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Published in final edited form as: Exp Eye Res. 2021 Jul 21;210:108704. doi: 10.1016/j.exer.2021.108704

Advanced glycation end products in human diabetic lens capsules

Johanna Rankenberg 1, Stefan Rakete 1,5, Brandie D Wagner 1,2, Jennifer L Patnaik 1, Christian Henning 4, Anne Lynch 1, Marcus A Glomb 4, Ram H Nagaraj 1,3,6
PMCID: PMC8429260  NIHMSID: NIHMS1730493  PMID: 34302851

Abstract

Advanced glycation end products (AGEs) accumulate with age in human lens capsules. AGEs in lens capsules potentiate the transforming growth factor beta-2-mediated mesenchymal transition of lens epithelial cells, which suggests that they play a role in posterior capsule opacification after cataract surgery. We measured AGEs by liquid chromatography-mass spectrometry in capsulorhexis specimens obtained during cataract surgery from nondiabetic and diabetic patients with and without established retinopathy. Our data showed that the levels of most AGEs (12 out of 13 measured) were unaltered in diabetic patients and diabetic patients with retinopathy compared to nondiabetic patients. There was one exception: glucosepane, which was significantly higher in diabetic patients, both with (6.85 pmol/μmol OH-proline) and without retinopathy (8.32 pmol/μmol OH-proline), than in nondiabetic patients (4.01 pmol/μmol OH-proline). Our study provides an explanation for the similar incidence of posterior capsule opacification between nondiabetic and diabetic cataract patients observed in several studies.

1. Introduction

The human lens capsule is a basement membrane secreted by a monolayer of lens epithelial cells. It surrounds the lens and allows selective molecules to pass through to the lens (Danysh and Duncan, 2009; Danysh et al., 2010). It thickens with age; in the adult lens, the average thickness is ~12 μm at the anterior pole and ~5 μm at the posterior pole (Barraquer et al., 2006). The lens capsule is a reservoir of growth factors that are needed for lens epithelial cells to proliferate and differentiate into fiber cells (Danysh and Duncan, 2009; Tholozan et al., 2007; VanSlyke et al., 2018).

Lens posterior capsule opacification (PCO) occurs in many patients after cataract surgery and implantation of an intraocular lens (IOL). The residual lens epithelial cells on the anterior capsule after cataract surgery proliferate, migrate and undergo changes to a myofibroblast phenotype through epithelial to mesenchymal transition (EMT) and secrete excessive extracellular matrix proteins, which causes PCO through fibrosis (Wormstone and Eldred, 2016; Wormstone et al., 2020). PCO often leads to diminished vision. The incidence of PCO increases with time after cataract surgery, ranging between 4.7–18.6% at 3 years and 7.1–22.6% at 5 years in patients with a single piece IOL implanted (Ursell et al., 2020). Nd:YAG capsulotomy can be performed to clear the fibrous tissue and restore vision. The biochemical mechanisms underlying PCO are not fully understood.

The lens capsule has been studied as a contributor to PCO. Transforming growth factor beta-2 (TGFβ2)-mediated signaling has been implicated (Boswell et al., 2017; Meacock et al., 2000). Integrins, especially αV, have been shown to be important for LECs to undergo EMT, possibly through activation of latent TGFβ2 in the capsule (Mamuya et al., 2014). Additionally, recent studies also implicate the immune response following cataract surgery as a possible cause (Jiang et al., 2018; Logan et al., 2017).

Advanced glycation end products (AGEs), which can potentiate TGFβ2-mediated signaling and accelerate EMT of LECs (Nam and Nagaraj, 2018; Raghavan et al., 2016), are formed as a result of a chemical reaction between carbonyl compounds and protein amino groups (mainly those of lysine and arginine residues). Since capsule proteins have negligible turnover, they accumulate AGEs with age. Many AGEs have been detected in human lens proteins (Nagaraj et al., 2012; Smuda et al., 2015). In addition, lens capsule proteins have been shown to accumulate AGEs with aging (Raghavan et al., 2016), and AGEs are elevated in capsules of cataractous as compared to noncataractous lenses (Raghavan et al., 2016). Our previous study also demonstrated that TGFβ2-mediated EMT of LECs is directly related to the levels of AGEs in the lens capsule (Raghavan et al., 2016). In addition, we demonstrated that capsule AGEs interact with a receptor for AGEs, RAGE, in LECs during enhancement of EMT (Raghavan and Nagaraj, 2016). Our recent study (Nam et al., 2021) shows that RAGE in LECs is required for TGFβ2-mediated EMT. Together, these data suggest that lens capsule AGEs play a role in PCO.

Hyperglycemia in diabetes promotes AGE formation in tissues (Vlassara and Uribarri, 2014). Many studies have shown that AGEs accumulate at a higher rate in tissue proteins in diabetes, and in skin collagen, AGEs are directly related to long-term glycemic control (Beisswenger et al., 1993; Lyons et al., 1991). Some studies, but not all (Ahmed et al., 2003), have shown higher levels of AGEs in diabetic lenses (Hashim and Zarina, 2011; Zarina et al., 2000), which could be a reason for accelerated age-related cataracts in diabetic patients. It is not known whether capsule proteins accumulate higher levels of AGEs in diabetic patients. Since capsule AGEs are likely to play a role in PCO, it was of significance to determine the effect of diabetes on capsule AGE levels.

Several studies have shown a similar or lower incidence of PCO in diabetic patients than in nondiabetic patients (Knorz et al., 1991; Praveen et al., 2014; Zaczek and Zetterstrom, 1999), but some studies have shown a higher incidence rate in diabetic patients (Hayashi et al., 2002; Ionides et al., 1994; Wu et al., 2018). Thus, the effect of diabetes on PCO is not completely resolved. In this study, we sought to determine whether capsule AGE levels are elevated in two separate groups, diabetic patients and diabetic patients with established retinopathy, relative to a patient group of nondiabetic patients undergoing cataract surgery.

2. Methods

All reagents used were of at least analytical grade. Liquid chromatography-mass spectrometry (LC-MS/MS) solvents were of mass spectrometry grade.

2.1. Sample collection and storage

Capsulorhexis specimens were obtained at the time of cataract surgery at the University of Colorado Health Sue-Anschutz Rodgers Eye Center, Aurora, CO. Upon collection, samples were stored at −80°C until processing. On the day of cataract surgery, blood samples were collected from consented patients for HbA1C measurement. The study was approved by the Institutional Review Board of the University of Colorado School of Medicine and was performed in compliance with the Helsinki Declaration (ClinicalTrials.gov Identifier: NCT02662010).

2.2. Sample processing

Capsule specimens were blinded and assigned a numeric identifier. They were subjected to enzymatic hydrolysis after being denuded of any residual lens fiber mass by rocking in 0.85% NaCl for 3 days at room temperature. Specimens were suspended in 150 μL PBS (PBS-only samples were used as blanks). Samples were incubated while mixing at 300 rpm at 37°C. Enzymes were added in the following order: at 0 and 24 h, 10 μL 0.7 mg/mL collagenase (Worthington, Lakewood, NJ, Cat# 5275); at 48 and 72 h, 10 μL 3 mg/ml protease Type XIV (Sigma-Aldrich, St. Louis, MO, Cat# P-5147); at 96 h, 4 μL leucine aminopeptidase suspension (Sigma-Aldrich, Cat# L5006); and at 120 h, 12 μL 0.5 mg/ml carboxypeptidase Y (Sigma-Aldrich, Cat# C3888). In all incubations, flushing with argon was conducted after the addition of each enzyme, and the entire digestion procedure was carried out in the presence of a few crystals of thymol (Sigma-Aldrich, Cat# T-0501). The digested material was passed through a 3-kDa molecular weight cutoff centrifugal filter (VWR International, Tualatin, OR). The filtrate was analyzed by liquid LC-MS/MS for acid-labile AGEs. Fifty microliters of the digest from each sample was acid hydrolyzed with 6 N HCl by incubating at 110°C for 24 h under argon in a sealed glass ampule. The acid-hydrolyzed samples were dried in a speed vac concentrator. To remove residual HCl, the dried pellet was suspended in 500 μL water and dried again. The final pellet was suspended in 100 μL water, sonicated and then centrifuged to sediment insoluble particles. The supernatant was analyzed with LC-MS/MS for acid stable AGEs.

2.3. LC-MS/MS

Samples were separated on a Waters Acquity UPLC system (Milford, MA) using a Waters Acquity UPLC HSS T3 column, 100 X 2.1 mm, 1.8 μm with appropriate VanGuard column at a temperature of 40°C, with a solvent flow of 0.6 ml/min. The solvents used were A: water and B: acetonitrile/water (80/20, v/v), each containing 0.12% heptafluorobutyric acid. The percentages of solvent A were: 0–2.2 min, 98%; 3.3 min, 92%; 7.6 min, 66%; 7.8 min, 0%; 9.5 min, 0% and 12.2 min, 98%. For mass spectrometric detection on a Sciex 4500 QTrap, scheduled multiple-reaction monitoring (sMRM) mode was used, utilizing collision-induced dissociation of the protonated molecules with compound-specific orifice potentials and fragment-specific collision energies. The ion source was run under the following conditions: temperature, 650°C; ion spray voltage, 2500 V; curtain gas, 35 ml/min; nebulizer gas, 65 mL/min; heating gas, 70 mL/min. The declustering potential, collision energy and cell exit potential for each of the monitored precursor-to-product ion transitions are shown in Table 1. After confirmation of the peak position, peaks were integrated and blank subtracted. Analytes were quantified using the standard addition method as previously described (Raghavan et al., 2016; Smuda et al., 2015) and corrected for enzyme hydrolysis efficiency. The enzyme efficiency percentage in each sample was calculated based on the CML and CEL contents in the enzyme digest/CML and CEL contents in acid hydrolysate*100. The data were normalized to 1 μmol hydroxy-proline (OH-Pro) in the samples.

Table 1.

Scheduled multiple reaction monitoring parameters

precursorion production 1 production 2 production 3
AGE/amino acid internal standard RT m/z DP m/z CE CXP m/z CE CXP m/z CE CXP
OH-Pro 0.84 132.0 38 86.0 19.1 6.9.0 68.0 26.1 5.1 57.9 36.7 9.1
Glucosepane 6.67*
6.84		 429.3 20 384.5 38.0 19.0 269.2 55.0 20.0 339.2 55.0 20.0
GOLD 6.68 327.2 60 84.1 55.0 13.0 282.3 29.0 11.0 198.1 25.0 19.0
MODIC 7.10 357.3 25 312.2 31.0 14.0 267.3 45.0 15.0 197.4 45.0 14.0
GALA 2.36 205.2 40 142.1 19.0 10.0 84.1 25.0 13.0 159.1 15.0 13.0
MOLD 7.10 341.3 45 296.3 33.0 18.0 84.2 52.0 14.0 212.3 29.0 21.0
MG-H3 6.00 229.2 45 114.1 22.5 9.0 70.1 45.0 14.0 116.1 21.0 9.0
MG-H1 6.00 229.2 55 70.1 43.0 12.0 116.1 20.5 9.0 114.1 22.5 9.0
CMA 4.89 233.1 45 70.1 45.0 15.0 116.1 23.0 10.0 118.2 22.0 5.5
Pyrraline 6.81 255.2 38 175.2 17.0 14.0 237.2 12.0 11.0 148.3 25.0 10.0
DT-Ha 5.47 259.1 45 144.1 22.0 9.0 70.0 45.0 10.0 116.1 25.0 17.0
CEA 5.88 247.1 51 70.2 48.0 12.0 116.2 25.0 10.0 132.1 24.0 10.0
CML 2.36 205.1 40 130.2 17.0 11.0 84.1 25.0 13.0 56.1 50.0 10.0
CEL 4.24 219.1 54 84.1 33.0 11.0 130.1 18.0 12.0 56.1 59.0 8.0
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RT: retention time (min), m/z: mass-to-charge ratio (atomic mass unit), DP: declustering potential (V), CE: collision energy (eV), CXP: cell exit potential (V)

*

The two isomer peaks with different retention times were integrated together and the sum was used.

2.4. Statistical analyses

Levels for each of the analytes were compared across groups using linear regression, and linear contrasts were used to test pairwise comparisons. P-values for comparisons across the three groups were adjusted for multiple comparisons using the false discovery rate as described by Benjamini and Hochberg (Benjamini et al., 2001). These comparisons were also made after adjusting for age and sex. Sensitivity analyses using log-transformed values were performed. All analyses were performed using SAS version 9.4 (The SAS Institute, Cary, NC).

3. Results

The average ages of the 120 included patients among the three groups are shown in Table 2. The average age of diabetic patients with DR was 4 years lower than both diabetic and nondiabetic patients. The HbA1C levels were significantly higher in diabetic patients than in nondiabetic patients. We measured 13 AGEs in this study, among which 2 were derived from glycation initiated by glucose, 4 were derived from glyoxal, 6 were derived from methylglyoxal and one was derived from ascorbate (Fig. 1). The sMRM chromatograms for AGEs are shown in Supplementary Fig. 1. The levels of most AGEs were < 50 pmoles/μmol OH-Pro. Sensitivity analyses evaluating the comparison across groups after adjusting for age and gender or after log transformation yielded similar results; therefore, the unadjusted analyses using the original scale for each analyte are presented. Among the 13 AGEs measured, the levels of the majority of AGEs, 12 out of the 13, were similar in diabetic patients and diabetic patients with DR when compared to those in nondiabetic patients after correcting for multiple comparisons (Figs. 2 to 5). One exception was glucosepane, with a multiple testing corrected p-value < 0.01. The mean ± standard error levels were 8.32 ± 0.76 pmol/μmol OH-Pro in diabetic patients and 6.85 ± 0.89 pmol/μmol OH-Pro in diabetic patients + DR, which were significantly higher (p<0.01 and p=0.01, respectively) than those in nondiabetic patients (4.01 ± 0.71 pmol/μmol OH-Pro) (Fig. 2). However, there was no difference between diabetic patients and diabetic patients + DR (p=0.21). The other glucose-derived AGE, pyrraline, showed no differences between groups.

Table 2.

Patient demographics

Nondiabetic (ND) (n = 48) Diabetic w/o retinopathy (DB) (n = 42) Diabetic w/retinopathy (DB+DR) (n = 30) p-value*
Female 30 (63%) 25 (60%) 9 (30%) 0.01
Age (years), mean ± SD 68 ± 6 68 ± 7 64 ± 8 0.02
HbA1C, mean ± SD 5.5 ± 0.3 7.6 ± 1.7 8.1 ± 1.7 <0.01
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SD = standard deviation.

*

p-values were calculated with either a chi-squared test or an analysis of variance, as appropriate.

Fig. 1. Structure of AGEs measured in this study.

Fig. 1.

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They are categorized into four classes based on their primary precursor carbonyl compounds. The structures shown in red are measured in enzyme-digested material, and those in blue are measured in acid-hydrolyzed material.

Fig. 2. The levels of glucose-derived AGEs.

Fig. 2.

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In nondiabetic (ND), diabetic (DB) and diabetic with retinopathy (DB + DR) capsulorhexis specimens. Points represent observed values, and the mean and 95% confidence intervals are displayed with dashed lines and whiskers, respectively. *p=0.01, **p<0.01, ns=nonsignificant

Fig. 5. The levels of an ascorbate-derived AGE.

Fig. 5.

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In nondiabetic (ND), diabetic (DB) and diabetic with retinopathy (DB + DR) capsulorhexis specimens. Points represent observed values, and the mean and 95% confidence intervals are displayed with dashed lines and whiskers, respectively. The multiple testing corrected p-value comparing all three groups was >0.5 for all analytes, so the pairwise comparisons are not presented.

Among the glyoxal-derived AGEs, the levels of CMA were the highest for all patient groups: 208.1 ± 20.9 pmol/μmol OH-Pro, 248.8 ± 22.4 pmol/μmol OH-Pro and 211.9 ± 26.4 pmol/μmol OH-Pro and not significantly different among the nondiabetic, diabetic and diabetic patients + DR, respectively (Fig. 3). The levels of other glyoxal-derived AGEs, GALA and CML did not exhibit any significant differences across groups. However, the observation of CMA levels that were several-fold higher than the levels of CML was unexpected. Further studies are required to determine the reasons underlying this observation. We note here that ~10–15% of CML measured could have formed as a result of acid hydrolysis of proteins, which could have caused an increase in the measured amounts in samples.

Fig. 3. The levels of glyoxal-derived AGEs.

Fig. 3.

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In nondiabetic (ND), diabetic (DB) and diabetic with retinopathy (DB + DR) capsulorhexis specimens. Points represent observed values, and the mean and 95% confidence intervals are displayed with dashed lines and whiskers, respectively. The multiple testing corrected p-value comparing all three groups was >0.5 for all analytes, so the pairwise comparisons are not presented.

Likewise, methylglyoxal-derived AGEs, MODIC, MG-H1, MG-H3, CEA and CEL showed no differences among the three groups (Fig. 4). Finally, the levels of DT-Ha, a 3-deoxythresone (ascorbate)-derived AGE (Rakete and Nagaraj, 2016), were not different across the three groups (Fig. 5).

Fig. 4. The levels of methylglyoxal-derived AGEs.

Fig. 4.

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In nondiabetic (ND), diabetic (DB) and diabetic with retinopathy (DB + DR) capsulorhexis specimens. Points represent observed values, and the mean and 95% confidence intervals are displayed with dashed lines and whiskers, respectively. The multiple testing corrected p-value comparing all three groups was >0.5 for all analytes, so the pairwise comparisons are not presented.

4. Discussion

The objectives of this study were 1) to determine whether diabetic lens capsules contained higher levels of AGEs than nondiabetic lens capsules and 2) to determine whether AGE levels were higher in diabetic patients with established retinopathy than in diabetic patients without retinopathy. Based on the findings in other basement membranes, for example, in the tubular basement membrane of kidneys (Bendayan, 1998; Copeland et al., 1987) and Bruch’s membrane (Handa et al., 1999), we anticipated diabetic capsules, being basement membranes, to have higher levels of AGEs. However, 12 of the 13 AGEs measured were similar between diabetic patients and nondiabetic patients. This is interesting and, at the same time, unexpected. The lack of an increase in capsule AGEs in diabetes suggests the possibility that most glycation precursor levels are not elevated in the milieu of the lens capsule (aqueous humor) in diabetes. This possibility is supported by the observation that the AGE levels in aqueous humor in diabetic patients are similar to those in nondiabetic patients (Franke et al., 2003). Despite a significant elevation of AGEs in the aqueous humor of diabetic + DR patients compared to diabetic patients without DR (Endo et al., 2001), we found no difference in the majority of AGEs between the two groups. The absence of such an increase suggests that AGE-bearing proteins in aqueous humor are probably derived from plasma, not generated in situ in aqueous humor. Among all AGEs, only glucosepane was elevated in diabetic capsules relative to nondiabetic capsules. This AGE is derived solely from glucose (Biemel et al., 2002). Elevated glucose levels in the aqueous humor (Gomel et al., 2021) and/or in lens (Bron et al., 1993) could have led to this increase, but this needs to be investigated in a future study. An interesting observation in this study is ~60–80 times lower levels of CML than CMA. This was unexpected, as both AGEs are likely derived from glyoxal. Further work is needed to understand their mechanism of formation in lens capsules.

The fact that the AGE levels are largely similar between diabetic and nondiabetic patients supports our hypothesis that capsule AGEs promote the TGFβ2-mediated EMT of lens epithelial cells during PCO and that the incidence of PCO should be similar between the two groups. This is in fact the case in several studies, but as mentioned above, the PCO incidence was higher in diabetic patients in some studies. In this context, it should be noted that the occurrence of PCO also depends on the nature of the implanted IOL; round-edged IOLs and acrylic hydrophilic IOLs have higher rates of PCO than square-edged IOLs and acrylic hydrophobic IOLs (Duman et al., 2015; Hazra et al., 2012). Thus, the discrepancy between studies could be attributable to differences in the implanted IOLs or due to other potential confounding factors, such as patient age.

In conclusion, our study revealed that AGE levels are similar between diabetic and nondiabetic human lens capsules. This provides a biochemical basis for the lack of difference in the PCO incidence in the two groups observed in several studies.

Supplementary Material

1

Fig. S1. Representative LC-MS/MS sMRM chromatograms for AGEs

NIHMS1730493-supplement-1.tiff (1,007.6KB, tiff)

Highlights.

  • Advanced glycation endproducts (AGEs) in human lens capsules were measured by LC-MS/MS

  • The levels of majority of AGEs were similar between diabetic and nondiabetic lens capsules

  • Glucosepane levels were significantly higher in diabetic than in nondiabetic lens capsules

Acknowledgements

This work was supported by the National Institutes of Health Grants EY028836 and EY023286 and an unrestricted grant from Research to Prevent Blindness to the Department of Ophthalmology, University of Colorado. We would like to thank Levi Bonnell, Jennifer Cathcart, Tara Churney and Ruth T. Eshete for their help with obtaining patient consent and specimen collection.

Footnotes

Commercial relationship

None.

Declaration of competing interest

The authors declare that they have no conflicts of interest

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Data availability statement

All data generated or analyzed during this study are included in this article.

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Associated Data

This section collects any data citations, data availability statements, or supplementary materials included in this article.

Supplementary Materials

1

Fig. S1. Representative LC-MS/MS sMRM chromatograms for AGEs

NIHMS1730493-supplement-1.tiff (1,007.6KB, tiff)

Data Availability Statement

All data generated or analyzed during this study are included in this article.

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