Diabetic Neuropathy - Pathology

Advanced Glycation End products (AGEs) - updated: 15 March 2008

Advanced Glycation Endproducts (AGEs) are the result of a chain of chemical reactions after an initial glycation reaction. The intermediate products are known, variously, as Amadori, Schiff base and Maillard products, named after the researchers who first described them. The literature is imprecise in usages of these terms. For example, Maillard reaction products are sometimes considered an intermediate step and other times as AGEs. Side products generated in the intermediate steps may be oxidizing agents such as hydrogen peroxide, and others, such as beta amyloid proteins. Glycosylation is also sometimes used as a synonym for glycation in the literature, but is then usually referred to as 'non-enzymatic glycosylation.'.

In the pathogenesis of diabetes-related AGE formation, hyperglycemia results in higher cellular glucose levels in those cells unable to reduce glucose intake (e.g. endothelial cells). This in turn results in increased levels of NADH and FADH, increasing the proton gradient beyond a particular threshold at which the complex III prevents further increase by stopping the electron transport chain.[citation needed] This results in mitochondrial production of reactive oxygen species, activating PARP1 by damaging DNA. PARP1 in turn, ADP-ribosylates GAPDH, a protein involved in glucose metabolism, leading to its inactivation and an accumulation of metabolites earlier in the metabolism pathway. These metabolites activate multiple pathogenic mechanisms, one of which includes increased production of AGEs.

AGEs may be less, or more, reactive than the initial sugars they were formed from. Foods may be up to 200 times more immunoreactive after cooking. Many cells in the body (for example endothelial cells, smooth muscle or cells of the immune system) from tissue such as lung, liver, kidney or peripheral blood bear the Receptor for Advanced Glycation Endproducts (RAGE) that, when binding AGEs, contributes to age- and diabetes-related chronic inflammatory diseases such as atherosclerosis, asthma, arthritis, myocardial infarction, nephropathy, retinopathy or neuropathy. There may be some chemicals, such as aminoguanidine, that limit the formation of AGEs.

The total state of oxidative and peroxidative stress on the healthy body, and the accumulation of AGE-related damage is proportional to the dietary intake of exogenous (preformed) AGEs, the consumption of sugars with a propensity towards glycation such as fructose and galactose. AGEs affect nearly every type of cell and molecule in the body, are thought to be major factors in aging and age related chronic diseases. They are also believed to play a causative role in the vascular complications of diabetes mellitus.

They have a range of pathological effects, including increasing vascular permeability, inhibition of vascular dilation by interfering with nitric oxide, oxdising LDL,binding cells including macrophage, endothelial and mesangial cells to induce the secretion of a variety of cytokines and enhancing oxidative stress

Source: Wikipedia

The diabetic neuropathies

Neurologist. 2004 Nov;10(6):311-22

Gooch C, Podwall D.

BACKGROUND: Diabetes remains the most common cause of neuropathy in the United States and is a significant source of morbidity and mortality, accounting for substantial suffering and billions of dollars in health care expenditures each year. REVIEW SUMMARY: Our insight into the pathophysiology of the diabetic neuropathies has increased considerably over the last decade. aided by advances in the basic science of diabetes itself. A wide variety of potential mechanisms for nerve injury in diabetes has been identified, including the polyol pathway of glucose metabolism, oxidative nerve injury, the deposition of advanced glycosylation end products within the nerve and the effects of vascular insufficiency, among others. Diabetic neuropathy may take a variety of clinical forms beyond the well-known distal symmetric neuropathy, many of which are often misdiagnosed or overlooked entirely, sometimes with serious consequences for the patient. Proper therapy after diagnosis is also critical and may include not only primary management, but also treatment of painful diabetic neuropathy through an expanding repertoire of increasingly effective pharmacologic agents. Though primary treatment trials have not yet provided effective therapies, ongoing and future trials offer continuing promise. CONCLUSIONS: The diabetic neuropathies are exceedingly common, but often improperly diagnosed and incompletely treated. A proper understanding of the mechanisms underlying these diseases and the clinical recognition of their various forms is highly important as appropriate primary and symptomatic management can substantially reduce the morbidity and mortality associated with these disorders.

Publication Types:

• Review

Advanced glycation end-products and the progress of diabetic vascular complications

Physiol Res. 2004;53(2):131-42

Jakus V, Rietbrock N.

Epidemiological studies have confirmed that hyperglycemia is the most important factor in the onset and progress of vascular complications, both in Type 1 and 2 diabetes mellitus. The formation of advanced glycation end-products (AGEs) correlates with glycemic control. The AGE hypothesis proposes that accelerated chemical modification of proteins by glucose during hyperglycemia contributes to the pathogenesis of diabetic complications including nephropathy, retinopathy, neuropathy and atherosclerosis. Recent studies have shown that increased formation of serum AGEs exists in diabetic children and adolescents with or without vascular complications. Furthermore, the presence of diabetic complications in children correlates with elevated serum AGEs. The level of serum AGEs could be considered as a marker of later developments of vascular complications in children with Type 1 and 2 diabetes mellitus. The careful metabolic monitoring of young diabetics together with monitoring of serum AGEs can provide useful information about impending AGE-related diabetic complications. It is becoming clear that anti-AGE strategies may play an important role in the treatment of young and older diabetic patients. Several potential drug candidates such as AGE inhibitors have been reported recently

Publication Types:

• Review

Orally absorbed reactive glycation products (glycotoxins): An environmental risk factor in diabetic nephropathy

Proc. Natl. Acad. Sci. USA Vol. 94, pp. 6474-6479, June 1997

Theodore Koschinsky, Ci-Jiang He, Richard Bucala, Christina Buenting, Kirsten Heitmann, and Helen Vlassara

Endogenous advanced glycation endproducts (AGEs) include chemically crosslinking species (glycotoxins) that contribute to the vascular and renal complications of diabetes mellitus (DM). Renal excretion of the catabolic products of endogenous AGEs is impaired in patients with diabetic or nondiabetic kidney disease (KD). The aim of this study was to examine the oral absorption and renal clearance kinetics of food AGEs in DM with KD and whether circulating diet-derived AGEs contain active glycotoxins. Thirty-eight diabetics (DM) with or without KD and five healthy subjects (NL) received a single meal of egg white (56 g protein), cooked with (AGE-diet) or without fructose (100 g) (CL-diet). Serum and urine samples, collected for 48 hr, were monitored for AGE immunoreactivity by ELISA and for AGE-specific crosslinking reactivity, based on complex formation with 125I-labeled fibronectin. The AGE-diet, but not the CL-diet, produced distinct elevations in serum AGE levels in direct proportion to amount ingested (r = 0.8, P < 0.05): the area under the curve for serum (approx. 30% of amount absorbed), in DM it correlated inversely with degree of albuminuria, and directly with creatinine clearance (r = 0.8, P < 0.05), reduced to <5% in DM with renal failure. Post-AGE-meal serum exhibited increased AGE-crosslinking activity (two times above baseline serum AGE, three times above negative control), which was inhibited by aminoguanidine. In conclusion, (i) the renal excretion of orally absorbed AGEs is markedly suppressed in diabetic nephropathy patients, (ii) daily influx of dietary AGEs includes glycotoxins that may constitute an added chronic risk for renal-vascular injury in DM, and (iii) dietary restriction of AGE food intake may greatly reduce the burden of AGEs in diabetic patients and possibly improve prognosis.

The Pathobiology of Diabetic Complications

Diabetes 54:1615-1625, 2005

Michael Brownlee

It’s a great honor to join the exceptional club of Banting Award winners, many of whom were my role models and mentors. In addition, giving the Banting Lecture also has a very personal meaning to me, because without Frederick Banting, I would have died from type 1 diabetes when I was 8 years old. However, it was already apparent at the time I was diagnosed that for too many people like me, Banting’s discovery of insulin only allowed them to live just long enough to develop blindness, renal failure, and coronary disease. For example, when I started college, the American Diabetes Association’s Diabetes Textbook had this to say to my parents: "The person with type 1 diabetes can be reassured that it is highly likely that he will live at least into his 30s." Not surprisingly, my parents did not find this particularly reassuring. At the same time we were reading this in 1967, however, the first basic research discovery about the pathobiology of diabetic complications had just been published in Science the previous year. In my Banting Lecture today, I am thus going to tell you a scientific story that is also profoundly personal. I’ve divided my talk into three parts. The first part is called "pieces of the puzzle," and in it I describe what was learned about the pathobiology of diabetic complications starting with that 1966 Science paper and continuing through the end of the 1990s. In the second part, I present a unified mechanism that links together all of the seemingly unconnected pieces of the puzzle. Finally, in the third part, I focus on three examples of novel therapeutic approaches for the prevention and treatment of diabetic complications, which are all based on the new paradigm of a unifying mechanism for the pathogenesis of diabetic complications.

Advanced glycation end products and diabetic complications

Expert Opin Investig Drugs. 2002 Sep;11(9):1205-23

Stitt AW, Jenkins AJ, Cooper ME.

Diabetic complications are major cause of morbidity and mortality in patients with diabetes. While the precise pathogenic mechanism(s) underlying conditions such as diabetic retinopathy, diabetic nephropathy and increased risk of atherosclerosis remain ill-defined, it is clear that hyperglycaemia is a primary factor that initiates and promotes complications. Formation of advanced glycation end products (AGEs) correlate with glycaemic control, and these reactive adducts form on DNA, lipids and proteins where they represent pathophysiological modifications that precipitate dysfunction at a cellular and molecular level. Many of these adducts form rapidly during diabetes and promote progression of a raft of diabetes-related complications. Recent evidence also suggests an important interaction with other pathogenic mechanisms activated within the diabetic milieu. This review outlines the nature of AGE formation in biological systems and highlights accumulative evidence that implicates these adducts in diabetic complications. As more therapeutic agents are developed to inhibit AGE formation or limit their pathogenic influence during chronic diabetes, it is becoming clear that these anti-AGE strategies have an important role to play in the treatment of diabetic patients.

Publication Types:

• Review

TAGE (toxic AGEs) theory in diabetic complications

Curr Mol Med. 2006 May;6(3):351-8

Sato T, Iwaki M, Shimogaito N, Wu X, Yamagishi S, Takeuchi M.

Diabetic complication is a leading cause of acquired blindness, end-stage renal failure, a variety of neuropathies and accelerated atherosclerosis. Chronic hyperglycemia is initially involved in the pathogenesis of diabetic micro- and macro-vascular complications via various metabolic derangements. High glucose increased production of various types of advanced glycation end-products (AGEs). Recently, we found that glyceraldehyde-derived AGEs (AGE-2) play an important role in the pathogenesis of angiopathy in diabetic patients. There is considerable interest in receptor for AGEs (RAGE) found on many cell types, particularly those affected in diabetes. Recent studies suggest that interaction of AGE-2 (predominantly structure of toxic AGEs; TAGE) with RAGE alters intracellular signaling, gene expression, release of pro-inflamatory molecules and production of reactive oxygen species (ROS) that contribute towards the pathology of diabetic complications. We propose three pathways for the in vivo formation of AGE-2 precursor, glyceraldehyde, such as i) glycolytic pathway, ii) polyol pathway, and iii) fructose metabolic pathway. Glyceraldehyde can be transported or can leak passively across the plasma membrane. It can react non-enzymatically with proteins to lead to accelerated formation of TAGE at both intracellularly and extracellularly. In this review, we discuss the molecular mechanisms of diabetic complications, especially focusing on toxic AGEs (TAGE) and their receptor (RAGE) system.

Publication Types:

• Review

Role of advanced glycation end products and their receptors in development of diabetic neuropathy

Ann N Y Acad Sci. 2005 Jun;1043:598-604

Wada R, Yagihashi S.

Diabetic neuropathy is a life-threatening complication involving both peripheral and autonomic nerves. The hyperglycemia-induced polyol pathway as well as enhanced oxidative stress are among the factors implicated in the pathogenesis of diabetic neuropathy. Their effects are possibly exerted by direct nerve tissue damage or mediated by endothelial injury or vascular dysfunction. Formation of advanced glycation end product (AGE) is another important candidate for the cause of peripheral neuropathy. Indeed, the levels of AGEs were increased in the serum and also in the peripheral nerves obtained from diabetic patients. Structural and functional proteins of those nerves are also glycated, resulting in impaired nerve function and characteristic pathologic alterations. In addition, interaction between AGEs and their receptors induce biological effects on the target tissues for diabetic complications. In the peripheral nerve, the receptor for AGE (RAGE) is expressed in endothelial and Schwann cells. It is thus anticipated that interactions between AGEs and RAGE facilitate endoneural vascular dysfunction, leading to microangiopathy in the peripheral nerve. The roles of these mechanisms, in particular on the molecular mechanisms of AGE-RAGE interactions in the development of diabetic neuropathy are largely still speculative and yet to be explored.

Publication Types:

• Review

Glycation in diabetic neuropathy: characteristics, consequences, causes, and therapeutic options

Int Rev Neurobiol. 2002;50:37-57

Thornalley PJ.

Glycation is the nonenzymatic reaction of glucose, alpha-oxoaldehydes, and other saccharide derivatives with proteins, nucleotides, and lipids. Early glycation adducts (fructosamines) and advanced glycation adducts (AGEs) are formed. "Glycoxidation" is a term used for glycation processes involving oxidation. Sural, peroneal, and saphenous nerves of human diabetic subjects contained AGEs in the perineurium, endothelial cells, and pericytes of endoneurial microvessels and in myelinated and unmyelinated fibres localized to irregular aggregates in the cytoplasm and interstitial collagen and basement membranes. Pentosidine content was increased in cytoskeletal and myelin protein extracts of the sural nerve of human subjects and cytoskeletal proteins of the sciatic nerve of streptozotocin-induced diabetic rats. AGEs in the sciatic nerve of diabetic rats were decreased by islet transplantation. Improved glycemic control of diabetic patients may be expected to decrease protein glycation in the nerve. Protein glycation may decrease cytoskeletal assembly, induce protein aggregation, and provide ligands for cells surface receptors. The receptor for advanced glycation and products (RAGE) was expressed in peripheral neurons. It is probable that high intracellular glucose concentration is an important trigger for increased glycation, leading to increased formation of methylglyoxal, glyoxal, and 3-deoxyglucosone that glycate proteins to form AGEs intracellularly and extracellularly. Oxidative stress enhances these processes and is, in turn, enhanced by AGE/RAGE interactions. An established therapeutic strategy to prevent glycation is the use of alpha-oxoaldehyde scavengers. Available therapeutic options for trial are high-dose nicotinamide and thiamine therapies to prevent methylglyoxal formation. Future possible therapeutic strategies are RAGE antagonists and inducers of the enzymatic antiglycation defense. More research is required to understand the role of glycation in the development of diabetic neuropathy.

Publication Types:

• Review

Publication Types:

• Review