Abstract

An in vitro study was performed to evaluate noninvasive spectroscopic measurement of advanced glycation endproducts (AGEs) in skin collagen. A porcine dermis preparation was incubated in solutions simulating normal and hyperglycemic conditions. The AGEs kinetics of increase were determined by HPLC and GC/MS assays, and compared to near-infrared (NIR) and ultraviolet/visible fluorescence skin spectra. Multivariate analysis indicated that, although NIR did not discriminate between collagen samples exposed to different glucose concentrations, fluorescence changes were readily detected and correlated strongly with skin concentration of AGEs. These results suggest that measurement of skin AGEs by fluorescence spectroscopy may be useful for detection and diagnosis of type II diabetes.

© 2004 Optical Society of America

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References

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    [CrossRef]
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    [CrossRef] [PubMed]
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    [CrossRef] [PubMed]
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    [CrossRef] [PubMed]
  40. B.A. Buckingham, J. Uitto, C. Sandborg, T. Keens, T. Roe, G. Costin, F. Kaufman, B. Bernstein, B Landing, and A. Castellano, �??Scleroderma-like changes in insulin-dependent diabetes mellitus: Clinical and biochemical studies,�?? Diabetes Care 7, 163-169 (1984).
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    [CrossRef]
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3rd Ann. Mtg. of the Diabetes Techn. Soc (1)

C.M. Fleming, H.T. Davis, R. Ratner, C.D. Brown, M.N. Ediger, E.L. Hull, R. Udell, and J.D. Maynard, �??Use of Near-Infrared Spectroscopy to Detect Diabetes Based on Noninvasive Skin Measurements,�?? poster presentation at the 3rd Annual Meeting of the Diabetes Technology Society, San Francisco, CA, November 6-8, 2003.

Anal. Chem. (1)

D.M. Haaland and E.V. Thomas, �??Partial least-squares methods for spectral analyses. 1. Relation to other quantitative calibration methods and the extraction of qualitative information,�?? Anal. Chem. 60, 1193-1202 (1988).
[CrossRef]

Ann. Mtg. of the Diabetes Techn. Soc. 03 (1)

H.M. Heise, S. Haiber, D. Ihrig, M. Licht, M. Stücker and C. Moll, �??Non-Invasive Diabetes Screening By Near Infrared Spectroscopy,�?? poster presentation at the 3rd Annual Meeting of the Diabetes Technology Society, San Francisco, CA, November 6-8, 2003.

Appl. Opt. (3)

Cardiovasc. Res. (1)

K.E.Juhani Airaksinen, P.I. Salmela, M.K. Linnaluoto, M.J. Ikaheimo, K. Ahola, and L.J. Ryhanen, �??Diminished arterial elasticity in diabetes: association with fluorescent advanced glycosylation end products in collagen,�?? Cardiovasc. Res. 27, 942-945 (1993).
[CrossRef] [PubMed]

Clin. Biomech. (1)

R. Reihsner, M. Melling, W. Pfeiler, and E.J. Menzel, �??Alterations of biochemical and two-dimensional biomechanical properties of human skin in diabetes mellitus as compared to effects of in vitro non-enzymatic glycation,�?? Clin. Biomech. 15, 379-386 (2000).
[CrossRef]

Diabetes (1)

V.M. Monnier, O. Bautista, D. Kenny, D.R. Sell, J. Fogarty, W. Daahms, P.A. Cleary, J. Lachin, S. Genuth, and the DCCT Skin Collagen Ancillary Study Group, �??Skin collagen glycation, glycoxidation, and crosslinking are lower in subjects with long-term intensive versus conventional therapy of type 1 diabetes,�?? Diabetes 48, 870-880 (1999).
[CrossRef] [PubMed]

Diabetes Care (7)

P. Hogan, T. Dall, P. Nikolov, American Diabetes Association, �??Economic Costs of Diabetes in the U.S. in 2002,�?? Diabetes Care 26, 917-932 (2003).
[CrossRef] [PubMed]

M.I. Harris, K.M. Flegal, C.C. Cowie, M.S. Eberhardt, D.E. Goldstein, R.R. Little, H.M. Wiedmeyer and D.D. Byrd-Holt, �??Prevalence of diabetes, impaired fasting glucose, and impaired glucose tolerance in U.S. adults, The Third National Health and Nutrition Examination Survey, 1988-1994,�?? Diabetes Care 21, 518-24 (1998).
[CrossRef] [PubMed]

M.I. Harris, R. Klein, T.A. Welborn, and M.W. Knuiman, �??Onset of NIDDM Occurs at least 4-7 yr before clinical diagnosis,�?? Diabetes Care 15, 814-819 (1992).
[CrossRef]

American Diabetes Association Position Statement, �??Screening for Type 2 Diabetes,�?? Diabetes Care 26, S21-S24 (2003).

M.M. Engelgau, K.M.V. Narayan, and W.H. Herman, �??Screening for Type 2 diabetes,�?? Diabetes Care 23, 1563-1580 (2000).
[CrossRef] [PubMed]

M.H. Dominiczak, J. Bell, N.H. Cox, D.C. McCruden, S.K. Jones, A.Y. Finlay, I.W. Percy-Robb, and B.M. Frier, �??Increased collagen-linked fluorescence in skin of young patients with type 1 diabetes mellitus,�?? Diabetes Care 13, 468-72 (1990).
[CrossRef] [PubMed]

B.A. Buckingham, J. Uitto, C. Sandborg, T. Keens, T. Roe, G. Costin, F. Kaufman, B. Bernstein, B Landing, and A. Castellano, �??Scleroderma-like changes in insulin-dependent diabetes mellitus: Clinical and biochemical studies,�?? Diabetes Care 7, 163-169 (1984).
[CrossRef] [PubMed]

Diabetes Metab. Res. Rev. (1)

M.I. Harris and R.C. Eastman, �??Early detection of undiagnosed diabetes mellitus: a US perspective,�?? Diabetes Metab. Res. Rev. 16, 230-236 (2001).
[CrossRef]

Diabetes Research (1)

S.M. Manley, L.C. Meyer, H.A.W. Neil, I.S. Ross, R.C. Turner and R.R. Holman, �??UKPDS 6 Complications in newly diagnosed type 2 diabetic patients and their association with different clinical and biologic risk factors,�?? Diabetes Research 13, 1-11 (1990)

Diabetologia (2)

J.M. Mooy, P.A. Grootenhuis, H. de Vries, P.J. Kostense, C. Popp-Snijders, L.M. Bouter, R.J. Heine, �??Intraindividual variation of glucose, specific insulin and proinsulin concentrations measured by two oral glucose tolerance tests in a general Caucasian population: the Hoorn Study,�?? Diabetologia 39, 298-305 (1996).
[CrossRef] [PubMed]

P. Koefoed Theil, T. Hansen, M. Larsen, O. Pedersen, and H. Lund-Andersen, �??Lens autofluorescence is increased in newly diagnosed patients with NIDDM,�?? Diabetologia 39, 1524-1527 (1996).
[CrossRef]

Exp. Eye Res. (1)

T. Abiko, A. Abiko, S. Ishiko, M. Takeda, S. Horiuchi, and A. Yoshida A, �??Relationship between autofluorescence and advanced glycation end products in diabetic lenses,�?? Exp. Eye Res. 68, 361-366 (1999).
[CrossRef] [PubMed]

Global Burden of Disease 2000 (1)

S. Wild, G. Roglic, R. Sicree, A. Green, H. King, �??Global burden of diabetes mellitus in the year 2000,�?? in Global Burden of Disease 2000 (World Health Organization, Geneva, 2003).

J. Am. Acad. Dermatol. (1)

W. Hanna, D. Friesen, C. Bombardier, D. Gladman, and A. Hanna, �??Pathologic features of diabetic thick skin,�?? J. Am. Acad. Dermatol. 16, 546-553 (1987).
[CrossRef] [PubMed]

J. Biol. Chem. (2)

N. Verzijl, J. DeGroot, S.R. Thorpe, R.A. Bank, J.N. Shaw, T.J. Lyons, J.W.J. Bijlsam, F.P.J.G. Lafeber, J.W. Baynes, and J.M. TeKoppele, �??Effect of collagen turnover on the accumulation of advanced glycation end products,�?? J. Biol. Chem. 275, 39027-39031 (2000).
[CrossRef] [PubMed]

D.L. Price, P.M. Rhett, S.R. Thorpe, and J.W. Baynes, �??Chelating activity of Advanced Glycation Endproduct inhibitors,�?? J. Biol. Chem. 276, 48967-48972 (2001).
[CrossRef] [PubMed]

J. Biomed. Optics (1)

S Yeh, O.S. Khalil, C.F. Hanna, and S. Kantor, �??Near-infrared thermo-optical response of the localized reflectance of intact diabetic and nondiabetic human skin,�?? J. Biomed. Optics 8, 534-544 (2003).
[CrossRef]

J. Biomed. Optics. (1)

N. Yu, B.S. Krantz, J.A. Eppstein, K.D. Ignotz, M.A. Samuels, J.R. Long, and J. Price, �??Development of a noninvasive diabetes screening device using the ratio of fluorescence to Rayleigh scattered light,�?? J. Biomed. Optics. 1, 280-288 (1996).
[CrossRef]

J. Clin. Invest. (3)

D.G. Dyer, J.A. Dunn, S.R. Thorpe, K.E. Bailie, T.J. Lyons, D.R. McCance, and J.W. Baynes, �??Accumulation of Maillard reaction products in skin collagen in diabetes and aging,�?? J. Clin. Invest. 91, 2463-2469 (1993).
[CrossRef] [PubMed]

R. McCance, D.G. Dyer, J.A. Dunn, K.E. Bailie, S.R. Thorpe, J.W. Baynes, and T.J.Lyons, �??Maillard reaction products and theor relation to complications in insulin-dependent diabetes mellitus,�?? J. Clin. Invest. 91, 2470-2478 (1993).
[CrossRef] [PubMed]

B. Buckingham and K.M. Reiser, �??Relationship between the Content of Lysyl Oxidase-dependent Crosslinks in Skin Collagen, Nonenzymatic Glycosylation, and Long-Term Complications in type 1 Diabetes Mellitus,�?? J. Clin. Invest. 86, 1046-1054 (1990).
[CrossRef] [PubMed]

J. Invest. Dermatol. (2)

L. Brancaleon, G. Lin, and N. Kollias, �??The in vivo fluorescence of tryptophan moieties in human skin increases with UV exposure and is a marker for epidermal proliferation,�?? J. Invest. Dermatol. 113, 977-982 (1999).
[CrossRef] [PubMed]

R. Gilles, G. Zonios, R.R. Anderson, and N. Kollilas, �??Fluorescence excitation spectroscopy provides information about human skin in vivo,�?? J. Invest. Dermatol. 115, 704-707 (2000).
[CrossRef]

J. Near Infrared Spectroscopy (1)

P. Geladi, J. Nyström, J.W. Eriksson, A. Nilsson, F. Lithner, and B. Lindholm-Sethson, �??A multivariate NIR study of skin alterations in diabetic patients as compared to control subjects,�?? J. Near Infrared Spectroscopy 8, 217-27 (2000).
[CrossRef]

Lancet (1)

UK Prospective Diabetes Study (UKPDS) Group, �??Intensive blood-glucose control with sulphonylurias or insulin compared with conventional treatment and risk of complications in patients with type 2 diabetes (UKPDS 33),�?? Lancet 352, 837-853 (1998).
[PubMed]

Med. Biol. Eng. Comput. (1)

J. Nystrom, B. Lindholm-Sethson, L. Stenberg, S. Ollmar, J.W. Eriksson, and P. Geladi, �??Combined nearinfrared spectroscopy and multifrequency bioimpedance investigation of skin alterations in diabetes patients based on multivariate analyses,�?? Med. Biol. Eng. Comput. 4, 9-324 (2003).
[CrossRef]

N. Eng. J. Med. (1)

The Diabetes Control and Complications Trial Research Group, �??The effect of intensive treatment of diabetes on the development and progression of long-term complications in insulin-dependent diabetes mellitus,�?? N. Eng. J. Med. 329, 977-986 (1993).

Opt. Lett. (1)

Photochem. Photobiol. (1)

J.C. Finlay, D.L. Conover, E.L. Hull, and T.H. Foster, �??Prophyrin bleaching and PDT-induced spectral changes are irradiance-dependent in ALA-sensitized normal rat skin in vivo,�?? Photochem. Photobiol. 73, 54-63 (2001).
[CrossRef] [PubMed]

Proc 2nd Int???l Symp Information Theory (1)

H. Akaike, �??Information theory and an extension of the maximum likelihood principle,�?? Proc 2nd Int�??l Symp Information Theory, 267-281, (1973).

Other (5)

C. Huberty, Applied Discriminant Analysis, (J Wiley and Sons, NY, 1994).

H. Martens and T. Naes, Multivariate Calibration, (John Wiley and Sons, Chichester, 1989).

National diabetes fact sheet: general information and national estimates on diabetes in the United States 2000,�?? (Centers for Disease Control and Prevention, U.S. Department of Health and Human Services Atlanta, GA 2002).

The Third National Health and Nutrition Examination Survey (NHANES III, 1988-94), National Center for Health Statistics, Centers for Disease Control and Prevention (1996), <a href="http://www.cdc.gov/nchs/about/major/nhanes/NHANESIII_Reference_Manuals.htm">http://www.cdc.gov/nchs/about/major/nhanes/NHANESIII_Reference_Manuals.htm</a>

Diabetes Detection Initiative, US Department of Health and Human Services,<a href="http://www.ndep.nih.gov/ddi/"> http://www.ndep.nih.gov/ddi/</a>

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Figures (9)

Fig. 1.
Fig. 1.

Accumulation of CML (left) and pentosidine (right) during incubation.

Fig. 2.
Fig. 2.

Mean intra-subject variance of corrected fluorescence (left) and correlation between subject age and corrected fluorescence (right) as function of correction factors kx and km.

Fig. 3.
Fig. 3.

Schematic representation of a single cross-validation iteration. Validation data (red box) consisted of all spectra from a given specimen collected on a single study day (in this case, the fourth normoglycemic specimen on the third study day). Calibration data (blue boxes) consisted of spectra from all specimens except the validation specimen (i.e., the vertical column of gray boxes) obtained on all days except the validation study day (i.e., the horizontal row of gray boxes). Calibration data were mean-centered according to their incubation medium in order to eliminate medium-specific biases that could unfairly inform the PLS model. The mean spectrum of the calibration data from the appropriate incubation medium was subtracted from the validation data prior to generation of PLS AGE estimates.

Fig. 4
Fig. 4

Average NIR reflectance spectra for all specimens in each incubation medium. Each trace depicts the average spectrum of all specimens in a given incubation medium on one of the 10 days of spectral data acquisition during the 5-week experiment. Vertical axes are identical for all three panels.

Fig. 5
Fig. 5

Average fluorescence excitation spectra (λ x = 315-385 nm, λ m = 400 nm) for all specimens in each incubation medium.

Fig. 6
Fig. 6

Cross-Validated Standard Errors of Prediction for CML and Pentosidine using both NIR data sets (transmission, reflectance; dashed lines), the three independent fluorescence data sets (M1, X1, X2; thinner solid lines), and the three fluorescence data sets appended together into a single large spectrum (thick solid line). ● = statistically significant result, □= optimum number of PLS model factors as computed by Akaike’s Information Criterion [37].

Fig. 7
Fig. 7

PLS predictions from analysis of the appended fluorescence spectral data set vs. wet-chemical assay results for CML (left panel) and pentosidine (right panel).

Fig. 8
Fig. 8

Control CVSEP curves for CML and Pentosidine using both NIR data sets (transmission, reflectance; dashed lines), the three independent fluorescence data sets (M1, X1, X2; thinner solid lines), and the three fluorescence data sets appended together into a single large spectrum (thicker solid line). For the control cases, the reference values for the hyperglycemic and normoglycemic specimens were switched. ● = statistically significant result.

Fig. 9.
Fig. 9.

Left panel: CML concentrations from wet chemical assays of punch biopsy specimens taken from Type 1 diabetic patients and nondiabetic controls (reproduced from Ref. 16). Right panel: Receiver-Operator Characteristic (ROC) curves calculated by cross-validated quadratic discriminants analysis of the data in the left panel under assumptions noninvasive measurement errors of zero (blue line), 0.5 mmol/mol lysine (green line), and 1.0 mmol/mol lysine (red line). The measurement error encountered in the in vitro experiment was 1.24 mmol/mol lysine.

Equations (3)

Equations on this page are rendered with MathJax. Learn more.

f xm = F xm R x k x R m k m
AGE = b ̂ · s val ,
CVSEP = i = 1 N pred e i 2 / ( N pred 3 ) ,

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