Sci. Aging Knowl. Environ., 12 March 2003
Vol. 2003, Issue 10, p. pe6
[DOI: 10.1126/sageke.2003.10.pe6]

PERSPECTIVES

Vitamin B1 Blocks Damage Caused by Hyperglycemia

Mark E. Obrenovich, and Vincent M. Monnier

The authors are in the Department of Pathology at Case Western Reserve University, Cleveland, OH 44106, USA. E-mail: vmm3{at}po.cwru.edu (V.M.M.)

http://sageke.sciencemag.org/cgi/content/full/sageke;2003/10/pe6

Key Words: vitamin B1 • thiamine • diabetes • retinopathy • reactive oxygen species

Introduction

A recent study published in Nature Medicine (1) shows that treatment of diabetic rats with high doses of thiamine (vitamin B1) can prevent diabetic complications. Diabetes is characterized by a deficiency in the ability to produce or respond to insulin, which results in elevated glucose concentrations in the blood (hyperglycemia). Hyperglycemia-associated vascular damage can result in a variety of complications, including failure of the renal system and blindness. The present study reveals that vitamin B1 inhibits biochemical pathways that lead to such damage. The mechanism of action appears to involve the diversion of "excess" metabolic load (glycolytic intermediates) away from glycolysis and toward the so-called reductive pentose pathway, a secondary pathway for glucose catabolism. The study thus indicates that it might be possible to combat the effects of hyperglycemia without acting on glycemia itself. In addition, possible connections between vitamin B1 and longevity are suggested (discussed below).

This research is based on two fundamental observations from the laboratories of Michael Brownlee and Paul Thornalley. A number of biochemical abnormalities are observed in diabetic patients, such as activation of the polyol pathway and the hexosamine pathway, activation of protein kinase C (PKC) and the transcriptional activator NF-{kappa}B, and an increase in intracellular concentrations of advanced glycation end products (AGEs; see below)--all of which could occur because of the diversion of glycolytic intermediates to alternative pathways (Fig. 1). Brownlee and colleagues hypothesized that many of these aberrations result from a single unifying mechanism, which involves increased mitochondrial production of reactive oxygen species (ROS) (2) (and see "The Two Faces of Oxygen"). According to this hypothesis, these pathways would be activated because metabolites would accumulate upstream from a critical enzyme of glycolysis, glyceraldehyde phosphate dehydrogenase (GAPDH), which is highly susceptible to loss of function by oxidative damage (Fig. 1). Indeed, the group demonstrated that inhibition of mitochondrial ROS production by several methods prevented the biochemical and cellular abnormalities and preserved the function of GAPDH.



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Fig. 1. The link between glycolysis and the activation of metabolic pathways that are implicated in the complications of diabetes. Thiamine supplementation was shown to stimulate transketolase (TK) activity, resulting in an increase in the flux of the glycolytic intermediates glyceraldehyde 3-phosphate and fructose 6-phosphate toward the reductive pentose shunt, and the relative deactivation of the boxed pathways. These pathways signal glucose overuse and contribute to diabetic complications when they are activated. Activation of the polyl pathway causes sorbitol accumulation (2). Increased flux through the hexosamine pathway is implicated in the activation of transforming growth factor-{beta} and diabetic nephropathy (kidney disease). Diacylglycerol (DAG) formation causes increased PKC activity, which in turn can activate NF-{kappa}B. NF-{kappa}B activation is implicated in the overexpression of a large number of genes associated with microvascular disease (15). Finally, an increased concentration of methylglyoxal results in increased formation of AGEs, which are associated with dysfunction of various intracellular and extracellular proteins (16, 17, 18). P, phosphate; NADH, nicotinamide adenine dinucleotide; GFAT, glutamine; fructose-6-phosphate amidotransferase; UDP-GlcNAc, uridine 5'-diphosphate N-acetylglucosamine; DHAP, dihydroxyacetone phosphate. [Reprinted from (1) with permission from Nature Publishing Group]

 
The second fundamental observation was made by Thornalley and colleagues, who studied the in vitro activation of transketolase (TK), an enzyme that functions at the branch point between the reductive pentose pathway and glycolysis, by its physiological substrate vitamin B1 (3). The researchers found that activation of TK caused a decrease in the formation of intracellular AGEs derived from methylglyoxal (Fig. 2), an oxoaldehyde that increases in concentration when GAPDH is inhibited (Fig. 1, and see Monnier Perspective for further discussion of the connection between AGEs and diabetes). Activation of TK with its cofactor thiamine would be expected to shift glycolytic intermediates that increase in concentration during hyperglycemia toward the reductive pentose pathway and thereby decrease the metabolic stress resulting from inefficient processing of excess carbohydrates by glycolysis.



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Fig. 2. Examples of advanced glycation end products derived from methylglyoxal that are found in vivo.

 
Effects of Benfotiamine on Hyperglycemia-Induced Biological and Biochemical Abnormalities

In order to test this hypothesis, Hammes et al. (1) first examined the ability of benfotiamine, a lipid-soluble form of vitamin B1, to increase TK activity in bovine aortic endothelial cells. Vascular endothelial cells exposed to high concentrations of glucose are uniquely unable to down-regulate glucose transport. As a result, the cells develop intracellular hyperglycemia, which causes overproduction of the ROS superoxide by the mitochondrial electron transport chain. In the process, thiamine is oxidized into the biologically nonfunctional products thiochrome and oxodihydrothiochrome. The researchers found that 50 to 100 µM benfotiamine was needed to increase TK activity fourfold in the endothelial cells. When the cells were incubated in media containing a high concentration of glucose (30 mM), benfotiamine blocked hyperglycemic damage by preventing activation of the hexosamine pathway, intracellular AGE formation, and activation of PKC and NF-{kappa}B. Thus, benfotiamine clearly prevented the three mechanisms of glucose-mediated damage through the activation of TK in vitro. It is interesting that although thiamine is also a cofactor for the pyruvate dehydrogenase and alpha-ketoglutarate dehydrogenase complexes [which function just before and in the tricarboxylic acid (TCA) cycle, respectively], benfotiamine had no effect on TCA cycle activity and did not affect other aspects of glucose metabolism, including body weight and HbA1c (glycated hemoglobin) values.

The Brownlee group also explored the effects of benfotiamine in vivo in rats with experimentally induced diabetes (caused by injection of streptozotocin, which kills pancreatic B cells and thereby prevents insulin production). Orally administered benfotiamine was found to activate TK in the retina and prevent diabetic retinopathy, a complication that, if untreated, leads to blindness.

The data from this set of experiments demonstrate convincingly that high doses of benfotiamine can prevent the activation of deleterious pathways of hyperglycemic signaling and the associated molecular damage. The most likely mechanism of action of thiamine appears to involve activation of TK. Another mechanism could involve thiamine acting as an antioxidant indirectly, because such effects have been previously reported (4). In support of this possibility, parameters of oxidative protein damage were suppressed in diabetic kidneys after administration of thiamine (5). However, Hammes et al. (1) observed no decrease in mitochondrial ROS production in cultured endothelial cells exposed to high glucose levels and thiamine, suggesting that the vitamin acts upstream from the mitochondria and GAPDH. The consequences of thiamine administration might also result from a so-called "AGE-breaker" effect; that is, thiamine's potential ability to cleave dicarbonyl bonds that form during advanced glycation (6). Further research will be needed to fully explain the mechanism of thiamine action with respect to hyperglycemia.

Significance for the Treatment of Diabetes

The significance of this study for the clinical treatment of diabetic complications is potentially enormous. Without a doubt, clinical trials will be carried out to explore the potential role of vitamin B1 for the treatment of hyperglycemia-induced damage. A critical question is whether individuals with diabetes should, on their own, treat themselves with vitamin B1. Extrapolation of the amount of benfotiamine needed to obtain beneficial effects in the rat (70 mg/kg/day) to the human indicates that between 4 and 5 g of the vitamin per day might be needed for an average-sized human being. Although no harm is expected from a regular supplement of vitamin B1 within the context of a daily pill of multivitamins, the chronic consumption of high doses of this vitamin without additional clinical data is potentially hazardous. As an example, it is well known that the treatment of folic acid deficiency without concomitant vitamin B12 supplementation can worsen neuropathy and megaloblastic anemia (7). Thus, individuals with diabetes should not ingest large quantities of the vitamin without further clinical data and medical supervision.

Possible Connections Between Vitamin B1 and Aging

By extrapolation, vitamin B1 might be useful for delaying the aging process, because increasing evidence implicates excess signaling along the glucose-insulin axis as a life span-limiting process. For example, mutations in chico, which encodes an insulin receptor substrate in Drosophila melanogaster (8), and daf-2, which encodes an insulin receptor-like protein in Caenorhabditis elegans (9, 10), both result in an increase in life expectancy. In Saccharomyces cerevisiae, loss of SIR2, which encodes a nicotinamide adenine dinucleotide (NAD+)-dependent histone deacetylase, causes decreased life span. The requirement for NAD+, a product of oxidative phosphorylation, suggests a connection between metabolism and aging (11) (see "High-Octane Endurance--Yeast in the Metabolic Fast Lane Live Longer"). In addition, caloric restriction, which is associated with decreased glycemic levels in rodents and other species, is also associated with increased life span (see Weindruch Classic Paper and Masoro Subfield History). Vice versa, diabetes, which is defined by hyperglycemia, is itself associated with decreased life span. Although the precise mechanisms by which glycemia is linked to variation in longevity need to be elucidated, evidence implicates the activation of deleterious signaling pathways and damage to critical molecules resulting from a combination of oxidant and carbonyl stress (12).

The tight relationship between old age and glucose intolerance also suggests that vitamin B1 supplementation might be useful to ward off the chronic effects of mildly elevated glycemia. Elderly individuals with impaired glucose tolerance do not develop diabetic complications but suffer from accelerated cardiovascular diseases. Thus, studies on whether high doses of vitamin B1 can decrease the cardiovascular risk will be needed. In the meantime, although data show that regular multivitamin supplementation in moderate amounts is associated with a decreased risk of certain age-related ailments, such as cataracts (13), the intake of megadoses of any vitamin or supplement currently has no proven efficacy in increasing human life span (14). Nevertheless, the studies from the Brownlee laboratory show for the first time the exciting possibility of decreasing the activity of deleterious metabolic pathways in hyperglycemic conditions with a "simple" vitamin instead of a complex pharmaceutical agent. Thus, a new field of investigation that is potentially of broad relevance to both diabetes and aging has been initiated.


March 12, 2003
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Citation: M. E. Obrenovich, V. M. Monnier, Vitamin B1 Blocks Damage Caused by Hyperglycemia. Sci. SAGE KE 2003, pe6 (12 March 2003)
http://sageke.sciencemag.org/cgi/content/full/sageke;2003/10/pe6








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