An Advanced Glycation End Product (AGE)-Rich Diet Promotes NÎµ

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An Advanced Glycation Endproduct (AGE)-rich Diet Promotes N#carboxymethyl-lysine Accumulation in the Cardiac Tissue and Tendons of Rats Irene Roncero-Ramos, Celine Niquet-Leridon, Christopher Strauch, Vincent M. Monnier, Frederic J. Tessier, Maria Pilar Navarro, and Cristina Delgado-Andrade J. Agric. Food Chem., Just Accepted Manuscript • DOI: 10.1021/jf501005n • Publication Date (Web): 03 Jun 2014 Downloaded from http://pubs.acs.org on June 7, 2014

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Journal of Agricultural and Food Chemistry is published by the American Chemical Society. 1155 Sixteenth Street N.W., Washington, DC 20036 Published by American Chemical Society. Copyright © American Chemical Society. However, no copyright claim is made to original U.S. Government works, or works produced by employees of any Commonwealth realm Crown government in the course of their duties.

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Journal of Agricultural and Food Chemistry

TOC Graphic Animal experiment Long-term feeding of weaning Wistar rats with diets low or high in advanced glycation endproducts (AGEs) (3 months)

Carboxymethyl-lysine intake and excretion

Carboxymethyl-lysine in different tissues

100 200

Heart

60 % 40 20 0 Feces Low AGEs diet

Urine

Total excretion

0,10 CML (µmol/mol lysine)

CML (µmol/mol lysine)

80 150 100 50 0

Tendon

0,08 0,06 0,04 0,02 0,00

Control

High AGEs diet

ACS Paragon Plus Environment

GL

Control

GL


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An Advanced Glycation Endproduct (AGE)-rich Diet Promotes Nε-

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carboxymethyl-lysine Accumulation in the Cardiac Tissue and

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Tendons of Rats

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Irene Roncero-Ramos1, Céline Niquet-Léridon2, Christopher Strauch3, Vincent M.

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Monnier3, Frédéric J. Tessier2, María Pilar Navarro1,4, Cristina Delgado-Andrade1,4

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1

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18100, Granada, Spain.

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2

Institut Polytechnique LaSalle Beauvais, Beauvais, France.

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3

Depts of Pathology and Biochemistry, Case Western Research University, Cleveland,

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Ohio, USA.

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Instituto en Formación de Nutrición Animal, Estación Experimental del Zaidín, CSIC,

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These authors share the same authorship

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Short title: High AGEs intake induces CML accumulation in heart and tendons

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*Corresponding author:

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Cristina Delgado-Andrade

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Instituto en Formación de Nutrición Animal, Estación Experimental del Zaidín, CSIC

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Camino del Jueves s/n, 18100, Armilla, Granada, Spain.

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Telephone +34 958 572757

19

Fax +34 958 572753

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e-mail: [email protected]

21 1


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Abstract

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The purpose of this study was to investigate the intake, excretion and tissue

24

accumulation of carboxymethyl-lysine (CML), after feeding rats a diet containing

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advanced glycation end-products (AGEs) from a glucose-lysine (GL) model system.

26

Rats were distributed into two groups and assigned to a Control diet or a diet including

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3% heated GL (GL diet) for three months. Feces and urine were collected over the last

28

week. After sacrifice, serum was obtained and some organs removed for CML analysis.

29

The percentage of fecal CML was 2.5-fold higher in the animals fed the GL diet (33.2

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vs. 76.5 % for Control and GL group), whereby total recovery was 91.8% compared

31

with a level of 54.6% in the animals fed the Control chow, demonstrating evidencing

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the importance of the physico-chemical form and the net quantity of dietary CML on its

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elimination. We suggest that dietary dicarbonyl compounds from GL diet or dietary

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CML itself are responsible for CML accumulation in hearts and tendons. The most

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significant result of the present study is that the regular consumption of dietary AGEs in

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healthy individuals promotes CML accumulation in some organs.

37 38

Keywords: Advanced glycation end-products; carboxymethyl-lysine; bone; heart;

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tendon; serum.

40 41

2



42

Introduction

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Advanced glycation end-products (AGEs) are compounds formed by the nonenzymatic

44

reaction between reducing sugars and free amino groups in proteins, lipids or nucleic

45

acids, called Maillard reaction. This reaction takes place during thermal processing of

46

food by techniques such as frying, baking or roasting and is responsible for the

47

formation of characteristic flavours, colours and tastes that are desirable to the

48

consumer.1 On the other hand, the formation of AGEs could lead to a decrease in the

49

nutritional value of the food due to the destruction of vitamins,2 loss of essential amino

50

acids or lower protein digestibility.3,4

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AGEs may also be generated in biological systems by the reaction of α-dicarbonyl

52

compounds with amino groups of endogenous proteins which accumulate in some

53

tissues or are present in the systemic circulation and play a physiopathological role in

54

cases of metabolic and degenerative disorders.5 In addition to endogenous synthesis,

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food can provide a significant amount of AGEs, since glycation derivatives are widely

56

consumed as part of the human diet.6,7 AGEs are thought to be absorbed in the process

57

of digestion, increasing the circulating level and being deposited in different tissues and

58

organs.8

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Carboxymethyl-lysine (CML) is one of the best characterised AGEs and is

60

frequently used as a marker of glycation product formation in food and in vivo.9 Several

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authors have correlated the CML accumulation in plasma and in different tissues with

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the progression of diabetes and with the acceleration of the aging process.10,11 However,

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to date, its absorption, metabolism and elimination have been only partially

64

elucidated.12 A direct correlation between the intake of CML and its elimination in feces

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and urine has been established in several studies. Thus, in the assay of Birlouez-Aragon

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et al.13 carried out in humans, the urinary excretion of CML increased by 40% after the 3


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consumption of a diet rich in this compound compared with a low-AGE diet; moreover,

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its presence in plasma was 7% higher. Delgado-Andrade et al.12 corroborated a higher

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CML elimination in feces when human volunteers consumed a diet containing large

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quantities of AGEs. However, the urinary excretion was weakly correlated, probably

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because renal excretion may be saturated or limited, exceeding kidney’s detoxification

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capacity. Renal clearance saturation has also been described in a rat study by Alamir et

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al.14 after the intake of a diet based on crushed extruded biscuits rich in CML.

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Derivatives from the glucose-lysine model system are frequently used to study

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diverse aspects of AGE effects. Their advantage is that they are easy to produce under

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laboratory conditions and the results obtained after in vivo trials are often simpler and

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with a more easily interpreted than in other complex systems. AGEs from lysine are

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commonly present in food, since this amino acid is very sensitive to thermal treatment

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and highly reactive in the Maillard reaction.15

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The aim of the present study is to investigate CML intake and excretion after

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feeding rats a diet containing AGEs from a heated glucose-lysine model system. The

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main originality of this work is the seeking of possible target organs for the CML

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deposit in the organism of healthy subjects. For that reason, total CML in different

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tissues and the protein-bound fraction in serum were measured. to detect possible target

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organs of accumulation.

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MATERIALS AND METHODS

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Chemicals

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All the chemical products and solvents for all the analyses were of the highest grade

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available and acquired from Sigma (Sigma-Aldrich, St. Louis, MO) and Merck

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(Darmstadt, Germany). CML and (D2)-CML were provided by PolyPeptide Laboratories

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France SAS (Strasbourg, France).

93 94

Sample preparation

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Glucose (Merck, Darmstadt, Germany) and lysine (Sigma Chemical, St. Louis, MO.,

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USA) were used to prepare the sample. Equimolar mixtures of glucose-lysine-HCl (GL)

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(40% moisture) were heated in open recipients in an oven (Selecta 2000210; Barcelona,

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Spain) at 150°C for 90 min to obtain the GL sample. This procedure tried to simulate a

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usual home cooking. After heating, the reaction was stopped by cooling in an ice bath

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and the products were then removed, frozen, lyophilized, and stored at 4ºC as described

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by Delgado-Andrade et al.16 until required for preparing the diets.

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Preparation of diets

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The AIN-93G purified diet for laboratory rodents (Dyets Inc, Bethlehem, PA) was used

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as the control diet. The GL sample was added to the AIN-93G diet to reach a final

106

concentration of 3%. This diet was termed GL. The individual analysis of the GL diet

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revealed no modification of the overall nutrient composition, compared with the Control

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diet (AIN-93G). The mean ± SD nutrient content of the diets was: moisture (%) 8.14 ±

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0.08; protein (g/kg) 176.6 ± 3.1; fat (g/kg) 78.1 ± 0.9 and ashes (%) 2.55 ± 0.13.

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The higher Maillard reaction products (MRPs) content in the GL diet with respect to the

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Control one was confirmed by analysing the furosine, hydroxymethylfurfural (HMF)

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contents and total MRPs associated fluorescence as described in previous

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publications.17,18 The data obtained for furosine (mean ± SD) were as follows: 28.8 ±

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0.5 and 1787.08 ± 7.31 mg/kg diet for Control and GL diets, respectively. The results 5


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for HMF (mean ± SD) were as follows: 0.44 ± 0.06 and 5.15 ± 0.08 mg/kg diet for

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Control and GL diets, respectively. In the case of total MRPs associated fluorescence

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(mean ± SD), they were as follows: 1.1 ± 0.1 and 10.3 ± 0.1 105 fluorescence units/g

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diet for Control and GL diets, respectively.

119 120

Biological assays

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Twenty-four weanling Wistar rats weighing 39.76 ± 0.85 g (mean ± SE) were used in

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the study. They were randomly distributed into two groups (12 animals per group) and

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each group was assigned to one of the dietary treatments. The animals were individually

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housed in metabolic cages in an environmentally controlled room under standard

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conditions (temperature: 20-22ºC with a 12 h light-dark cycle and 55-70% humidity).

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The rats had ad libitum access to their diets and demineralized water (Milli-Q Ultrapure

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Water System, Millipore Corps., Bedford, MA, USA).

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The experiment involved a preliminary 81-day period during which solid food

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intake and body weight changes were monitored weekly, followed by a 7-day period in

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which feces and urine from each animal were collected daily and stored separately as a

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1-week pool. The feces were weighed, lyophilized, powdered and then homogenized.

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The urine was collected in 0.5 % HCl (vol/vol), filtered (Whatman Filter Paper No. 40,

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ashless, Whatman, England) and diluted to an appropriate volume. On day 88, after an

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overnight fast, the animals were anaesthetized with sodium pentobarbital (5 mg per 100

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g of body weight) (Abbott Laboratories, Granada, Spain) and terminal exsanguination

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was performed by a cannulation of the carotid artery. Blood was drawn to obtain serum.

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Hearts, the right pelvic bones and the tail tendons were removed, weighed and frozen at

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-80ºC until CML analysis.

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All management and experimental procedures carried out in this study were in

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strict accordance with the current European regulations (86/609 E.E.C.) regarding

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laboratory animals. The Bioethics Committee for Animal Experimentation at our

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institution (EEZ-CSIC) approved the study protocol.

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Sample preparation for CML analysis

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For CML determination, feces, urines and hearts were lyophilized and powdered, while

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diets, serum and tail tendons were directly processed. Bones were powdered and

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homogenized. In all samples, an equivalent to 10 mg proteins was weighted to perform

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the analytical CML determination. In the case of serum, a step prior to the acid

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hydrolysis was carried out for protein precipitation using trichloroacetic acid. Therefore

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in this last case only protein-bound CML was quantified. The total content of CML

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(free and protein-bound) was measured in all other samples.

152 153

Analytical techniques

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The CML and lysine analysis in extracts of diets, feces, urine, serum, hearts and bones

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were performed at the Institut Polytechnique LaSalle Beauvais. All the extractions were

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done in triplicate and analysis in duplicate, when possible, using the method recently

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developed by Niquet-Léridon and Tessier.19 Each sample was treated with sodium

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borohydride to stabilize the Amadori products and to prevent their conversion into CML

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during the acid hydrolysis. A quantity of reduced sample, equivalent to 10 mg protein,

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was dissolved in 5 mL of 6 M HCl and incubated at 110°C for 20 h. Three hundred

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microliters of each acid hydrolysate was dried under vacuum and reconstituted in 300

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µL of internal standard containing 0.15 µg of (D2)-CML and 12.5 µg of (15N2)-lysine

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(dissolved in 20 mM nonafluoropentanoic acid (NFPA)) prior to analysis by LC– 7


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MS/MS. The use of internal standards which are isotopes of CML and lysine,

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respectively, increases the precision and the accuracy of the measurements compared

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with previous studies.13 Liquid chromatography coupled to linear ion trap tandem mass

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spectrometry was used for the analysis of CML. The following instrumentation and

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criteria were used: Surveyor HPLC system coupled to an LTQ mass spectrometer

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working in its tandem operation mode (ThermoFisher Scientific, Courtaboeuf, France);

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thermostat, 10°C; column Hypercarb, 100 mm × 2.1 mm, 5 µm with a guard column

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Hypercarb, 10 mm × 2.1 mm, 5 µm; injection volume, 10 µL; flow rate, 0.2 mL/min;

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mobile phase, 20 mM NFPA in a water–acetonitrile gradient (linear increase of

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acetonitrile from 0 to 50 % over 20 min), electrospray ionization in positive mode;

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multiple reaction monitoring with the specific transitions m/z 205.0/130.0 and m/z

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207.0/130.0 for CML and (D2)-CML, respectively, with a normalized collision energy

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of 37 % to achieve optimum fragmentations of the parent ions . Lysine and its isotope

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were detected with the specific transitions m/z 147.0/130.0 and m/z 149.0/131.0,

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respectively.

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The CML and lysine analysis for tail tendons were carried out at Case Western

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Reserve University (Cleveland, OH). CML and lysine were determined in acid

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hydrolysates of processed collagen tendon samples and derivatized as its trifluoroacetyl

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methyl esters by selected ion monitoring gas chromatography GC/MS as previously

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described by Sell et al.20

184 185

Statistical analysis

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After checking the normal distribution of data, they were statistically tested with a

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Student’s unpaired t test to compare means that showed a significant variation (p
75%) compared with the Control diet (33%), its possible net absorption

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could be higher than in the control animals due to the great CML exposure of this diet

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(Table 1). Moreover, The CML included in the GL diet and originated from a glucose-

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lysine model system is more likely present as a free adduct although other forms could

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exist, free CML – the more easily absorbed form of the compound would mainly be

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formed (Table 1).

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The animals in the GL group eliminated significantly more urinary CML than

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did those in the Control group (Table 1). As before, this difference was related to the

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amount of CML consumed by each group; this is corroborated by the strong correlation

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between CML intake and its urinary elimination (r = 0.943, p < 0.001) (Figure 1).

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Previous studies have also reported CML intake to be significantly correlated with its

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urinary elimination, both in humans13 and in rats.14,23 However, the findings obtained by

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our research group working with AGEs derived from bread crust did not reflect any

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relationship between these parameters.22 The lack of concordance between the two

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assays might be related to the form of CML preferentially ingested in each case.

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Whereas in the present assay free forms of CML were predominant in the GL diet, in

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our previous experiment bread crust was used as the source of glycoproteins, and in this

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latter case protein-bound CML forms would predominate. However, it is worthy to note

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that Alamir et al.14 used a protein-bound CML source in their study and found a good

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correlation between dietary CML and its urinary excretion. Lastly, it must be also

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noticed that the excretion rate of urinary CML in the rats of the present assay was much

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higher than that recorded for humans in the ICARE study.13 This fact points out strong

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differences between rats and human species with special relevance for CML

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metabolism.

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The intake of free CML, a more absorbable form than the protein-bound

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compounds, could elevate the circulating CML and thus explaining the high net renal

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clearance of CML in the GL diet (Table 1), which is corroborated by the existence of an

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important direct relationship between CML intake and its urinary elimination.

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Expressed as a percentage of ingested CML, urinary excretion was lower in the GL 10



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group than in the Control group, a logical data in view of the higher rate of fecal

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excretion of CML.

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With respect to the total percentage of CML excreted, the Control group rats

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recovered approximately 50% while those in the GL group recovered 92% (Table 1).

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Results similar to those for our Control group have been observed in other studies

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working with CML from food. Thus, Delgado-Andrade et al.12 reported recovery rates

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of 45-50% in human volunteers, and Somoza et al.25 found that 50% of the CML

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ingested was excreted in the feces and urine. Probably, the high difference between the

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recovery in the human studies and that from the GL group was mainly due to the great

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difference in the CML fecal elimination. Focused exclusively in the rate of total CML

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recovery, its high value The high rate of CML recovery in the GL group, once again,

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highlights the importance of the form of ingested CML (free or linked to a protein

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backbone) as well as the level of the oral dose of CML. Food-derived CML has a

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different chemical form and molecular weight to CML obtained from a model system.

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Available information regarding AGE absorption indicates that its absorption strongly

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depends on whether these compounds are present in protein-bound form or not. Low

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molecular weight AGEs may be relatively quickly absorbed, metabolized and excreted;

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however, high molecular weight AGEs may remain relatively non-absorbed due to

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insufficient degradation by gastrointestinal enzymes.26

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The results obtained in the present paper for total CML recovery in the GL

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group (92%) are in line with the recovery described for pyrraline by Foerster and

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Henle.27 However, unlike the CML, pyrraline was almost entirely absorbed from foods,

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and after its metabolic transit, was eliminated rapidly and almost completely in the

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urine, with only slight metabolism within the body.

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CML in plasma and tissues

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As has been observed previously, diets rich in AGEs can increase levels of circulating

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CML in serum.25 Several authors have described a significant positive correlation

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between dietary intake of AGEs and CML concentrations in the blood.28,29 In the

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present assay, the protein-bound CML in serum was measured and no differences was

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were found in CML level in serum between the GL group and the Control group

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(Figure 2). In this case, the fraction measured was the protein-bound CML, which

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better represents the in vivo synthesis. Recent studies have described stability in serum

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protein-bound CML in serum after the consumption of diets rich in this AGE,14,30 which

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is consistent with the results of the present work. It has been suggested that free CML is

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more affected by dietary exposure and this fact could be used to know the real index of

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the CML obtained from the diet.12 In the study by Alamir et al.,14 in which rats were fed

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a diet based on crushed extruded biscuits, the protein-bound CML level in plasma did

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not vary, but the free fraction increased with consumption of this diet. In the light of

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these data it could be hypothesized that free CML is more affected by dietary exposure

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than protein-bound fraction, and this fact could be used to know the real index of the

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CML obtained from the diet. Unfortunately, this measurement could not be obtained in

280

the present study.

281

A significant increase in tissue CML concentration has been observed under

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pathological conditions such as diabetes.11 Although the accumulation of CML in the

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kidney, skin and blood vessels in diabetic subjects is well established,31 its

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accumulation in the heart has yet to be completely elucidated. Subsequent studies

285

suggested that an increase in CML levels in cardiac tissue could play an important role

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in the pathogenesis of heart disease.32,33 Moreover, our research group recently showed

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that after rats were fed an AGE-enriched diet elaborated from bread crust, the total 12



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CML level in cardiac tissue increased.22 In the present assay, consumption of the GL

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diet significantly raised the total concentration of CML in the heart, in comparison with

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the animals given the Control diet (Figure 3) (p = 0.035). In this respect, it should be

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noted that the remaining blood was not completely removed from the heart prior to the

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CML analysis, and so some contribution to the final CML content in the heart cannot be

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excluded. However, taking into account that no modifications were detected in the

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protein-bound CML of the plasma (which is could be more representative of the

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endogenous CML), its accumulation in the heart could have a dietary origin. Supporting

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this hypothesis, a correlation between the daily intake of CML and its accumulation in

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the heart (r = 0.785; p = 0.003) was detected. But in any case, the in situ CML

298

formation from dietary dicarbonyl compounds must be also considered due to the

299

elevated recovery rate of the compound in urine and feces. The effect of a high dietary

300

AGEs intake in increasing the heart AGEs content has been previously established.34

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With respect to the concentration of CML in the bones, the GL group presented

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a significantly lower CML content than the Control group. However, in the case of the

303

tail tendons, total CML was significantly increased when the animals consumed the GL

304

diet (Figure 3). This fact could be due to the tendon collagen being more susceptible to

305

glycation than is bone collagen,35 It has been reported that the mineral phase of bone

306

provides some protection against glycation.36 The high CML accumulation could also

307

be explained by the lower turnover of collagen type I in the tendons and other

308

connective tissues, such as cartilage or ligaments,37 the turnover of this type of collagen

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in bones is faster and this, too, could be significant in the lesser accumulation of AGEs.

310

CML in the tendons might come from the direct deposition of ingested CML, and/or

311

from absorbed dicarbonyl compounds, which could act as promoters for the in vivo

312

formation of CML. Several authors have described the accumulation of AGEs in the 13


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bones38 as well as in the tendons39 under conditions of diabetes or aging,40 but further

314

studies are necessary to clarify the question of CML deposit or its formation by dietary

315

exposure.

316

In summary, the results of the present study, together with those of previous

317

work by our research group, underline the importance of the physico-chemical form of

318

dietary CML in its fecal and urinary excretion. The simpler forms of the compound in

319

the diet increase its net possible absorption and possibly its plasma level, with a

320

subsequent high renal clearance in comparison with the intake of the protein-bound

321

CML. In view of the high rate of CML recovery observed in the GL group, we believe

322

that in addition to dietary CML, dietary dicarbonyl compounds could be partly

323

responsible for CML accumulation in the heart. In parallel, those products could also be

324

involved in the increased amount of CML in the tail tendons but not in the bones, due to

325

the greater turnover of its collagen. Possibly the most significant result of the present

326

study is the demonstration that the uninterrupted consumption of dietary AGEs

327

promotes CML accumulations in the target tissues of healthy individuals, a fact which

328

could have pathophysiological implications especially in the elderly population.

329 330

Acknowledgments

331

This work was supported by a project of the Spanish Ministry of Economy and

332

Competitiveness. The authors thank Grupo Siro, a Spanish manufacturer of cereal-

333

derived food products for supplying the bread crust samples and Philippe Jacolot for his

334

technical support. The authors declare there is no conflict of interest.

335 336

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References

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(1) Ames, J. M., Control of the Maillard reaction in food systems. Trends Food. Sci.

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Tech. 1990, 1, 150-154.

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(2) Finot, P. A., BROWNING|Toxicology of nonenzymatic browning. In Encyclopedia

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of Food Sciences and Nutrition (2nd), Benjamin, C., Ed. Academic Press: Oxford,

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2003; pp 673-678.

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(3) Seiquer, I.; Diaz-Alguacil, J.; Delgado-Andrade, C.; Lopez-Frias, M.; Munoz

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Hoyos, A.; Galdo, G.; Navarro, M. P., Diets rich in Maillard reaction products affect

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protein digestibility in adolescent males aged 11-14 y. Am J. Clin. Nutr. 2006, 83, 1082-

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(4) Singh, S.; Wakeling, L.; Gamlath, S., Retention of essential amino acids during

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extrusion of protein and reducing sugars. J. Agric. Food Chem. 2007, 55, 8779-8786.

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(5) Tessier, F.; Birlouez-Aragon, I., Health effects of dietary Maillard reaction products:

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the results of ICARE and other studies. Amino acids 2012, 42, 1119-1131.

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(6) Koschinsky, T.; He, C.-J.; Mitsuhashi, T.; Bucala, R.; Liu, C.; Buenting, C.;

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Heitmann, K.; Vlassara, H., Orally absorbed reactive glycation products (glycotoxins):

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An environmental risk factor in diabetic nephropathy. Proc. Nat. Acad. Sci. 1997, 94,

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(7) Vlassara, H., Advanced glycosylation in nephropathy of diabetes and aging. Adv.

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Nephrol. 1996, 25, 303-307.

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(8) Luevano-Contreras, C.; Chapman-Novakofski, K., Dietary advanced glycation end

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products and aging. Nutrients 2010, 2, 1247-1265.

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(9) Hull, G.; Woodside, J.; Ames, J.; Cuskelly, G., N-epsilon-(carboxymethyl)lysine

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content of foods commonly consumed in a Western style diet. Food Chem. 2012, 131,

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170–174.

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(10) Knecht, K. J.; Dunn, J. A.; McFarland, K. F.; McCance, D. R.; Lyons, T. J.;

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Thorpe, S. R.; Baynes, J. W., Effect of diabetes and aging on carboxymethyllysine

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Table 1. CML daily intake and excretion during last week of the assay. Percentage of fecal, urinary and total CML excreted from the intake. Groups

Intake

Feces µg/day A

Control

30.2 ± 1.56

GL

175± 14.7

B

Urine Feces A

9.96 ± 0.63

B

135 ± 13.1

A

6.41 ± 0.61

26.9 ± 3.25

B

CML excretion rate (%) Urine Total A

33.2 ± 1.88

B

76.5 ± 2.45

A

21.4 ± 1.85

B

15.3 ± 1.20

A

54.6 ± 2.21

B

91.8 ± 2.21

Values are means ± SE, (n = 6). Different letters within a column indicate significant differences between groups (p < 0.05).

21


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Figure captions

Figure 1. Relationship between CML intake (µg/day) and either fecal CML (a), urinary CML (b) or total excretion (c). p < 0.05 indicates the existence of a significant correlation (♦ Control group; ▲ GL group). Figure 2. Protein-bound CML in serum expressed as µmol/mol lysine (mean ± SE, n = 6). No significant differences were found between the groups (p > 0.05). Figure 3. CML in heart, bone and tail tendon (µmol/mol lysine) (mean ± SE, n = 6). Different letters indicate significant differences between the groups (p < 0.05).

22



Page 24 of 26

Figure 1

(a)

(b)

(c)

23


Page 25 of 26


Figure 2

24



Page 26 of 26

Figure 3

25


An Advanced Glycation End Product (AGE)-Rich Diet Promotes NÎµ

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