in various tissues in unbound forms.
Exogenous LA is enzymatically reduced to
DHLA. This latter compound is a strong anti-oxidant capable of scavenging ROS
and regenerating endogenous anti-oxidants such as vitamin C, vitamin E and
glutathione. LA has also been shown to
bind Fe 2+, a transition metal ion required for the generation of hydroxyl
radical (·OH) the most active ROS. Thus the main potential role of LA in the
management of DM is to prevent the detrimental effect of ROS generated by
glycoxidation including the prevention or alleviation of glucose resistance .In
the case of diabetic neuropathy, other potential roles include the enhancement
of ATP production since glucose uptake in neurons is not insulin dependent, and
possibly also increased synthesis of the neurotransmitter acetylcholine due to
the increased availability of acetyl-CoA.
Author: Purnomo Suryohudoyo
Journal Code: jpkedokterangg050036
