Type 2 Diabetes Mellitus (T2DM) is a systemic metabolic disorder
associated with serious and often life-threatening complications.
Diabetic neuropathy is a common complication affecting more than
half of T2DM patients [1]. Neurological abnormalities affecting the
distal lower extremities are known to appear in the early stages of
T2DM and even in patients with pre-diabetes and abnormal glucose
tolerance [2].
There is no widely accepted consensus on the treatment of
neurological abnormalities in diabetics. No drugs have been specifically
approved for patients with diabetic neuropathy. For decades
pharmacological interventions aimed at the normalization of glucose
turnover and hemoglobin A (1C) level have remained a mainstay of
therapy for diabetic neuropathy patients [3]. Other pharmacological
options include pain management (tricyclic antidepressants, serotoninnorepinephrine
reuptake inhibitors, α2δ ligands, antiepileptics, opioids)
and anti-inflammatory drugs [4]. Although innovative treatment
approaches (gene therapy, steam cell therapy, use of neurotrophic
and growth factors) are under development, their rapid introduction
into routine clinical practice seems to be problematical [4,5]. Even
though symptomatic treatment usually produces some temporary
improvements in the health status of patients, the etiology- and
mechanism-driven approach to the treatment of diabetic neuropathy is
not available, remaining in its infancy due to lack of precise knowledge
about the pathophysiological mechanisms underlying neurological
defects in T2DM. It has been clearly shown for decades that diabetic
neuropathy is a direct consequence of abnormal glucose turnover
mirroring improvements and deteriorations in glucose homeostasis.
Chronic hyperglycemia in T2DM leads to up to a four-fold increase in
the neuronal glucose level which cannot be neutralized by anaerobic
and glycolytic burst as happens in the muscle cells [6]. Glucose
neurotoxicity develops due to the unique oxidative biochemistry of
glucose leading to accumulation of free radicals in the neuronal tissue
via non-enzymatic, enzymatic and mitochondrial mechanisms [7].
Hyperglycemia promotes the formation of O2
΄- superoxide through
the polyol (sorbitol) pathway which is accompanied by non-enzymatic
generation of Amadori products and the subsequent formation of
advanced glycation end products [8]. Moreover, reactive oxygen
species have been shown to be generated in the nitric oxide synthase,
NAD(P)H oxidase and xanthine oxidase systems [9]. It is now believed
that oxidative damage is a primary pathogenetic mechanism causing
impaired axonal transport, structural breakdown of Schwann cells and
subsequent abnormalities in the propagation of action potential [10].
Due to advances in the understanding of the mechanisms of
oxidative stress it recently became feasible to target oxidative stress
using in particular nutraceuticals with antioxidant properties. This
may create an important novel strategy in the treatment of diabetic
neuropathy. The latest developments in clinical and experimental
diabetology fully support this assumption. The most exciting results
come from the recently published multicenter randomized doublemasked
parallel Neurological Assessment of Thioctic Acid in Diabetic
Neuropathy (NATHAN) 1 trial which involved 460 patients with mild
to moderate distal symmetric diabetic polyneuropathy. It was well
documented that four year treatment with α -lipoic acid led to clinically
relevant improvement of neurological functions as evaluated by seven nerve function tests in patients with diabetic polyneuropathy [11].
Although α -lipoic acid treatment did not affect the nerve conduction
parameters in patients, the Neuropathy Impairment Score of the lower
limbs (NIS-LL) was improved in the lipoic acid treatment group and
worsened in the placebo [11]. Similar improvements in neurological
functions were recently shown on a smaller scale in comparable clinical
settings [12] and animal studies [13,14]. Therefore, despite of some
limitations, the results of NATHAN-1 trial represent the first systematic
and considerable piece of evidence revealing the therapeutic effect of
an antioxidant in diabetic neuropathy confirmed by others. Such an
outcome is particularly welcome due to multiple failures to show any
clinically measurable effect of antioxidants in different clinical settings.
α -lipoic acid, otherwise known as thioctic acid, is an orthomolecular
nutrient with extremely potent free radical scavenging capabilities
reported in different systems [15]. Besides reducing lipid peroxidation,
α -lipoic acid has been shown to normalize microcirculation and
insulin sensitivity, enhance endogenous superoxide dismutase, reduce
ischemia-reperfusion syndrome and prevent apoptosis [16]. Generally,
α -lipoic acid is well tolerated and has low toxicity. However, the results
of the NATHAN 1 trial reveal a tendency towards a higher incidence of
adverse effects in the treatment group as compared to the placebo. This
issue could be addressed in the future by a lowering of the therapeutic
dose or the use of other isoforms of the compound. The antioxidant
properties of α -lipoic acid are mediated by balanced conversion of the
compound to dihydrolipoic acid, a reduced metabolite [15]. It has been
shown recently under in vitro conditions that dihydrolipoic acid has
superior antioxidant potency when compared to α -lipoic acid [17].
Therefore assessment of in vitro and in vivo toxicity and the possible
introduction of dihydrolipoic acid into therapeutic formulations may
provide a reasonable solution for the reduction of adverse effects of
lipoic acid.
On the other hand, the implications of the NATHAN 1 trial go far
beyond the therapeutic use of α -lipoic acid in diabetes care. It has been
shown recently that the effect of α -lipoic acid in diabetic neuropathy can
be enhanced by other antioxidants, in particular superoxide dismutase
[18]. Therefore it is plausible to assume that the effect of α -lipoic acid
is unlikely to be attributable to its particular chemical nature but is
rather related to the antioxidant properties of the compound. Indeed,
many other nutrients (resveratrol, lycopene, soy isoflavones) with
antioxidant properties have been shown in both in vitro and in vivo
systems to have a significant positive impact on the complications of
T2DM [19]. The success of the NATHAN 1 trial has opened the door for new clinical trials which may unveil the possible benefits of antioxidant
use in T2DM. However, there are multiple challenges to clinical use of
nutrients with antioxidant properties. Unlike α -lipoic acid many of
them are susceptible to auto-oxidation [20], have limited absorption
[21] and/or can be rapidly metabolized by the gut microbiota [22].
Therefore stabilized formulations of antioxidants would be required
for new clinical research projects.
Nevertheless, the success of the NATHAN 1 trial gives great
inspiration to new attempts at micronutrient use in diabetes. It is
important to realize that T2DM is a nutritional disorder arising entirely
from excessive and/or unbalanced food intake. Therefore nutritional
interventions as well as the selective use of different food ingredients
seem to be a most appropriate and promising treatment option
for T2DM. The idea of using food ingredients as medicinal agents
originated in ancient times. In particular, Hippocrates’ statement “Let
food is your medicine and medicine is your food” provides a backbone
for the current philosophy of T2DM management. The diverse and
extremely powerful physiological effects of some food constituents,
comparable to the effects of some pharmacological agents - has led
to the introduction of the relatively new term ‘nutraceuticals’ whose
potential therapeutic use in T2DM patients has yet to be further
explored in well-designed clinical trials.
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