FRUCTOSIS.com
The CURSE of dietary fructose and hyperglycemia
FRUCTOSIS

Do you think children might be responding to fructose in food like lab animals used to test diabetes medications in the 1990s?

Sugar Basics...There are three sugar molecules commonly found in our food. Glucose, galactose and fructose. Grains like rice quickly digest into mostly GLUCOSE.  Glucose is required as a fuel for brain and other functions.  If you do not eat glucose your body converts protein you eat into needed glucose and fat.  If you don't eat enough protein the body converts your muscle into needed glucose. Starvation is complete when the is no muscle left to convert to needed glucose.  GALACTOSE is the milk sugar and is found naturally in breast milk.  Lactose is a combination of one galactose and one glucose molecule.  FRUCTOSE is found naturally in fruit and some vegetables such as sugar beets.  You don't have to eat any fructose, your cells make the little they need for replication from glucose.
The fructose your body doesn't need
is found mainly in sucrose (table sugar) 50% by dry weight, High Fructose Corn Syrup (HFCS) usually 55% or more by dry weight and fruit 10-50% fructose by dry weight of part you eat. Before any food you eat gets into your blood, it digested (processed) into molecules such as galactose or glucose.  Only molecules make it in, not containers like "fruit" or vitamin pills.  

When I first looked into fructose over 23 years ago, drug companies were testing type2 diabetes (T2D) drugs on healthy rats they had turned into type2 diabetics.  This was done by replacing half a young rat’s chow with same fructose sold in health food stores as good for diabetics.  Thus fed, healthy rats became lethargic, obese, hypertensive, insulin resistant (metabolic syndrome) and developed many other chronic diseases.  The same happens with hamsters, guinea pigs, dogs, cats, etc.. You decide if it happens to some of our children. 

If you think kids today are responding like young rats, you might want to know the mechanisms that make dietary fructose a problem and what individuals like you can do.  Drug and food marketers and the organizations they fund knew even before 1990.  If they didn't tell you, I can help you catch up.

By 1990 the incidence of many chronic disease including T2D had already increase over 10 fold since 1900.  If the public for good reason stopped eating fructose it meant a 10 fold decrease in profits from treatments over time.  It meant a 10-fold increase in $profits and donations overtime if the public was not warned and kept eating fructose.  If this seems ridiculous see www.motherjones.com/environment/2012/10/sugar-industry-internal-documents-revealed     (and related articles) 

ASBESTOSIS is a name given a chronic inflammatory disease of the lungs described in 1924 and caused by asbestos molecules found in nature.  Governmental controls to protect humans from asbestos were started in 1932 just eight years after the initial finding that asbestos is highly adverse to humans when inhaled.  

FRUCTOSIS
 is an appropriate name for the adverse inflammation and cellular changes triggered by an abnormal presence of fructose molecules within cells due to hyperglycemia or eating fructose.

Pediatric Nonalcoholic Fatty Liver Disease (NAFLD) 
is a good example of fructosis.  NAFLD is a chronic inflammatory disease of the liver first described 1983 and caused by fructose molecules.
 After 30 years the government still offers no warning to parents or children about adverse effects of fructose.  NAFLD is currently the primary form of liver disease among children.  Unless fructose is removed from diet and hyperglycemia controlled, disease can progress to NASH (the second leading cause for liver transplantation).
 

Mechanism... I suspect that if there is no safe amount of alcohol, cigarette smoke or mercury, there may be no safe threshold for fructose in cells either.  How can this be? It is the alcohol metabolite acetaldehyde that is a carcinogen and triggers liver disease.  It is the fructose metabolite glyceraldehyde (GA) that is a carcinogen and triggers liver disease.  Both aldehydes cause advanced glycation end products (AGE).  Fructose derived AGE is called TAGE or Toxic AGE by researchers.  GA is most reactive sugar in humans and can react directly with functional and messenger proteins in cell where GA is formed causing cell dysfunction.  For example coronary artery disease is caused by dysfunction of the endothelial cells that line coronary arteries. Being a small 3 carbon molecule, allows GA to leave the  cell and react with most reactive protein in serum called lysine.  This forms the Toxic Advanced Glycation End product or TAGE that is recognized by our innate immune system as part of a bacteria. TAGE attaches to receptors (RAGE) on cells and sends inflammatory messages that trigger many common problems.  TAGE also abnormally increases VegF.  Abnormal VegF involved in over 50 chronic diseases.  All this is far more complex, but it does give one a realization of why our beloved fructose can cause so much havoc.  See www.FructoseFree.com for more details.
 

Dietary fructose was limited before 1900 and Diabetes incidence was about 1%.  Since then both type one and type two diabetes has increased many times over.  Recent studies from UCSF suggest a 20 grams of fructose per day increase in many countries increases incidence of diabetes 11 fold.  20 grams of fructose is amount in one 12oz. soda or two medium sized apples.  As fructose consumed increased so did the premature expression of many diseases, disabilities and rising health-care costs.  Most recognized are coronary artery disease, diabetes, liver disease, metabolic syndrome and obesity.
 
For professors honestly debating the health effects of fructose, there is a research article that reveals many of the complexities behind why dietary fructose and hyperglycemia are so adverse to humans.  It is very technical, but few things as important as this debate are easy... so be prepared to struggle.  It also explains how the dysfunction associated with diabetes is really due to metabolites of fructose.  It clearly states that both elevated postprandial hyperglycemia and dietary fructose cause the problems associated with diabetes.    To obtain copy directly from PubMed with diagrams go to  http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2905918/pdf/JOP2010-170393.pdf  

Fructose molecules can cause problems.
  Fructose is not an essential nutrient. Fructose however is required when a cell replicates.  Gut cells for example replicate every three days and endothelial cells every 5years.  Very little fructose is needed and it is provided JITD (just in time delivery).  No fructose is sitting around in a healthy (except sperm cells).  Cells of uncontrolled diabetics are loaded with fructose.  Yes it is metabolites of fructose that lead to all the cellular dysfunction suffered by advanced diabetics. Many cancer cells lack the sorbitol pathway needed to make fructose.  If one avoids dietary fructose and maintains a healthy blood glucose control many cancers have difficulty growing. 

  

OBESITY... From what I have observed and researched, obesity is not the problem.  It is just the most obvious effect of eating fructose or having hyperglycemia.  Hyperglycemia is adverse because it pushes sorbitol pathway producing fructose in cells. Metabolic syndrome is mainly caused by dietary fructose and intracellular fructose created by hyperglycemia.  High triglycerides in most cases are due to dietary fructose or hyperglycemia. Fructose is probably addicting to 10% of population and this is why the number of extremely obese will approach about 10% and like alcoholics be difficult to treat. . Unhealthy obesity is one of hundreds of conditions expressed when fructose is eaten or hyperglycemia is present.  Most extremely obese individuals and most NASH folks are addicted to fructose, just as most folks with alcohol cirrhosis are addicted to alcohol.  So in effect you are treating “Sugarholics”as explained by Jack Lalanne in the 1950s.  The magic pill is getting them off alcohol (fructose)… it isn’t easy when everyone else is guzzling it. See http://www.youtube.com/watch?v=LJVEPB_l8FU …Jack LaLanne. 

So how much fructose is safe?  The answer is just enough to make the new nuclear material needed when healthy cells replicate no more, no less.  To repeat, this is normally provided by sorbitol pathway in just the amount needed in the moment. Many cancer cells lack this ability and depend on dietary fructose or hyperglycemia to replicate. (A reason to avoid fructose and keep blood glucose normal if you have cancer)

 

In third world populations the incidence of diabetes is very low.  A 20.6 gram/day increase in dietary fructose over time raises diabetes prevalence 11-fold.  This fits well with 20 grams of alcohol being significant and that there probably is no safe lower limit for alcohol, fructose or cigarette smoke.      See…

http://www.huffingtonpost.com/robert-lustig-md/sugar-toxic_b_2759564.html

http://www.plosone.org/article/info%3Adoi%2F10.1371%2Fjournal.pone.0057873 This includes many good references.      

Quote from Lustig…“Bottom line -- only changes in sugar availability explained changes in diabetes prevalence worldwide; nothing else mattered.

Total caloric availability was unrelated to diabetes prevalence; for every extra 150 calories per day, diabetes prevalence rose by only 0.1 percent. But if those 150 calories per day (20.6 grams of fructose jw note) happened to be a can of soda (usually sucrose outside US, not HFCS note jw), diabetes prevalence rose 11-fold, by 1.1 percent (and Americans on average consume the added sugar equivalent of 2.5 cans of soda per day, so that's 2.75 percent!).  And this effect of sugar was exclusive of obesity; controlling for body mass index did not negate the effect. Even more important, we showed that the change in sugar availability preceded the change in diabetes (that's cause, not effect); and we showed directionality -- those countries where sugar availability rose showed increases in diabetes, while those where sugar availability fell showed decreases in diabetes. This is a very robust signal, with little noise. While epidemiology can't prove scientific causation, the data allow for objective inference. Sugar drives diabetes world-wide and unrelated to its calories.” End quote… Too bad the story is probably the same with many chronic diseases.  I know it is true with CAD, NASH, PCOS, metabolic syndrome and many others.

Until proven otherwise mothers may want to avoid what is becoming recognized as a toxin. Fructose like alcohol is proving to be adverse before conception, in the womb and as child grows. Pregnant mother, baby, child or students eating lots of what gram for gram may be worse than alcohol is a healthy diet tradition in USA. Unlike alcohol, students are not intoxicated after 12 ounces of apple juice so it seems alcohol must be worse than the sweet fruit sugar God provided. It doesn't seem possible that fruit sugar can be addicting and cause liver failure, cancer and death like alcohol! It is inconvenient I know, but fructose is addicting for many. Both alcohol and fructose are mainly detoxified in the liver.  Fructose is the leading cause of liver disease in USA, not alcohol, not infection. NASH (caused by unhealthy amount of fructose in cells) is second only to hepatitis C as a reason for liver transplantation. Liver disease is only one of many diseases that fructose started before one is born can increases 10 to 20 fold or more. 1½ shot (drinks) is 20 grams of alcohol molecules. One medium sized apple contains 10 grams of fructose molecules. A 12 oz soda contains 20 grams. 12 oz apple juice has 24 grams of fructose.

What is significance of only 20 grams of alcohol per day? The American Journal of Public Health concludes… (Daily consumption of up to 20 grams of alcohol (≤ 1.5 drinks) accounted for 26% to 35% of alcohol-attributable cancer deaths. Alcohol remains a major contributor to cancer mortality and Years per Life Lost. Higher consumption increases risk but there is no safe threshold for alcohol and cancer risk.) http://www.ncbi.nlm.nih.gov/pubmed/23409916 I suspect that if there is no safe amount of alcohol, there is also no safe threshold for fructose in cells either. It is the alcohol metabolite acetaldehyde that is a carcinogen and triggers liver disease. It is the fructose metabolite glyceraldehyde that is a carcinogen and triggers liver disease. Both aldehydes are toxic to functional proteins in cells where they are formed.  Both cause toxic advanced glycation end products (TAGE). 

Amazing

Would you help reduce chronic disease by 90% if you could?  We live in amazing times when it may be possible for young women who understand what I am saying to personally do something amazing in addition to having a baby.  Why not include reducing the probability their children will express a major mental illness, type one and two diabetes or other genetic disease predispositions including NASH and maybe cancer by 90% compared to USA norm.

https://www.youtube.com/watch?v=jj69eDFu-_A&feature=related Latest Lustig Video Part 1

https://www.youtube.com/watch?v=nac7Ydoj0Rg&feature=relmfu Part 2 Lustig

https://www.youtube.com/watch?v=kzdxeO6LKlc&feature=relmfu Part 3 Lustig

https://www.youtube.com/watch?v=Rj8uQUkhEAg&feature=relmfu  Questions Lustig

https://www.youtube.com/watch?v=QYmInK5xo6g 

 

What can be done?

Cesar Chavez 
Social injustice from working conditions to pesticides led Cesar Chavez to action.  Non-violet confrontations, boycotts and Gandhi-like fasts.  H
e studied the plague of pesticides and found it was a far greater problem than he had thought.  The solution came from actions of concerned individuals created by
Cesar’s personal suffering as he fasted 36 days.
 
We don't have to starve for 37 days.  We can now do wonders by not eating fructose and be able to explain why to others! 

Help folks to be aware of FRUCTOSIS and realize why they need to limit their cell fructose to only what is needed for cell replication by keeping their blood glucose normal (by diet and exercising effectively and if necessary medication). 
 

Make it easy to avoid fructose by encouraging marketers to provide fructose free options of favorite foods (this includes food labels with amount of fructose and warnings as for alcohol). 

If necessary boycott prepared and processed foods containing fructose until marketers feel it is profitable to provide fructose free options. 

Encourage informed folks to create and volunteer to staff effective ways to help folks addicted to fructose to get off fructose.
  

What has been done?  
Ancient cultures including native Californians were smart enough to realize acorns from oak trees would make a wonderful food similar to corn meal or flour, but only if they learned to process out the toxin (gallotannin).  Modern Americans are smart enough to realize fruit will make a wonderful food when the toxin (fructose) is removed.   Ancients solved their problem.  Can we solve ours?  Wiki… acorn 

Some folks feel eating meat for various reasons is not a good thing, so they stop eating meat.
Some folks eat only foods labeled "organic", others a void "processed" foods.


John E Weaver MD                    JohnWeaverMD@gmail.com

See www.FructoseFree.com  for more about avoiding dietary fructose, diabetes and preventable diseases.  It also has the exercises that I do and have found helpful for ages 5 to 100.

If you have time the following article and references many include the best explanations of the mechanisms involved in fructose triggering disease predispositions.  The references are many.

http://www.hindawi.com/journals/jop/2010/170393.html TAGE and RAGE


Involvement of TAGE-RAGE System in the Pathogenesis of Diabetic Retinopathy

Masayoshi Takeuchi,1 Jun-ichi Takino,1 and Sho-ichi Yamagishi2

1Department of Pathophysiological Science, Faculty of Pharmaceutical Sciences, Hokuriku University, Ho-3 Kanagawa-machi, Kanazawa 920-1181, Japan

2Department of Pathophysiology and Therapeutics of Diabetic Vascular Complications, Kurume University School of Medicine, 67 Asahimachi, Kurume 830-0011, Japan

Received 25 November 2009; Accepted 29 March 2010

Academic Editor: Susanne Mohr

Copyright © 2010 Masayoshi Takeuchi et al. This is an open access article distributed under the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

Abstract

Diabetic complications are a leading cause of acquired blindness, end-stage renal failure, and accelerated atherosclerosis, which are associated with the disabilities and high mortality rates seen in diabetic patients. Continuous hyperglycemia is involved in the pathogenesis of diabetic micro- and macrovascular complications via various metabolic pathways, and numerous hyperglycemia-induced metabolic and hemodynamic conditions exist, including increased generation of various types of advanced glycation end-products (AGEs). Recently, we demonstrated that glyceraldehyde-derived AGEs, the predominant structure of toxic AGEs (TAGE), play an important role in the pathogenesis of angiopathy in diabetic patients. Moreover, recent evidence suggests that the interaction of TAGE with the receptor for AGEs (RAGE) elicits oxidative stress generation in numerous types of cells, all of which may contribute to the pathological changes observed in diabetic complications. In this paper, we discuss the pathophysiological role of the TAGE-RAGE system in the development and progression of diabetic retinopathy.

1. Introduction

Diabetic complications are a leading cause of end-stage renal failure, acquired blindness, and cardiovascular disease (CVD) and are involved in the disabilities and high mortality rates observed in patients with type 1 or type 2 diabetes [1]. Although various hyperglycemia-induced metabolic and hemodynamic conditions are proposed to contribute to complications in diabetes [2, 3], recent clinical studies have suggested the concept of “hyperglycemic memory” in the pathogenesis of vascular injury in diabetes [46]. Indeed, the Diabetes Control and Complications Trial-Epidemiology of Diabetes Interventions and Complications (DCCT-EDIC) Study demonstrated that the reduction in the risk of progressive retinopathy and nephropathy brought about by intensive therapy in patients with type 1 diabetes persisted for at least eight years, despite increasing hyperglycemia [4, 5]. The intensive therapy administered during the DCCT resulted in decreased progression of intima media thickness (IMT) and had reduced the risk of nonfatal myocardial infarction, stroke, or death from CVD by 57% by 11 years after the end of the trial [6].

Furthermore, a recent follow-up study, the United Kingdom Prospective Diabetes Study (UKPDS), has also shown that the benefits of intensive therapy in patients with type 2 diabetes were sustained after the cessation of the trial [7]. In this study, despite the early loss of glycemic differences between intensive and conventional therapy, the reductions in microvascular risk and emergent risk reductions for myocardial infarction and death from any cause were maintained during 10 years of posttrial follow-up [7]. These observations indicate that intensive therapy to control blood glucose has long-term beneficial effects on the risk of diabetic retinopathy, nephropathy, CVD, and death in patients with type 1 or type 2 diabetes, strongly suggesting that so-called “metabolic memory” causes chronic damage in diabetic vessels that is not easily reversed, even by subsequent, relatively good control of blood glucose. Among the various pathways activated under diabetes, as described above, the biochemical nature of advanced glycation end-products (AGEs) and their mode of action are the most compatible with the theory of “hyperglycemic memory” [8, 9].

There is a growing body of evidence to suggest that continuous hyperglycemia under diabetic conditions enhances the formation of AGEs, senescent macroprotein derivatives, through nonenzymatic glycation (called the “Maillard reaction”). There is also accumulating evidence that the binding of the receptor for AGEs (RAGE) with AGEs elicits oxidative stress generation and subsequently evokes inflammatory and/or thrombogenic responses in various types of cells, thus participating in the development and progression of diabetic angiopathies [1018]. Recently, we demonstrated that glyceraldehyde-derived AGEs (Glycer-AGEs), the predominant structure of toxic AGEs (TAGE), play an important role in the pathogenesis of angiopathy in diabetic patients [10, 19, 20]. Furthermore, there is a growing body of evidence to suggest that the interaction of TAGE with the RAGE alters intracellular signaling, gene expression, and the release of pro-inflammatory molecules and elicits oxidative stress generation in numerous types of cells, all of which may contribute to the pathological changes seen in diabetic complications. Therefore, the inhibition of TAGE formation, blockade of TAGE-RAGE interactions, and the suppression of RAGE expression or its downstream pathways are promising targets for therapeutic intervention against diabetic complications.

In this paper, we discuss the pathophysiological role of the TAGE-RAGE-oxidative stress system in the development and progression of diabetic retinopathy and related therapeutic interventions.

2. Alternative Routes for the Formation of AGEs In Vivo

AGEs are formed by the Maillard process, a non-enzymatic reaction between aldehyde or ketone group of the reducing sugars (such as glucose, fructose, and trioses etc.) and the amino groups of proteins that contribute to the aging of proteins and to the pathological complications of diabetes [1013, 1924]. In the hyperglycemia elicited by diabetes, this process begins with the conversion of reversible Schiff base adducts to more stable, covalently bound Amadori rearrangement products. Over the course of days to weeks, these Amadori products undergo further rearrangement reactions to form irreversibly bound moieties known as AGEs. AGEs were originally characterized by their yellow-brown fluorescent color and their ability to form cross-links with and between amino groups, but the term is now used for a broad range of advanced products of the glycation process, including N-(carboxymethyl)lysine (CML) and pyrraline, which show neither color nor fluorescence and are not cross-linked proteins [8, 2125]. The formation of AGEs in vivo is dependent on the turnover of the chemically modified target, the time available, and the sugar concentration. The structures of the various cross-linked AGEs that are generated in vivo have not yet been completely determined. Due to their heterogeneity and the complexity of the chemical reactions involved, only some AGEs have been structurally characterized in vivo. The structural identities of AGEs with cytotoxic properties therefore remain unknown.

Recent studies have suggested that AGEs can arise not only from reducing sugars, but also from carbonyl compounds derived from the autoxidation of sugars and other metabolic pathways [2628]. Indeed, we have recently demonstrated that glucose,

-hydroxyaldehydes (glyceraldehyde and glycolaldehyde), and dicarbonyl compounds (methylglyoxal; MGO, glyoxal; GO, and 3-deoxyglucosone, 3-DG) are actively involved in the protein glycation process [21, 2931]. Six immunochemically distinct classes of AGEs (glucose-derived AGEs; Glc-AGEs, glyceraldehyde-derived AGEs; Glycer-AGEs, glycolaldehyde-derived AGEs; Glycol-AGEs, MGO-derived AGEs; MGO-AGEs, GO-derived AGEs; GO-AGEs, and 3-DG-derived AGEs; 3-DG-AGEs) are found in the sera of type 2 diabetic patients during hemodialysis [21, 2931]. Based on these data, we proposed a pathway for the in vivo formation of distinct AGEs involving the Maillard reaction, sugar autoxidation, and sugar metabolic pathways, as shown in Figure 1.

170393.fig.001

Figure 1: Alternative routes for the formation of various distinct AGEs in vivo. Glc-AGEs; glucose-derived AGEs, Glycer-AGEs; glyceraldehyde-derived AGEs, Glycol-AGEs; glycolaldehyde-derived AGEs, MGO-AGEs; methylglyoxal (MGO)-derived AGEs, GO-AGEs; glyoxal (GO)-derived AGEs, and 3-DG-AGEs, 3-deoxyglucosone (3-DG)-derived AGEs, CML; N-(carboxymethyl)lysine, and P-NH2; free amino residue of protein.

3. Receptors for AGEs

Such receptors may play a critical role in AGEs-related biology and the pathology associated with diabetic complications and aging disorders. Several types of AGEs binding proteins and/or receptors for AGEs such as RAGE [3236]; oligosaccharyl transferase-48 (AGE-R1) [37]; galectin-3 (AGE-R3) [38]; CD36 [39]; macrophage scavenger receptors types 1 and 2 (MSRs-1 & -2) [40]; and fasciclin EGF-like, laminin-type EGF-like, and link domain-containing scavenger receptors 1 and 2 (FEELs-1 & -2) [41] have been reported. The relative pathogenic contributions of these receptors to diabetic complications are poorly defined, although RAGE is by far the best characterized, and mechanistic in vitro and in vivo studies on AGEs and their regulatory fragments such as soluble RAGE (sRAGE) have indicated that they play important roles in pathobiology [36, 42]. RAGE is normally expressed in a variety of cells, including endothelial cells (EC), pericytes, neurons, and microglia, [3234]. We have recently found that glyceraldehyde rapidly reacts with the amino groups of proteins to form Glycer-AGEs both in vitro and in vivo [19, 21, 30]. Furthermore, Glycer-AGEs have the strongest binding affinity for RAGE and subsequently elicit oxidative stress generation and vascular inflammation and are therefore implicated in accelerated atherosclerosis in diabetes [43, 44]. Recently, we also demonstrated that Glycer-AGEs, the predominant structure of toxic AGEs (TAGE), play an important role in the pathogenesis of angiopathy in diabetic patients [19, 20]. Moreover, there is a growing body of evidence to suggest that the interaction of TAGE with RAGE elicits oxidative stress generation in numerous types of cells, all of which may contribute to the pathological changes observed in diabetic complications [10, 19, 20].

4. Pathway of Glycer-AGEs (TAGE) Formation In Vivo

Glyceraldehyde is derived from two distinct pathways in vivo, (1) the glycolytic pathway and (2) the fructose metabolism pathway [19, 20, 45]. (1) The glycolytic intermediate glyceraldehyde-3-phosphate (G-3-P) is normally catabolized by the enzyme glyceraldehyde-3-phosphate dehydrogenase (GAPDH). With a decline in GAPDH activity, G-3-P accumulates intracellularly. G-3-P metabolism then shifts to another route, and the amount of glyceraldehyde is increased, which leads to an increase in the formation of TAGE. This suggests a positive feedback mechanism; that is, the TAGE-induced GAPDH suppression further stimulates the generation of TAGE. (2) Under hyperglycemic conditions, the increased intracellular glucose concentration stimulates the polyol pathway to generate fructose in insulin-independent tissues such as the lens, kidney, nerve tissue, brain, and red blood cells [4648]. Furthermore, fructose, a component of table sugar and high-fructose corn syrup, is also obtained from the diet [49]. Fructose is phosphorylated to fructose-1-phosphate (F-1-P) and then catabolized to glyceraldehyde and dihydroxyacetone-phosphate by aldolase B [4851]. The newly synthesized glyceraldehyde is then transported or leaks passively across the plasma membrane. Glyceraldehyde promotes the formaion of TAGE both intracellularly and extracellularly (Figure 2).

170393.fig.002

Figure 2: Production routes of glyceraldehyde-derived AGEs (Glycer-AGEs) in vivo. TAGE; toxic AGEs (glyceraldehyde-derived AGEs), RAGE; receptor for AGEs, ROS; reactive oxygen species, HFCS; high-fructose corn syrup, AR; aldose reductase, SDH; sorbitol dehydrogenase, FK; fructokinase, GAPDH; glyceraldehyde-3-phosphate dehydrogenase, *; TAGE.

5. Diabetic Retinopathy

Diabetic retinopathy is one of the most important microvascular complications in diabetes and is a leading cause of acquired blindness among people of occupational age [52]. Hyperglycemia damages retinal microvascular cells and causes various changes in retinal tissues such as enhanced vascular permeability due to pericyte loss, which is followed by microvascular occlusion in the retina [53, 54]. Pericytes are elongated cells of mesodermal origin, which wrap around and along the EC of small vessels [55]. As pericytes contain contractile muscle filaments on their EC side, they are regarded as microvascular counterparts of smooth muscle cells and are considered to be involved in the maintenance of capillary tone [56, 57]. AGEs have been postulated to play a role in the development and progression of microvascular disease in diabetes. Vascular endothelial growth factor (VEGF) is a specific mitogen to EC, which is also known as vascular permeability factor and is generally thought to be involved in the pathogenesis of proliferative diabetic retinopathy. Indeed, clinical observations have demonstrated that the VEGF level in ocular fluid is positively correlated with the amount of neovascularization in diabetic retinopathy [58, 59].

Retinal pericytes accumulate AGEs during diabetes [60], which is expected to have a detrimental influence on pericyte survival and function [61]. We have found that TAGE causes the apoptosis of retinal pericytes and induces the expression of VEGF by interacting with RAGE, indicating the involvement of TAGE in the pathogenesis of diabetic retinopathy, especially in the early stage [6264]. TAGE also induces VEGF expression, DNA synthesis, and angiogenesis in EC. These changes are the hallmark of proliferative diabetic retinopathy [65, 66]. These findings suggest that the TAGE-RAGE interaction facilitates angiogenesis by two distinct mechanisms, by relieving the restriction on EC growth due to the apoptotic cell death of pericytes and by autocrine and paracrine induction of VEGF proteins by vascular wall cells. Although the molecular mechanisms of the VEGF overexpression elicited by TAGE are not fully understood, our recent investigation suggested that the TAGE-RAGE interaction increases VEGF gene transcription in EC by NADPH oxidase-mediated reactive oxygen species (ROS) generation and the subsequent activation of nuclear factor

B (NF-

B) via the Ras-mitogen activated protein kinase pathway [65, 66]. There has been increasing interest in the role of inflammatory reaction in diabetic retinopathy [67]. AGEs have recently been shown to increase leukocyte adhesion to cultured retinal microvascular EC by inducing intracellular cell adhesion molecule-1 (ICAM-1) expression [68]. Furthermore, TAGE also induces monocyte chemoattractant protein-1 (MCP-1) expression in EC through intracellular ROS generation [69].

6. Postprandial Hyperglycemia is Associated with Increased Risk of Diabetic Retinopathy

While it is well known that postchallenge and postprandial hyperglycemia are related to the development and progression of diabetic macrovascular disease [70, 71], there are limited data on the relationship between postprandial hyperglycemia and microvascular complications. A recent observational prospective study from Japan demonstrated that postprandial hyperglycemia is a better predictor of diabetic retinopathy that glycated hemoglobin A1c (HbA1c) [72]. Shiraiwa et al. performed a cross-sectional study of 232 people with type 2 diabetes who were not being treated with insulin injections. Multiple regression analysis revealed that postprandial hyperglycemia was independently correlated with the incidence of diabetic retinopathy and neuropathy. Additionally, postprandial hyperglycemia was also found to be associated, although not independently, with the incidence of diabetic nephropathy.

We have previously shown that glyceraldehyde reacts rapidly with the amino groups of proteins to form TAGE in vivo, which evokes vascular inflammation and oxidative stress generation, thereby implicating them in accelerated atherosclerosis in diabetes [10, 19, 20]. More recently, we investigated the effects of nateglinide, which has been known to improve postprandial hyperglycemia, on HbA1c, Glc-AGE, and TAGE levels in Goto-Kakizaki (GK) rats, one of the rat models of type 2 diabetes, fed twice a day [73]. After 6 weeks, nateglinide treatment was found to not only prevent postprandial hyperglycemia, but also to reduce TAGE levels in GK rats. However, it did not cause a significant difference in HbA1c or Glc-AGE levels [73]. This study suggests that TAGE is formed more rapidly than HbA1c, a precursor of Glc-AGEs, under postprandial hyperglycemic states and shows potential as novel markers of cumulative postprandial hyperglycemia. In this study, although we did not clarify the exact molecular mechanism by which TAGE is formed under postprandial hyperglycemic conditions, hyperglycemia-induced oxidative stress-mediated inhibition of GAPDH may lead to the elevation of glyceraldehyde levels and subsequently enhance the formation of TAGE during the postprandial period [74]. The relative contribution of postprandial glucose decreased progressively from the lowest to the highest quintile of HbA1c; whereas, the relative contribution of fasting glucose increased gradually with increasing levels of HbA1c [75]. These observations suggest that a decrease in HbA1c levels does not necessarily reflect a reduction in postprandial hyperglycemia, especially in poorly controlled diabetic patients.

7. Serum Levels of TAGE in Diabetes

The above-discussed effect of TAGE strongly suggests a pathological role for these senescent macroproteins in diabetic complications. Furthermore, Glc-AGEs and TAGE are present in human serum, and the level of both AGEs is elevated in type 1 and type 2 diabetes [7679]. These AGEs, especially TAGE-epitopes, elicit angiogenesis at the concentrations present in the sera of diabetic patients. These results suggest the involvement of TAGE-epitopes in pathologic angiogenesis in vivo. Recently, we demonstrated that the vitreous levels of both TAGE and VEGF were significantly higher in diabetic patients than in control subjects and that these levels were elevated in association with the severity of neovascularization in diabetic retinopathy. In addition, there was a significant correlation between vitreous TAGE and VEGF levels [80, 81]. Furthermore, we have recently found that serum TAGE levels are positively correlated with thrombogenic markers in humans. Plasminogen activator inhibitor-1 and fibrinogen levels are positively associated with serum TAGE levels [82].

While many of the reported studies measured a range of ill-defined AGEs moieties, others evaluated defined adducts such as CML, pentosidine, and crossline in association with diabetic retinopathy [83, 84]. In addition, other studies have reported no correlation between AGE levels and retinopathy in diabetic patients [83, 85], although the apparent disparity between the findings of various studies may be related to variations in patient populations and/or the nonuniform assays used for plasma AGEs-quantification. Our studies suggest that an elevated TAGE level in diabetic patients is an important factor for the initiation and progression of retinopathy. Therefore, the inhibition of TAGE formation and the blockade of TAGE-RAGE interactions are potential therapeutic strategies for the prevention of diabetic retinopathy.

8. Serum Levels of Soluble RAGE in Diabetes

The administration of a recombinant soluble form of RAGE (sRAGE) consisting of its extracellular ligand-binding domain has recently been shown to not only suppress the development of atherosclerosis but also to stabilize established atherosclerosis in diabetic apolipoprotein E-null mice [86, 87]. The blockade of the AGEs-RAGE axis by the administration of sRAGE also ameliorates neuronal dysfunction and reduces the development of acellular capillaries and pericyte ghosts in hyperglycemic and hyperlipidemic mice [88]. Furthermore, Kaji et al. have also shown that attenuation of the RAGE axis with sRAGE inhibits retinal leukostasis and blood-retinal barrier breakdown in diabetic C57/BJ6 and RAGE-transgenic mice, which are accompanied by decreased expression of VEGF and ICAM-1 in the retina [89]. These observations suggest that exogenously administered sRAGE captures and eliminates circulating AGEs, thus protecting against AGEs-elicited tissue damage by acting as a decoy.

Recently, endogenous sRAGE has been identified in humans [42]. Endogenous sRAGE may be generated from the cleavage of cell surface full-length RAGE or novel splice variants of RAGE (the C-truncated splice isoform of secretory RAGE; esRAGE) [42]. Endogenous total sRAGE levels are elevated in patients with type 1 or 2 diabetes [9093]. Furthermore, we, along with others, have recently demonstrated that serum total sRAGE levels are positively, rather than inversely, associated with TAGE levels in both nondiabetic and diabetic subjects [93, 94]. Age-, sex-, and body mass index-adjusted TAGE levels are also significantly increased in proportion to the increasing levels of sRAGE in nondiabetic subjects [93, 94]. These findings suggest that the sRAGE pool is not able to efficiently capture and eliminate circulating TAGE in vivo by working as a decoy receptor. Since TAGE is a positive regulator of the cell expression of RAGE, circulating sRAGE levels may reflect tissue RAGE expression and be elevated in parallel with serum TAGE levels as a counter system against TAGE-elicited tissue damage [9598].

The serum levels of esRAGE are also correlated with the levels of circulating AGEs such as CML and pentosidine in type 1 diabetes [99]. However, in contrast to the case for total sRAGE, circulating esRAGE levels are decreased, rather than increased, in both type 1 and 2 diabetes. Katakami et al. reported in Japanese that the serum levels of esRAGE were significantly decreased in patients with type 1 diabetes compared with nondiabetic subjects [100], and esRAGE levels were found to be significantly lower in type 1 diabetic patients with retinopathy than in those without retinopathy [100, 101]. Decreased esRAGE levels were also found to be an independent risk factor for carotid atherosclerosis [102]. Indeed, Koyama et al. reported that esRAGE levels were decreased in Japanese type 2 diabetic patients compared with nondiabetic subjects and that low levels of esRAGE were associated with the components of metabolic syndrome and carotid atherosclerosis [102]. These observations were contrary to the finding of previous reports that total sRAGE levels were associated with conventional coronary risk factors including inflammatory markers and were independent determinants of coronary artery disease in diabetes [91, 95, 96]. Therefore, the kinetics and role of sRAGE and esRAGE in diabetes may differ [97]. Decreased levels of esRAGE may be associated with comorbidities such as diabetic retinopathy and atherosclerosis via mechanisms other than its role as a decoy because esRAGE levels are approximately 3

4-fold lower than total sRAGE levels and may not be sufficient to efficiently eliminate circulating AGEs in humans. Furthermore, sRAGE, but not esRAGE, was recently found to be independently correlated with albuminuria in type 2 diabetic patients [103].

9. Agents That Could Potentially Suppress TAGE-RAGE Interaction

9.1. Inhibitors of the Renin-Angiotensin System (RAS)

The interaction of the RAS and TAGE-RAGE systems has also been proposed. We have found that angiotensin II potentiates the deleterious effects of TAGE in pericytes by inducing RAGE protein expression [64]. In vivo, TAGE-injection stimulated RAGE expression in the eyes of spontaneously hypertensive rats, which was blocked by telmisartan. In vitro, angiotensin II-type 1 receptor-mediated ROS generation elicited RAGE gene expression in retinal pericytes through NF-

B activation. Furthermore, angiotensin II augmented TAGE-induced pericyte apoptosis, the earliest hallmark of diabetic retinopathy. Telmisartan also blocks angiotensin II-induced RAGE expression in EC [104].

There is an increasing interest in the role of inflammatory reactions and immune phenomena in the pathogenesis of diabetic complications [105107]. Indeed, leukocyte adhesion to diabetic retinal vasculature is considered to be a critical early event in diabetic retinopathy, the development of which is mainly mediated by VEGF, ICAM-1, and MCP-1 expression [105107]. ICAM-1 and MCP-1 are essential chemokines that mediate the recruitment of leukocytes to mesangial lesions [108, 109]. The selective targeting of ICAM-1 or MCP-1 was also shown to markedly decrease albuminuria and renal injury in experimental diabetic nephropathy [108, 109]. Furthermore, several experimental studies have supported the pathological role of VEGF in diabetic nephropathy: antibodies raised against VEGF have been reported to improve hyperfiltration and albuminuria in diabetic rats [110, 111]. In addition, atherosclerosis is also an inflammatory-proliferative disease [112], and the administration of VEGF is reported to enhance atherosclerotic plaque progression in animals [113]. We have recently found that treatment with telmisartan or olmesartan inhibits the TAGE-evoked inflammatory responses in EC via downregulation of RAGE expression [114118]. These observations suggest that the blockade of the TAGE-RAGE signaling pathways by RAS inhibitors may be clinically relevant to the prevention of diabetic complications.

9.2. Pigment-Epithelium-Derived Factor (PEDF)

PEDF is a glycoprotein that belongs to a superfamily of serine protease inhibitors with complex neurotrophic, neuroprotective, antiangiogenic, antioxidative, and anti-inflammatory properties, any of which could potentially be exploited as a therapeutic option for the treatment of vascular complications in diabetes [119, 120]. PEDF inhibits TAGE-induced ROS generation and subsequently prevents apoptotic cell death in pericytes by restoring downregulation of the gene expression of the antiapoptotic factor bcl-2 [121]. Furthermore, PEDF also inhibits TAGE-induced ICAM-1, VEGF, and MCP-1 upregulation as well as NO suppression in EC by blocking NADPH oxidase-mediated ROS generation [69, 122126]. In vivo, the administration of PEDF or pyridoxal phosphate, an AGEs inhibitor, decreased the retinal levels of 8-hydroxydeoxyguanosine (8-OHdG), an oxidative stress marker, and subsequently suppressed ICAM-1 gene expression and retinal leukostasis in diabetic rats [127]. Moreover, intravenous administration of TAGE to normal rats increased ICAM-1 gene expression and retinal leukostasis, which were blocked by PEDF [127]. PEDF inhibited diabetes- or TAGE-induced RAGE gene expression by blocking superoxide-mediated NF-

B activation [128]. In addition, we have recently found that intravenous administration of TAGE to normal rats not only increases retinal vascular permeability by stimulating VEGF expression, but also decreases retinal PEDF levels [129]. Simultaneous treatment with PEDF inhibited TAGE-elicited VEGF-mediated permeability by downregulating the mRNA levels of

and

, membrane components of NADPH oxidase, and subsequently decreasing retinal levels of the oxidative stress marker, 8-OHdG. PEDF also inhibited TAGE-induced vascular hyperpermeability (as measured by transendothelial electrical resistance) by suppressing VEGF expression. PEDF decreased ROS generation in TAGE-exposed EC by suppressing NADPH oxidase activity via downregulation of the mRNA levels of

and

. This led to blockade of TAGE-elicited Ras activation and NF-

B-dependent VEGF gene induction in EC. These results indicate that the central mechanism of PEDF inhibition of the TAGE-signaling related to vascular permeability is the suppression of NADPH oxidase-mediated ROS generation and subsequent VEGF expression [129].

The PEDF levels in the aqueous humor and vitreous are decreased in diabetic patients, especially in those with proliferative retinopathy, suggesting that loss of PEDF in the eye contributes to the pathogenesis of proliferative diabetic retinopathy [130, 131]. We have also found that the vitreous levels of TAGE and VEGF are significantly higher in diabetic patients than in control subjects [81] and detected a significant correlation between vitreous TAGE and VEGF levels. Total antioxidant status was also decreased in the vitreous in patients with diabetes compared with that in the controls. Furthermore, both the TAGE and VEGF levels (inversely) and those of PEDF (positively) were associated with the total antioxidant status of the vitreous [132, 133]. These observations further support the concept that PEDF is an endogenous anti-inflammatory and antioxidative agent that blocks the TAGE-VEGF axis, thereby protecting against the progression of diabetic retinopathy.

9.3. Statins and Bisphosphonates

We have found that protein prenylation is crucial for TAGE-RAGE signaling in EC [65, 66]. Cerivastain completely prevented TAGE-induced increases in NF-

B activity and VEGF expression and the resultant increase in DNA synthesis as well as tube formation in microvascular EC [65]. Since mevalonate blocked the growth-inhibitory effects of cerivastatin on TAGE-exposed EC and that FTI-276, an inhibitor of farnesyltransferase, mimicked the effects of cerivastatin, cerivastatin may block the TAGE-RAGE signaling involved in vascular hyperpermeability and angiogenesis via the suppression of protein prenylation. Furthermore, we have recently found that atorvastatin dose-dependently inhibited TAGE-induced ROS generation in Hep3B cells [134]. Atorvastatin as well as the antioxidant N-acetylcysteine (NAC) was found to suppress C-reactive protein (CRP) expression in TAGE-exposed Hep3B cells at both the mRNA and protein levels [134]. These results demonstrate that atorvastatin is able to block the TAGE-signaling involved in CRP expression through its antioxidative action. Taken together, these observations suggest that statins have vasculoprotective effects by inhibiting the deleterious effects of TAGE via the suppression of their downstream signaling.

Bisphosphonates are potent inhibitors of bone resorption and are widely used for the treatment of osteoporosis, osteolytic bone metastasis, and tumor-associated hypercalcemia [135137]. These compounds have a high affinity for calcium ions and therefore target bone mineral, where they are internalized by bone-resorbing osteoclasts and inhibit osteoclast function. Recently, farnesyl pyrophosphate synthase has been shown to be a molecular target of nitrogen-containing bisphosphonates such as incardronate disodium and minodronate, and the inhibition of the posttranslational prenylation of small molecular weight G proteins including Ras and Rac-1 is probably involved in their antiresorptive activity in osteoclasts [135137]. Since the protein prenylation of GTP-binding proteins is associated with various cellular functions such as cell growth and differentiation [135137], nitrogen-containing bisphosphonates may have pleitrophic effects by blocking the synthesis of isoprenoid intermediates. Indeed, incardronate disodium was found to inhibit TAGE-induced increases in NF-

B activity and VEGF expression as well as the proliferation and tube formation of EC [66]. Furthermore, we have recently found that minodronate inhibits TAGE–induced NF-

B activation and subsequently suppresses VCAM-1 gene expression by reducing ROS generation in EC [135]. Geranylgeranyl pyrophosphate reversed the antioxidative properties of minodronate in TAGE-exposed EC [135]. Taken together, these findings suggest that nitrogen-containing bisphosphonates are able to inhibit TAGE-elicited inflammatory-proliferative changes in EC by suppressing NADPH oxidase-derived ROS generation, probably via the inhibition of the geranylgeranylation of Rac-1, a component of endothelial NADPH oxidase [136, 137].

10. Conclusion

There is accumulating evidence that the TAGE-RAGE-oxidative stress system is actively involved in the pathogenesis of diabetic complications, especially diabetic retinopathy. We have reviewed the inhibitors of the TAGE-RAGE axis and their potential therapeutic implications in these devastating disorders.

Expert Opinion

 

Two recent large prospective clinical studies, DCCT and UKPDS, have shown that intensive blood glucose control effectively reduces the incidence of vascular complications among patients with diabetes [138, 139]. However, strict control of hyperglycemia is often very difficult to maintain and may increase the risk of severe hypoglycemia in diabetic patients. Inhibition of TAGE formation, blockade of TAGE-RAGE interactions, and the suppression of RAGE expression or its downstream pathways by the agents discussed here are promising novel therapeutic strategies for the treatment of patients with diabetic retinopathy. Further clinical studies are needed to clarify whether the use of these agents is able to reduce the risk of diabetic retinopathy beyond blood glucose-, blood pressure- or cholesterol-lowering effects.

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