Advanced glycation end products in serum predict changes in the kidney morphology of patients with insulin-dependent diabetes mellitus

doi:10.1016/S0026-0495(97)90010-X

Metabolism

Volume 46, Issue 6, June 1997, Pages 661-665

https://doi.org/10.1016/S0026-0495(97)90010-X Get rights and content

Abstract

The biochemical mechanisms that cause the development and progression of diabetic nephropathy are unknown. Advanced glycation end products (AGEs) might play a role, as shown by increased levels of tissue-bound and circulating AGEs that correlate with the severity of diabetic nephropathy. The aim of the present study was to investigate if circulating AGEs predict the progression of morphological pathology in patients with diabetic nephropathy. We have developed an immunoassay to determine serum levels of AGEs. In a prospective clinical trial of young insulin-dependent diabetes mellitus (IDDM) patients with microalbuminuria, kidney biopsies were taken at baseline and after 24 to 36 months. The biopsies were analyzed for structural changes in the glomeruli by quantitative morphometry (electron microscopy). We have retrospectively analyzed serum AGEs. The mean serum level of AGEs at the start of the study was 18.7 U/mL (95% confidence interval [CI], 16.9 to 20.5). A positive correlation between serum AGE levels at the start of study and changes from baseline to follow-up study in basement membrane thickness (r = .56, P < .02) and matrix/glomerular volume fraction (r = .57, P < .02) was demonstrated. In a stepwise regression analysis with changes in the matrix/glomerular volume fraction as the dependent variable, serum AGE levels at the start of the study proved to be a significant independent variable (P < .02), whereas the mean hemoglobin A_1c (HbA_1c) or HbA_1c at the start was not. This study shows that serum AGEs predict the progression of early morphological kidney damage during 2.5 years in patients with IDDM.

References (27)

AM Schmidt et al.
Isolation and characterization of two binding proteins for advanced glycosylation end products from bovine lung which are present on the endothelial cell surface
J Biol Chem
(1992)
Z Makita et al.
Immunochemical detection of advanced glycosylation end products in vivo
J Biol Chem
(1992)
P Papanastasiou et al.
Immunological quantification of advanced glycosylation end-products in the serum of patients on hemodialysis or CAPD
Kidney Int
(1994)
Z Makita et al.
Reactive glycosylation endproducts in diabetic uraemia and treatment of renal failure
Lancet
(1994)
T Nishino et al.
Immunohistochemical detection of advanced glycosylation end products within the vascular lesions and glomeruli in diabetic nephropathy
Hum Pathol
(1995)
K Dahl-Jørgensen
Near-normoglycemia and late diabetic complications
KF Hanssen et al.
Blood glucose control and diabetic microvascular complications: Longterm effects of near-normoglycaemia
Diabet Med
(1992)
P Reichard et al.
The effect of long-term intensified insulin treatment on the development of microvascular complications of diabetes mellitus
N Engl J Med
(1993)
The effect of intensive treatment of diabetes on the development and progression of long-term complications in insulin-dependent diabetes mellitus
N Engl J Med
(1993)
H-J Bangstad et al.
Improvement of blood glucose control in IDDM patients retards the progression of morphological changes in early diabetic nephropathy
Diabetologia
(1994)

RJ Koenig et al.

Correlation of glucose regulation and hemoglobin A_1c in diabetes mellitus

N Engl J Med

(1976)

M Brownlee et al.

Advanced glycosylation end products in tissue and the biochemical basis of diabetic complications

N Engl J Med

(1988)

J Brett et al.

Survey of the distribution of a newly characterized receptor for advanced glycation end products in tissues

Am J Pathol

(1993)

Cited by (117)

AGEs (advanced glycation end products): Pay attention. Formation, toxic effects and therapeutic options
2023, Cahiers de Nutrition et de Dietetique
Les produits terminaux de glycation avancée (AGE) constituent un ensemble non homogène et chimiquement diversifié de composés formés de manière exogène, ou endogène au cours de diverses voies dans le corps humain. En général, ils sont formés de manière non enzymatique par condensation entre les groupes carbonyles des sucres réducteurs et les groupes amines libres des protéines, suivis d’autres réarrangements donnant des produits finaux stables et irréversibles. Les AGE ont suscité l’intérêt de la communauté scientifique en raison de l’augmentation des preuves de leur implication dans de nombreuses pathologies, en particulier le diabète et ses complications cardiovasculaires et rénales, mais aussi le cancer et les maladies neurodégénératives. Les AGE sont reconnus par plusieurs récepteurs cellulaires et déclenchent de nombreuses voies de signalisation liées à l’inflammation et au stress oxydatif. Malgré les nombreux résultats associant recherches expérimentale et clinique, la complexité de leur implication dans la physiologie humaine et les états physiopathologiques nécessite de progresser davantage. Cette revue met l’accent sur quatre points : premièrement, les mécanismes d’action cellulaire des AGE ; deuxièmement, les maladies dans lesquelles les AGE sont impliqués ; troisièmement, le développement d’agents pharmacologiques visant à réduire les concentrations circulantes d’AGE et/ou le blocage des RAGE dans l’optique de gommer les conséquences néfastes de l’imprégnation tissulaire par les AGE ; quatrièmement, la pertinence d’un traitement diététique des complications AGE-dépendantes par la prise en compte des apports exogènes alimentaires en AGE.
Advanced glycation end-products (AGE) are an inhomogeneous and chemically complex set of compounds formed exogenously, or endogenously during various pathways in the human body. As a rule, they are formed non-enzymatically by condensation between the carbonyl groups of reducing sugars and the free amino groups of proteins, followed by further rearrangements giving stable and irreversible end products. AGE have aroused the interest of the scientific community due to the increasing evidence of their involvement in many pathophysiological processes and diseases, in particular diabetes and its cardiovascular and renal complications, but also cancer and neurodegenerative diseases. AGE are recognized by several cellular receptors and trigger many signaling pathways related to inflammation and oxidative stress. Despite the many results associated with experimental and clinical research, the complexity of their involvement in human physiology and pathophysiological states requires gradual progress. This review emphasizes four points: firstly, the cellular action mechanisms of AGE; secondly, the diseases in which AGE are implicated; thirdly, the development of pharmacological agents aimed at reducing circulating concentrations of AGE and/or blocking AGE receptors with a view to erasing the consequences of tissue impregnation by AGE; fourthly, the relevance of a dietary treatment of AGE-dependent complications by taking into account exogenous dietary intakes of AGE.
Glycation in Disease
2021, Comprehensive Glycoscience: Second Edition
Glycation, also called the “Maillard reaction,” is a reaction in which free amino groups of proteins, lipids and nucleotides are modified by monosaccharides, followed by the formation of a Schiff base, Amadori products, α-dicarbonyl compounds, and eventually, the formation of endproducts, collectively termed advanced glycation endproducts (AGEs). Since it is a non-enzymatic reaction, it is also referred to as “non-enzymatic glycation.” During the reaction, reactive oxygen species (ROS) and reactive carbonyl species are produced, causing oxidative stress and carbonyl stress. Glycation has been implicated in aging and the pathogenesis of various diseases, especially diabetic complications. Mechanisms by which glycation affects cells include (1) causing protein dysfunction by glycation, (2) producing oxidative stress and carbonyl stress, and (3) activation of deleterious signal transduction pathways.
It has been proposed that there are enzymatic pathways in which intermediate products of glycation are metabolized. These include the oxidation or the phosphorylation of Amadori products, and the reduction of α-dicarbonyl compounds. A number of glycation inhibitors have been developed for the therapeutic purposes. Since there is no ultimate solution for glycation-related pathogenesis at the present time, clarifying the pathways of glycation will be helpful for developing new strategies.
Diabetic Nephropathy
2015, Endocrinology: Adult and Pediatric
Glycated serum albumin: A potential disease marker and an intermediate index of diabetes control
2014, Diabetes and Metabolic Syndrome: Clinical Research and Reviews
Citation Excerpt :
AGEs have been linked in the induction of glomerular sclerosis and microalbuminuria, impaired function of endothelial barrier, expression of the adhesion molecule and impaired vasodilatory responses. The AGEs are associated with renal and retinal disorders in diabetic patients and alterations in kidney morphology of type 1 diabetes patients also [6]. Research evidence suggests that glycated albumin (GA) is prove to be a better diagnostic marker in diabetic dialysis patients than HbA1c [7].
Glycation is a non-enzymatic spontaneous process in proteins which has remarkable impact on its physical and functional aspect. This alteration with addition of carbohydrate residue to human serum albumin leads to several pathological events such as diabetic nephropathy, neuropathy, retinopathy and cardiovascular complications. Human serum albumin is the major protein and is most susceptible to non-enzymatic glycation. Structural and biological properties of functional albumin alter due to the addition of reducing carbohydrate to free amino terminal residues vivo. These irreversible changes in functional albumin are stable which makes this modified albumin as new gold standard future diagnostic marker in diabetes associated complications. Glycated albumin can be used to determine the glycemic control due to short half life than erythrocytes which makes it an alternate reliable disease marker in diabetes. In this review, Human serum albumin glycation has been overviewed, stating concept of glycation and sites that are prone to this modifications. Impact of non-enzymatic addition of carbohydrate to albumin's structural and biological properties has also been elaborated. Accurate measurements of glycated albumin with implications of new highly sensitive techniques have also been described briefly. Interestingly human serum albumin imposed glycation can serve as future tool not for diagnosing diabetes but also its potential in assessment of diabetes associated complications.
Impact of high glucose concentration on aspirin-induced acetylation of human serum albumin: An in vitro study
2014, EuPA Open Proteomics
Citation Excerpt :
This process leads to the formation of Amadori compounds which then undergo a series of oxidation, dehydration and fragmentation reactions, finally generating advanced glycation end-products (AGE) [18,19]. AGEs are associated to long term diabetic complications, such as retinopathy [20,21], nephropathy [22–24] and macroangiopathy [25,26]; this is due to the formation of cross-linked structures [27,28] that alter the structure/function of proteins, their turn-over, and tend to accumulate in specific tissues, impairing their homeostasis [29,30]. Apart from its clinical relevance as a more rapid indicator for glycaemic monitoringl than glycated haemoglobin (HbA1c), glycated HSA has also been described as having altered functions in diabetes (glycated albumin levels in plasma are considered to indicate the glycaemic state over the last 3 weeks, while HbA1c indicates the glycaemic state over the last 3 months) [31–33].
Aspirin (ASA) plays a key role in protecting high risk cardiovascular patients from ischaemic events. The modifications underlying its effects are the results of the trans-acetylation that occurs between ASA and the amino groups made up of lysine and N-terminal residues. ASA's effects have also been demonstrated on several plasma proteins, including human serum albumin (HSA). However, its beneficial effects seem to be lower in diabetic patients, suggesting that protein glycation may impair ASA's acetylation process. Using immunoblotting and mass spectrometry, this study characterized the degree of HSA acetylation mediated by ASA in vitro, as well as the impact of high glucose concentrations. Glycation's influence on HSA acetylation might impair the latter's biological functions, leading to a potential failure of ASA to prevent cardiovascular complications in diabetes.
Dietary resistant starch prevents urinary excretion of 25-hydroxycholecalciferol and vitamin D-binding protein in type 1 diabetic rats
2013, Journal of Nutrition
Diabetes is a rapidly growing epidemic affecting millions of Americans and has been implicated in a number of devastating secondary complications. We previously demonstrated that type 2 diabetic rats exhibit vitamin D deficiency due to aberrant megalin-mediated endocytosis and excessive urinary excretion of 25-hydroxycholecalciferol (25D3) and vitamin D-binding protein (DBP). Here, we examined whether a model of type 1 diabetes [T1D; streptozotocin (STZ)-treated Sprague-Dawley rats] would similarly excrete abnormally high concentrations of 25D3 and DBP due to renal damage and compromised expression of megalin and its endocytic partner, disabled-2 (Dab2). Moreover, we tested whether feeding diabetic rats starch that is resistant to digestion could alleviate these abnormalities. Control (n = 12) rats were fed a standard, semipurified diet (AIN-93G) containing 55% total dietary starch and STZ-treated rats were fed the AIN-93G diet (n = 12) or a diet containing 55% high-amylose maize that is partially resistant to digestion [20% total dietary resistant starch (RS); n = 12] for 2 and 5 wk. The RS diet attenuated weight loss and polyuria in STZ-treated rats. Histology and immunohistochemistry revealed that dietary RS also attenuated the loss of Dab2 expression in renal proximal tubules. Moreover, urinary concentrations of both 25D3 and DBP were elevated ∼10-fold in STZ-treated rats (5 wk post STZ injection), which was virtually prevented by the RS. We also observed a ∼1.5-fold increase in megalin mRNA expression in STZ-treated rats, which was attenuated by feeding rats the RS diet for 2 wk. Taken together, these studies indicate that consumption of low-glycemic carbohydrates can attenuate disruption of vitamin D homeostasis in T1D through the rescue of megalin-mediated endocytosis in the kidney.

View all citing articles on Scopus

^☆: Supported by the Norwegian Research Council, the J.E. Isberg Foundation, The Norwegian Diabetes Association, Novo Nordisk Pharma, The Novo Nordisk Foundation, The Blix Family Foundation, and Aker Diabetes Research Fund.

View full text

Advanced glycation end products in serum predict changes in the kidney morphology of patients with insulin-dependent diabetes mellitus☆

Abstract

J Biol Chem

J Biol Chem

Kidney Int

Lancet

Hum Pathol

Near-normoglycemia and late diabetic complications

Blood glucose control and diabetic microvascular complications: Longterm effects of near-normoglycaemia

Diabet Med

The effect of long-term intensified insulin treatment on the development of microvascular complications of diabetes mellitus

N Engl J Med

The effect of intensive treatment of diabetes on the development and progression of long-term complications in insulin-dependent diabetes mellitus

N Engl J Med

Improvement of blood glucose control in IDDM patients retards the progression of morphological changes in early diabetic nephropathy

Diabetologia

Correlation of glucose regulation and hemoglobin A1c in diabetes mellitus

N Engl J Med

Advanced glycosylation end products in tissue and the biochemical basis of diabetic complications

N Engl J Med

Survey of the distribution of a newly characterized receptor for advanced glycation end products in tissues

Am J Pathol

Correlation of glucose regulation and hemoglobin A_1c in diabetes mellitus