Free radicals and diabetes -
Australian scientists have identified a 'free radical' that appears to trigger insulin resistance, or glucose intolerance, one of the first stages in the development of Type 2 diabetes.
It has been known for decades that being overweight or eating too much sugar and fat can lead to insulin resistance, but until now no-one has identified the central mechanism, or cellular switch, that initiates the process. A group of scientists from Sydney's Garvan Institute of Medical Research, led by Dr Kyle Hoehn and Professor David James, believe they may have found that elusive switch.
Hoehn and colleagues have found that overeating may stimulate the conversion of the oxygen in the air we breathe into toxic free radicals, leading to insulin resistance. These important findings are published online this week in the prestigious international journal Proceedings of the National Academy of Sciences PNAS.
In this study, we show that mitochondrial superoxide is the common feature in all instances of insulin resistance, no matter how it's induced. Co-author on the project, Dr Nigel Turner, explained the finding from a slightly different perspective.
It exists in 8 different forms, of which α-tocopherol is the most active form in humans. Hydroxyl radical reacts with tocopherol forming a stabilized phenolic radical which is reduced back to the phenol by ascorbate and NAD P H dependent reductase enzymes [ 36 , 37 ].
CoQ 10 is an endogenously synthesized compound that acts as an electron carrier in the Complex II of the mitochondrial electron transport chain. Vitamin C ascorbic acid increases NO production in endothelial cells by stabilizing NOS cofactor BH 4 [ 41 ].
α-Lipoic acid is a hydrophilic antioxidant and can therefore exert beneficial effects in both aqueous and lipid environments. α-lipoic acid is reduced to another active compound dihydrolipoate. Dihydrolipoate is able to regenerate other antioxidants such as vitamin C, vitamin E and reduced glutathione through redox cycling [ 41 ].
Thus, both experimental and clinical studies summarized in the next sections utilized these naturally occurring antioxidants, especially vitamins C, E and α-lipoic acid, in order to delineate the role of oxidative stress in the development of vascular complications of diabetes.
A multitude of in vivo studies have been performed utilizing antioxidants in experimental diabetic models. The effects of antioxidants on oxidative stress are measured through certain observable biomarkers.
These markers include the enzymatic activities of catalase, SOD, GSH-Px, and GSH-reductase, as well as thiobarbituric acid reactants TBARS levels, an indirect measurement of free-radical production that has been shown to be consistently elevated in diabetes.
Many animal studies have been completed with this aim in mind and indeed have shown that diabetes-induced alterations of oxidative stress indicators can be reversed when the animals are treated with various antioxidants.
It should be noted that a plethora of studies have been done with numerous antioxidant compounds. We will, however, only cover a select few within the scope of this review, specifically the compounds for which a corresponding human clinical trial has been conducted. Mekinova et al. demonstrated that supplementation of streptozotocin STZ diabetic rats with vitamins C, E, and beta-carotene for 8 weeks produced a significant reduction of TBARS levels, GHS, and GHS-Px, an increase in Cu-SOD, and no change in catalase activity in kidneys [ 42 ].
Treatment with vitamins C and E was also shown to decrease urinary albumin excretion, glomerular basement membrane thickness, and kidney weight in STZ diabetic rats [ 43 ].
In the same study, vitamins C and E significantly lowered malondialdehyde TBARS levels and GSH-Px activity while increasing catalase and SOD activities when compared to unsupplemented diabetic animals [ 43 ]. A study by Cinar et el. demonstrated that supplementation with vitamin E significantly lowered liver and lung TBARS levels and improved impaired endothelium-dependent vasorelaxation in STZ diabetic rat aorta [ 44 ].
α-lipoic acid, which is involved in mitochondrial dehydrogenase reactions, has gained a considerable amount of attention as an antioxidant. Studies have demonstrated that intraperitoneal administration of α-lipoic acid to STZ diabetic Wistar rats normalizes TBARS level in plasma, retina, liver, and pancreas [ 45 ].
In the same study, Obrosova et. al observed a reduction of GSH activity in diabetic retina and that supplementation with α-lipoic acid produced no change [ 45 ]. However, another study demonstrated an increase in aortic GSH-Px in STZ diabetic rats that was normalized by treatment with α-lipoic acid [ 46 ].
Additionally, increased maximum contractile responses in diabetic aortic rings were ameliorated with α-lipoic acid treatment [ 46 ]. SOD activity is undoubtedly important to the regulation of oxidative status in diabetes.
However, there is variation as to the status of this enzyme in the diabetic state. Some studies have reported decreased SOD activity [ 43 , 45 ] while others have shown increases [ 47 ] or no change in the enzyme [ 42 , 48 ]. α-lipoic acid has been observed to normalize diabetes-induced decreases of SOD in rat heart [ 48 ] and retina [ 45 ].
A recent study by Brands et al. investigated the effect of oxidative stress in the development of hypertension in diabetes using the SOD mimetic tempol in a Type 1 model of diabetes where NOS is pharmacologically inhibited with a NOS inhibitor, L-NAME [ 49 ].
In this model, hyperglycemia causes hypertension implicating an important role for NO. In summary, there are differences in response to antioxidants in experimental diabetes in the prevention of cardiovascular complications. Studies in experimental models provide a foundation for the clinical studies but results should be interpreted cautiously since the experimental models of diabetes, duration and type of antioxidant treatment and markers of oxidative stress investigated in these studies exhibit a wide range.
Although studies with antioxidants in experimental models as well as observational studies strongly suggest that antioxidants should confer beneficial effects in reducing cardiovascular complications in diabetes, clinical evidence for the use of antioxidants is not solid.
It should be emphasized that clinical trials with antioxidants in diabetes are limited and majority of these trials focused on the use of vitamin E and C and lately α-lipoic acid. Thus, we will attempt to group the clinical trials by the antioxidants used.
Small trials with vitamin E demonstrated beneficial cardiovascular effects. In another study, Beckman et al. Other clinical trials on a larger scale include the Heart Outcomes Prevention Evaluation HOPE trial [ 53 ], Secondary Prevention with Antioxidants of Cardiovascular Disease in End Stage Renal Disease SPACE trial [ 54 ], the Steno trial [ 55 ], the Primary Prevention Project PPP trial [ 56 ] and the Study to Evaluate Carotid Ultrasound Changes in Patients Treated With Ramipril and Vitamin E SECURE trial [ 57 ].
The HOPE trial enrolled patients 55 years of age or older who were at high risk for cardiovascular disease and recruited significant number of patients with diabetes. Results with vitamin E and ramipril were evaluated separately as compared to respective placebo groups. In the vitamin E arm, patients received vitamin E and patients were given placebo.
In the treatment and placebo groups, the number of patients with diabetes was and , respectively. The primary endpoint was a composite of myocardial infarction, stroke and death from cardiovascular causes.
The trial was stopped for ethical reasons after 4. Results of the study were published in and demonstrated that there was no significant difference in the primary outcome between vitamin E and placebo groups [ 53 ].
Analyses of the secondary endpoints of the study, which included total mortality, hospitalizations for heart failure and unstable angina, revascularization and nephropathy, were recently published [ 58 ], and again vitamin E supplementation for 4.
It was also reported that there were no significant adverse events associated with vitamin E. The HOPE trial was the largest trial conducted thus far for the use of antioxidants in diabetes. The SECURE trial was designed as a substudy of the HOPE trial to evaluate the effects of long-term treatment with ramipril and vitamin E on atherosclerosis progression in high-risk patients.
In this trial, patients who had vascular disease or diabetes were randomized to two doses of 2. While ramipril slowed down atherosclerotic changes, vitamin E had no effect as compared to placebo group. The primary endpoint was a composite of myocardial infarction, stroke, peripheral arterial disease or unstable angina.
Similar to the studies discussed above, the primary endpoint was a composite of cardiovascular death, stroke or myocardial infarction. Out of the patients recruited, had diabetes. The PPP trial was stopped prematurely by the recommendations of an independent data and safety monitoring board based on the consistent beneficial effects of aspirin as compared to placebo group.
However, there was no significant effect of vitamin E treatment either in diabetic or nondiabetic subjects. In the intensive treatment group, patients received pharmacotherapy that targeted hyperglycemia, dyslipidemia, hypertension and microalbuminuria including daily supplementation of vitamin C mg , E mg , folic acid mg and chromium picolinate mg as well as behavior modification including low-fat diet, exercise and smoking cessation.
The control group received conventional therapy as recommended in national guidelines. Studies with α-lipoic acid are approved for the treatment of diabetic neuropathy and results are more promising than those obtained with vitamin E. The ALADIN II Study demonstrated that long-term 24 months use of α-lipoic acid or mg improved nerve function [ 60 ].
ALADIN III, a randomized multicenter double-blind placebo controlled study, showed that in a cohort of patients, mg α-lipoic acid administration for 6 months improved neuropathy impairment score as early as 19 days, which was maintained up to 7 months [ 61 ].
The DEKAN Deutsche kardiale autonome neuropathie study evaluated the effect of mg α-lipoic acid or placebo in diabetic patients with cardiac autonomic neuropathy for 4 months and showed that heart rate variability, an indicator of cardiac autonomic neuropathy, significantly improved with α-lipoic acid treatment [ 62 ].
The SYDNEY trial investigated the effect of α-lipoic acid treatment on sensory symptoms of diabetic polyneuropathy as assessed by the Total Symptom Score. Administration of this antioxidant over a 3-week period improved sensory symptoms such as pain, prickling and numbness [ 63 ].
In summary, clinical trials with conventional antioxidants in diabetic patients are limited. For major cardiovascular outcomes, vitamin E failed to provide any benefit. However, when study population was limited to diabetic patients alone as done in diabetic neuropathy trials, α-lipoic acid has proven to be effective.
As further discussed under Perspectives, this antioxidant may be a viable option in trials focusing on cardiovascular outcomes in diabetes. In addition to the many antioxidants examined above, a number of commonly used drugs have shown promising antioxidant activity in addition to their primary pharmacological activity.
These drugs include thiazolidinediones TZDs , HMG-CoA reductase inhibitors statins , and inhibitors of the renin-angiotensin system. Thiazolidinediones TZDs have been shown in many animal studies to have antioxidant effect.
In one study, pioglitazone-treated rats had reduced urinary excretion of isoprostane, a marker of oxidative stress [ 65 ]. In a trial with type-2 diabetic rats, Bagi et al demonstrated that treatment with rosiglitazone reduced NAD P H-derived ROS and increased the activity of catalase [ 66 ].
Another study using type-2 diabetic rats found that treatment with troglitazone lowered hydroperoxides and decreased SOD activity [ 67 ]. A study using troglitazone and pioglitazone in type-2 diabetic rats found that both agents reduced TBARS levels and increased the aortic vasorelaxation response [ 68 ].
There is substantial evidence from in vitro studies that statins exert an antioxidant effect. Studies have demonstrated that statin therapy markedly reduces oxidative stress markers such as nitrated tyrosine in animals [ 69 ]. Although the mechanisms for these actions are still being elucidated, Takayama et al have demonstrated in canine models that the antioxidant effect of statins is at least partially due to inhibition of NAD P H oxidase [ 70 ].
Statins have also been shown to stimulate the activity of the antioxidant enzyme thioredoxin [ 71 ]. Additionally, statin therapy has been shown to stimulate the activity of paraoxonase PON , which has a putative role in protecting LDL from oxidation [ 72 ].
Oxidation of LDL ex vivo has been shown to be inhibited by long-term statin therapy, an effect thought to be partly due to the binding of the statins to the LDL itself. It seems likely from the above studies that the antioxidant actions of statins are manifested via a variety of mechanisms.
Inhibitors of Angiotensin II Ang II activity, such as Angiotensin Converting Enzyme Inhibitors ACEIs and Angiotensin II receptor blockers ARBs have shown some beneficial effects that may stem from their antioxidant properties.
Angiotensin II has been shown to increase ROS levels in animal studies, through stimulation of NAD P H oxidase activity [ 15 , 73 ]. Studies have suggested that this effect also occurs in humans [ 73 , 74 ]. Ang II has also been implicated in upregulating the expression of the LOX-1 receptor, which is specific for oxidized LDL cholesterol.
Inhibition of the generation of Ang II, whether by ACEI or ARB, should therefore attenuate these deleterious processes. In summary, many of the agents which are a mainstay of pharmacotherapy in diabetes have been shown to have antioxidant properties in addition to their primary pharmacological actions.
These antioxidant properties may be a contributing factor to the therapeutic efficacy of these agents. Their antioxidant properties make the case for use of these drugs even more compelling. Particularly in light of the lackluster results seen in clinical trials with antioxidant supplementation, health care providers should redouble their efforts to ensure adequate usage of the demonstrably effective agents summarized above.
Although the clinical trials conducted to date failed to provide adequate support for the use of antioxidants in diabetes, it is still to early to reach a definitive conclusion on this issue.
As discussed above, with the exception of alpha-lipoic acid studies in diabetic neuropathy, data from clinical trials are limited. The majority of studies were not designed to assess the effect of antioxidant use specifically in diabetic patients.
This is an important point because diabetic patients represent a population in whom oxidative stress is much higher than in the general population. As was seen in the SPACE trial of patients on hemodialysis, patients exposed to very high oxidative stress responded favorably to vitamin E supplementation [ 54 ].
It is possible that antioxidants would be more demonstrably effective in a patient population chosen on the basis of elevated levels of oxidative stress. Unfortunately, none of the studies to date effectively assessed the baseline oxidative stress of the enrolled patients using any of the commonly accepted markers of inflammation.
The human trials to date used endpoints that were not directly related to oxidative stress, but rather gross markers of overall cardiovascular health, such as effect on mortality.
The studies failed to assess the duration of the diabetic disease states, arguably a large confounding variable. In assessing oxidative stress and the effects of antioxidants thereon, specific markers of oxidative stress should be measured.
With respect to the specific antioxidants studied, their selection was based on epidemiological and observational data, and in the absence of any solid grasp of the underlying mechanisms of action. Whereas observational studies are based on whole populations and reflect the lifelong influence of dietary habits, most of the studies were five years duration or less and included older patients average age It is possible that the study populations represented patients in whom the disease states had progressed too far to be amenable to antioxidant intervention.
In all likelihood, the choice and dose of antioxidant might be very important. The clinical trials focused mainly on the use of vitamin E. Negative results with vitamins cannot be generalized to all antioxidants. As has been eloquently argued elsewhere, treating the antioxidant vitamins as a single class of compounds with expected similar effects inappropriately disregards their wide range of chemical properties and pharmacodynamics [ 76 ].
Clinical trials to date have been conducted without any real understanding of the mechanisms of action or the concentrations of the various agents seen at different physiological sites. Indeed, there is not sufficient evidence to demonstrate that vitamin E reaches target cells.
Recently, it has been postulated that antioxidant potency of vitamins such as C and E is limited because these antioxidants work as scavengers of existing excess reactive species in a stoichiometric manner and this approach represents a symptomatic approach to oxidative stress-associated clinical problems [ 77 ].
Based on the new developments in our understanding of the pathophysiology of oxidative stress, it is clear that strategies to block the formation of reactive radicals will provide a targeted and causal approach to provide conclusive evidence whether antioxidants should be part of the cardiovascular treatment plan in diabetes.
Candidate agents include low molecular weight mitochondrial and cytosolic SOD and catalase mimetics, L-propionyl carnitine, PKC-β inhibitor LY, peroxynitrite catalyst FP15 and mitochondrial uncoupler DNP [ 9 , 77 , 78 ].
Given the number of shortcomings in the clinical trials, it seems clear that more research on the use of antioxidants in the prevention of cardiovascular complications in diabetes is necessary and strongly encouraged. From a clinical viewpoint, however, efforts for the prevention of diabetic complications should seek to maximize the benefits of proven therapeutic strategies including appropriate life style changes and controlling blood pressure, blood glucose and lipids.
In conclusion, the amount of evidence on the harmful effects of oxidative stress on vascular function and the link to pathophysiological mechanisms underlying diabetic complications is compelling. While the lack of clinical evidence on the beneficial effects of antioxidant vitamins in diabetes management should not deter us from more basic and clinical research on this issue, practice guidelines that are based on the results of numerous clinical trials should be our guide to evidence-based medicine in the prevention of cardiovascular disease in diabetes.
The recent American Heart Association science advisory on the subject of antioxidant vitamins and cardiovascular disease asserted that there is insufficient evidence to justify the use of antioxidant vitamins for cardiovascular disease risk reduction [ 79 ].
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