Title: The use of GLA and other compounds in the treatment of diabetic neuropathy
Key words: diabetic, neuropathy, complications, diabetes, GLA, gamma linoleic acid, lipid profile, desaturase, supplements, eicosanoids, myoinositol, PGE1, prostaglandins, prostacyclin, borage oil, free radicals, adhesion molecules, vascular, endothelial, docosahexanenoic acid, n-3 PUFA, polyunsaturated fatty acids, prostanoids, nerve conduction, superoxides, glucose, nitric oxide , NO, sorbitol, antioxidants,
Date: Oct 2006
Category: Micronutrients, Specific conditions
Author: Morgan, G
The use of GLA and other compounds in the treatment of diabetic neuropathy
Diabetic neuropathy is one of the chronic complications of diabetes and has in the past proved refractory to all forms of treatment, regardless of the degree of diabetic control. It is a major problem: 20 years after the onset of diabetes, it is estimated that 90% of all diabetics have clinical evidence of neuropathy although only 50% of these are symptomatic. A breakthrough in the understanding of the aetiology and treatment of this complication of diabetes has focussed the minds of many researchers over recent years. The role for the use of gamma linoleic acid (GLA) and other compounds is commented upon here.
Fatty acids in the pathogenesis of diabetic neuropathy
Brenner (1982), in one of the earliest papers on the possible role played by essential fatty acids (EFA) in the aetiology of this condition, observed that, in the animal model, high levels of linoleic acid and low levels of GLA and the long chain derivatives dihomogamma linoleic acid (DGLA) and arachidonic acid (AA) were present, indicating a failure of conversion of linoleic acid to GLA, presumably due to impaired delta-6 desaturase deficiency. Subsequent workers confirmed that providing GLA supplements corrected the abnormal lipid profile by bypassing this block.
Interest in the role of EFAs was stimulated by these initial findings on the basis that DGLA and AA were essential structural components of nerve cell membranes and were thought to mediate nerve conduction via the myoinositol-calcium system. They were also known to be essential precursors for the eicosanoids possessing vasomotor effects and gross pathological changes are seen in the vasa nervorum of diabetic nerves leading to compromised neural perfusion suggesting involvement of these compounds. Research in this area, using rat models has helped to elucidate the role played by the eicosanoids in this condition. PGE1, derived from DGLA, and prostacyclin, derived from AA, are two of these very biologically active prostanoids with marked vasodilator effects and have been implicated in the observed pathological changes in diabetic neurones. Thus supplementation with evening primrose oil (EPO), containing some 9% of GLA, leads to a doubling of prostacyclin synthesis from AA via the cyclooxygenase pathway (Fan 1992).
The sensitivity of GLA-containing oils in determining the composition of arachadonic acid (AA) derived prostanoids should also be highlighted. Borage oil, for example, though having a higher content of GLA than EPO is unable to increase neuronal perfusion in diabetic rats, an effect thought to be attributable to the concurrent synthesis of the strong vasoconstrictor thromboxane A2 via the same cyclooxygenase pathway (Jenkins 1988). Activation of the Th1 mediated pathway with the release of pro-inflammatory cytokines of the 2- and 4-series and associated acute phase proteins, adhesion molecules, free radicals and lymphocytic infiltration also undoubtedly play a role in the vascular endothelial changes leading to poor endoneurium perfusion seen in the pathology of this condition. The exact role of the anti-inflammatory n-3 PUFAs in diabetes is yet to be clarified however. Docosahexaenoic acid (DHA), for example, an important structural component of neural membranes, has contradictory effects on AA-derived prostanoids, the net result being no alteration in neuronal cell perfusion (Cameron 1996).
In the rat model perfusion deficits, following streptozotocin induced diabetes, precede those of impaired nerve conduction (Cameron 1996) indicating that the vascular changes are causal in the aetiology of the neuropathy. It is difficult, however, to extrapolate these findings to the more chronic pathology of adult human diabetes. What is clear is that GLA supplementation in rats can both prevent and correct the vascular changes leading to impaired endoneurium perfusion (Stevens 1993) and the results of this work is paralled by that of three separate studies in humans. These showed EPO supplementation resulted in improvement of all the 28 parameters of neural function measured in the trials (Horrobin 1997).
Combined therapy trials
Although positive, the neuronal improvements seen following GLA supplementation in both rats and humans have been relatively modest. Further research in to possible reactions between EFA and polyol pathways, using rat models, has helped to clarify ways in which responses to supplement combinations could be further improved (Cameron, Cotter, Hohman 1996). The micro-circulation hypoxia of neurones in diabetes is known to lead to the generation of free radicals and superoxides which, as well as damaging lipid cell membranes, also inhibits the production of nitric oxide (NO) an important vasodilator. NO synthase activity is inversely related to sorbitol levels, which rise in diabetes due to the free transport of glucose into the intracellular compartment of nerve cells and its conversion to sorbitol through the action of aldose reductase.
Raised sorbitol levels lead to diminished production of NADPH upon which NO synthase is dependent. raised sorbitol levels in themselves may well be cytotoxic due to osmotic damage and reduction in myoinositol. In rats it has been shown that giving combined cyclooxygenase and NO synthase inhibitors leads to slowing of neuronal conduction and other nerve changes which are identical to those of diabetes, changes that can be reversed with GLA and aldose reductase inhibitors (ARIs) (Cameron 1993). The close link between the polyol and EFA pathways is confirmed by other work such as that of Omawari et al. (1993). In rats, ARIs have been shown to improve nerve perfusion and function (Cameron 1994, Hotta 1995).
Most attention, however, has focussed on giving antioxidants in order to promote NO synthesis on the understanding that both GLA would act synergistically to restore NO synthase activity. Experiments to date with the antioxidants Vitamin C and alpha-lipoic acid (Cameron, Cotter 1996, Cameron 1998) have confirmed this prediction, showing both marked rises in endoneurium perfusion and nerve function in the treated group. In the ascorbate trial it was found that the combined treatment was 40 times more effective than EPO treatment alone, confirming the synergistic effects of the two agents. In another experiment looking at the synergistic effects of GLA and an ARI, similar results were obtained (Cotter 1995). In this experiment both GLA and the ARI led to increases in NO production of 16%. Giving the two agents together produced a rise in NO production of 71.5% which was much higher than predicted, confirming their synergistic effect.
The use of GPA in clinical practice is limited by compliance problems, given the high doses required for a therapeutic effect. Although not yet applied in practice, the results from recent animal studies and the previous congruous results between rat and human studies, leads one to believe that trials of combination therapies would produce much greater clinical benefit than GLA supplements alone. Combination GLA and antioxidant therapy has been shown to be considerably more effective in the animal model and such agents would be relatively cheap to produce and free of side effects. The use of ARIs has already been mentioned but such agents have yet to be developed for human use by the pharmaceutical industry. Given the chronic dystrophic changes present in diabetes it is doubtful if neurotrophic agents would prove of benefit in clinical practice and, indeed, in the rat model such agents have not proved to be effective. The effectiveness of agents acting on other biochemical pathways involved in the pathology of diabetic neuropathy, such as the protein kinase C (PKC) inhibitors or advanced Glycation End-products (AGE) blockers linked with the triose phospate pathway, has yet to be assessed. Undoubtedly, the future of drug therapy for diabetic neuropathy lies in the use of GLA with one or more of these agents.
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