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Advanced glycation end products (AGEs) that form in vivoare now implicated in causing many of the complications of diabetes and the deleterious changes associated with aging. Accumulation of AGEs contributes to plaque formation, basement membrane thickening, and loss of vascular elasticity, leading to cardiovascular disease. But glycation is a modifiable lifestyle factor, and rates of endogenous glycation can be slowed with the use of a growing number of natural products. This review will discuss some of these, in particular benfotiamine, along with chromium, biotin, and carnosine. All have been found to slow glycation and begin the process of restoring health.
Glycosylation is an enzymatic process in which glycans, such as fructose and glucose, bind with proteins, lipids, or other organic molecules. When this same reaction occurs without the control of an enzyme, it is called glycation. These reactions have been well studied in foods and are called Maillard browning reactions. The glycation products are responsible for the color and taste that we appreciate in many sugar-containing cooked foods. These reactions are referred to as exogenous glycation reactions; they occur outside the body. Exogenous glycation, also referred to as preformed glycation, a process that allows foods to brown during cooking, naturally occurs when sugars are cooked with proteins or fats. Some food manufacturers add sugar to products such as french fries and baked goods to enhance browning. One study on the effects of various methods of food preparation on AGE production found that the fattiest foods had the highest AGE content.1 Furthermore, the level of AGE content was directly related to cooking temperature, cooking time, and amount of moisture involved in the cooking process. In general, cooking at high temperatures (e.g., broiling and frying) resulted in higher AGE content in foods than did roasting and boiling.
Glycation also occurs in vivo, within the body. It is these internal "browning reactions" that are of great concern. These reactions tend to occur when blood sugar levels or oxidative stress levels in the body are high. Over the course of several weeks, the early glycation products undergo a series of chemical reactions to become irreversibly cross-linked protein derivatives, referred to as advanced glycation end products. These AGEs, in combination with their receptor (RAGE: receptor for AGE) trigger oxidative stress, inflammatory reactions, and thrombosis, thereby playing a part in vascular aging and damage. This AGE-RAGE system is now considered a target of treatment for reducing complications of diabetes and a number of other cardiovascular-related diseases.
The Effects of Glycation
Recent research increasingly reinforces the role of glycation and the accumulation of AGEs in inflammation and oxidative stress, both of which result in vascular aging and damage.2 These processes are known to be precursors to a number of disease states, including diabetes and cardiovascular disease, among others. An overview of the research linking glycation to these disease states follows.
Hyperglycemia is still considered the principal cause of diabetes complications. Its deleterious effects are attributable to, among other things, AGEs, the formation of which is markedly accelerated in diabetes because of the increased availability of glucose.3
AGEs accumulate in the body with age and at a much higher rate in diabetics than in the normal population.3,4 AGE serum levels are significantly higher in diabetic patients when compared with people who do not have diabetes and often are reported in clinical studies comparing diabetic patients with healthy individuals. In a 1999 study, AGE levels of 7.4 U/mL were recorded in diabetic patients vs. 4.2 U/mL in the normal population, and levels of CML (N-carboxymethyllysine), a commonly used indicator of AGE burden, were as high as 15.6 U/mL in diabetics vs. 8.6 U/mL in nondiabetics.4
Several studies and review articles support a correlation between AGEs and cardiovascular disease risk, particularly in diabetic patients. A number of clinical and experimental studies support the contention that AGEs might play a meaningful role in pathogenesis of heart failure by contributing to its development and progression either indirectly through mechanisms mediated through enhancing coronary artery disease or directly by causing myocardial damage independent of vascular effects.4 A review published in 2012 summarized clinical data on AGEs and their action on RAGE with regard to blood pressure and vascular disease. The review did not find evidence of a role in hypertension, but did find evidence of a role in vascular disease, including macrocirculation as well as microcirculation.5 An earlier 2007 review indicated that in patients with diabetes, AGE accumulation is associated with the development of cardiac dysfunction. There is also evidence to suggest that AGEs are related to the development and progression of heart failure in non-diabetic patients as well.6
Natural Products to Reduce Glycation
Intervention with natural products, particularly benfotiamine, has shown to be promising in the reduction of glycation and the development of AGEs, as described below.
A number of studies have demonstrated the AGE-limiting effects of benfotiamine, a derivative of thiamine, particularly in people with diabetes.7-11 A key characteristic of diabetes is postprandial endothelial dysfunction caused by hyperglycemia, hypertriglyceridemia, and AGEs. In a 2006 study, 13 patients with type 2 diabetes were given a heat-processed meal with high AGE content (HAGE) before and after a 3-day administration of 1050 mg of benfotiamine daily. During both test meal days (after the patients fasted overnight) and then at 2, 4, and 6 hours after the meal, the following were measured: macrovascular flow-mediated dilation (FMD); microvascular reactive hyperemia; and serum markers of endothelial dysfunction, oxidative stress, AGE, and methylglyoxal. The researchers found that the effects of HAGE on FMD and reactive hyperemia were entirely prevented by benfotiamine. Further, though serum markers of endothelial dysfunction, oxidative stress, and AGE increased after consumption of the HAGE meal, the effects were significantly reduced by benfotiamine.9
In another study by the same researchers, participants on a standard diabetes diet for a 9-day period were studied on 3 occasions after an overnight fast. The effects of HAGE and low AGE (LAGE) were studied on days 4 and 6. Sixteen patients were administered 350 mg benfotiamine 3 times a day on days 7 and 8 and 1050 mg 1 hour before the repeated intake of HAGE (HAGE plus benfotiamine) on day 9. Before HAGE and LAGE, fasting glucose was comparable but decreased after benfotiamine intake. Postprandial glucose – measured 2 hours after the meal – was significantly reduced by benfotiamine.10
A randomized, placebo-controlled, double-blind, two-center pilot study evaluated the efficacy of benfotiamine in the treatment of diabetic polyneuropathy.9 Forty patients with a history of type 1 or 2 diabetes and polyneuropathy of no more than 2 years participated in the study. Twenty patients were administered 100 mg benfotiamine 4 times daily, and 20 patients were administered placebo during the 3-week study period. A statistically significant (p = 0.0287) improvement in the neuropathy score was seen in the benfotiamine group compared with the placebo group, providing additional evidence for the beneficial effects of benfotiamine in patients with diabetic neuropathy.11
Chromium and Biotin
A 2004 study evaluated the effect of 6-week oral administration of chromium chloride (CC) on the glucose and lipid metabolism in streptozotocin (STZ) diabetic and neonatal-STZ (nSTZ) diabetic rats. The researchers found that treatment with CC improved the impaired glucose tolerance and insulin sensitivity of both STZ diabetic and nSTZ diabetic rats and also improved deranged lipid metabolism significantly.12
In a 2006 study conducted at the Yale University School of Medicine, 43 subjects with impaired glycemic control were randomized to receive 600 mg of chromium picolinate and biotin (CPB) in addition to their prestudy oral antihyperglycemic agent therapy after treatment with oral antihyperglycemic agents alone failed. Glycemic control and blood lipids were measured at baseline and again at 4 weeks. After 4 weeks, the CPB group saw a significant reduction (mean change −9.7%) vs. placebo (mean change +5.1%, p < 0.03) not just in the total area under the curve for glucose during the 2-hour oral glucose tolerance test, but also in measures of fructosamine (p < 0.03), triglycerides (p < 0.02), and triglycerides:high-density lipoprotein (HDL) cholesterol ratio (p < 0.05).13
Another study of 36 moderately obese subjects with type 2 diabetes randomized the subjects to receive CPB or placebo as well as their oral hyperglycemic agents for 4 weeks. After 4 weeks, glucose levels in the CPB group had decreased at 1 hour and 2 hours, and glucose area under the curve and fructosamine levels had decreased significantly. Ratios of total:HDL cholesterol, LDL:HDL cholesterol, and non-HDL:HDL cholesterol also decreased significantly.14 In a 2007 randomized, double-blind, placebo-controlled trial, 348 participants were randomly assigned to receive either CPB (600 mg chromium picolinate and 2 mg biotin) or a matching placebo daily for 90 days. The study found that compared with the placebo group, CPB reduced HbA1c (p < 0.05) and glucose (p < 0.02) significantly.15 No adverse events were associated with CPB treatment in any of these studies.13-15
A number of studies have supported the supplementation of carnosine in patients with diabetes. The authors of a 1999 study recommended supplementation of carnosine in patients with diabetes on the basis that examination of patients with diabetes mellitus type 1 showed that carnosine levels in red blood cells were low. Lower levels of carnosine in red blood cells indicate that carnosine is not adequately available for metabolic processes such as antioxidant reactions.16 Another study published in 2000 examined the effect of carnosine on red blood cell membranes in in vitro and in vivo experiments. Carnosine was shown to protect healthy donors' red blood cells from acidic hemolysis, resulting in an increase in the population of stable red blood cells and delaying time to maximal rate of hemolysis. Carnosine treatment in the model of streptozotocin-induced diabetes in rats prevented a decrease in the hemolytic stability of red blood cells, suggesting the usefulness of carnosine in the treatment of patients with diabetes.17
With respect to glycation specifically, a 2007 study supported the protective effects of carnosine. Glycation of low-density lipoprotein (LDL) by reactive aldehydes can result in cellular accumulation of cholesterol. The study showed that carnosine inhibits the modification of LDL by glycolaldehyde, a reactive aldehyde, when introduced at equal concentrations to the modifying agent. Consequently, the authors contend that carnosine may have therapeutic value in preventing diabetes-induced atherosclerosis.18 Another study looked at the effects of carnosine and related compounds on the formation of AGEs in uremic patients who had undergone peritoneal dialysis and found that carnosine slowed the development of AGEs better than the similar peptides anserine and homocarnosine.19
Diet and Exercise in the Management of Glycation
As with many biochemical processes, glycation can be managed to some degree not only through the use of natural products, but also by maintaining a healthful diet and exercising. In a 2009 study by Japanese researchers, having participants switch to a low-calorie diet even for just 2 months resulted in improvements in body mass index (BMI), waist circumference, and triglycerides. Further, AGEs decreased by 7.21% (range 0%–35%, p < 0.001), a change that was positively and significantly correlated with the changes in BMI (r = 0.42, p < 0.007), waist circumference (r = 0.40, p < 0.011), and triglycerides (r = 0.42, p < 0.009).20 A 2010 report in the Journal of the American Dietetic Association discussed the contribution of dietary advanced glycation end-products (dAGEs) to increased inflammation and oxidant stress, and contended that dAGEs can be limited by avoiding animal-derived foods that are high in fat and protein. Rather, the authors recommend a diet high in vegetables, fruits, whole grains, and milk, using cooking methods that involve moist heat, shorter cooking times, lower temperatures, and the use of acidic ingredients such as lemon juice or vinegar.21 A study published in the journal Metabolism drew a correlation between exercise and both reduction in advanced glycation and improvement in diabetic nephropathy in a rat model. Obese Zucker rats were left sedentary or subjected to 10 weeks' intermittent treadmill running of moderate intensity. The nonsedentary Zucker rats had significantly lower plasma AGEs-associated fluorescence; similarly, the amount of renal AGEs was lower in the rats that exercised.22 The finding that exercise decreased advanced glycation in a rat model warrants more research in this area.
A number of studies suggest a causative effect of glycation and the formation of AGEs on inflammation and oxidative stress and the consequent development of disease, including diabetes and cardiovascular disease. Fortunately, there is also evidence in the literature demonstrating the efficacy of benfotiamine, chromium picolinate and biotin, and carnosine in reducing glycation and the development of AGEs and therefore their harmful effects on the body.
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