Original article
Vol. 149 No. 5152 (2019)
Glycaemic patterns in healthy elderly individuals and in those with impaired glucose metabolism – exploring the relationship with nonglycaemic variables
- Pedro Medina Escobar
- Benjamin Sakem
- Lorenz Risch
- Martin Risch
- Chris Grebhardt
- Urs E. Nydegger
- Zeno Stanga
Summary
OBJECTIVE
The SENIORLABOR study data were explored (i) to examine the evolution during senescence of the differences between measured glycated haemoglobin (HbA1c) values and the values predicted by using regression to extrapolate from measured fructosamine levels; (ii) to scrutinise the relationship between the glycation gap and insulin resistance using a homeostasis model assessment, and between the glycation gap and a low-grade inflammation marker (C-reactive protein serum concentration); and (iii) to investigate the glycation gap ranges in relation to triglyceride levels and kidney function.
SUBJECTS AND METHODS
A total of 1432 Swiss individuals aged >60 years and classified as healthy (547), prediabetic (701) or diabetic (184) based on their fasting plasma glucose and HbA1c values were included in the study. The glycation gap was evaluated and assigned to one of four categories: <−0.5; −0.5 to <0.0; 0.0 to ≤0.5; >0.5.
RESULTS
In healthy and prediabetic participants, the homeostasis model assessment for estimation of insulin resistance (p <0.01), high-sensitivity C-reactive protein (p <0.001) and triglyceride (p = 0.02) values tended to increase with increasing glycation gap category and were highest in the glycation gap category >0.5. Homeostasis model assessment for estimation of insulin resistance, high-sensitivity C-reactive protein and triglyceride levels tended to increase with increasing glycation gap category and were highest in the glycation gap category >0.5. Significant differences (p <0.01) between glycation gap categories were seen among different high-sensitivity C-reactive protein concentration groups. Interestingly, in diabetic participants, homeostasis model assessment for estimation of insulin resistance values, triglyceride concentrations and estimation of glomerular filtration values all decreased with decreasing glycation gap category. In the group of participants with a glycation gap >0.5, high-sensitivity C-reactive protein values tended to increase with increasing glycation gap, whereas for participants with type 2 diabetes and in the glycation gap group >0.5, high-sensitivity C-reactive protein levels tended to decrease as the glycation gap increased. The percentage of participants with type 2 diabetes mellitus increased from 2% in the glycation gap category <−0.5 to 76% in the glycation gap category >0.5. In contrast, the percentage of healthy participants fell from 85% to 7%.
CONCLUSION
This is the first time that a direct comparison of healthy, prediabetic and diabetic participants, all assessed under identical conditions and using identical methodology, has clearly demonstrated a different glycation gap pattern. Thus, we contribute evidence that the glycation gap might be of interest in the care of diabetic patients and their prophylaxis, while acknowledging that more studies are needed to confirm our findings. (Trial registration number ISRCTN53778569)
References
- Vetter SW. Glycated Serum Albumin and AGE Receptors. Adv Clin Chem. 2015;72:205–75. doi:.https://doi.org/10.1016/bs.acc.2015.07.005
- Jensen JL, Indurthi VS, Neau DB, Vetter SW, Colbert CL. Structural insights into the binding of the human receptor for advanced glycation end products (RAGE) by S100B, as revealed by an S100B-RAGE-derived peptide complex. Acta Crystallogr D Biol Crystallogr. 2015;71(Pt 5):1176–83. doi:.https://doi.org/10.1107/S1399004715004216
- Haji-Ghassemi O, Blackler RJ, Martin Young N, Evans SV. Antibody recognition of carbohydrate epitopes. Glycobiology. 2015;25(9):920–52. doi:.https://doi.org/10.1093/glycob/cwv037
- Frank F, Bezold V, Bork K, Rosenstock P, Scheffler J, Horstkorte R. Advanced glycation endproducts and polysialylation affect the turnover of the neural cell adhesion molecule (NCAM) and the receptor for advanced glycation endproducts (RAGE). Biol Chem. 2019;400(2):219–26. doi:.https://doi.org/10.1515/hsz-2018-0291
- Mariño L, Casasnovas R, Ramis R, Vilanova B, Ortega-Castro J, Frau J, et al. Does glycation really distort the peptide α-helicity? Int J Biol Macromol. 2019;129:254–66. doi:.https://doi.org/10.1016/j.ijbiomac.2019.01.213
- Su D, Zhao H, Xia H. Glycosylation-modified erythropoietin with improved half-life and biological activity. Int J Hematol. 2010;91(2):238–44. doi:.https://doi.org/10.1007/s12185-010-0496-x
- Kurcon T, Liu Z, Paradkar AV, Vaiana CA, Koppolu S, Agrawal P, et al. miRNA proxy approach reveals hidden functions of glycosylation. Proc Natl Acad Sci USA. 2015;112(23):7327–32. doi:.. Corrections in: Proc Natl Acad Sci USA. 2015;112(33):E4631. Proc Natl Acad Sci USA. 2015;112(33):E4632–5 https://doi.org/10.1073/pnas.1502076112
- Goldin A, Beckman JA, Schmidt AM, Creager MA. Advanced glycation end products: sparking the development of diabetic vascular injury. Circulation. 2006;114(6):597–605. doi:.https://doi.org/10.1161/CIRCULATIONAHA.106.621854
- Shastri S, Katz R, Rifkin DE, Fried LF, Odden MC, Peralta CA, et al. Kidney function and mortality in octogenarians: Cardiovascular Health Study All Stars. J Am Geriatr Soc. 2012;60(7):1201–7. doi:.https://doi.org/10.1111/j.1532-5415.2012.04046.x
- Bansal N, Katz R, De Boer IH, Peralta CA, Fried LF, Siscovick DS, et al. Development and validation of a model to predict 5-year risk of death without ESRD among older adults with CKD. Clin J Am Soc Nephrol. 2015;10(3):363–71. doi:.https://doi.org/10.2215/CJN.04650514
- Frasca D, Blomberg BB. Inflammaging decreases adaptive and innate immune responses in mice and humans. Biogerontology. 2016;17(1):7–19. doi:.https://doi.org/10.1007/s10522-015-9578-8
- Campbell L, Pepper T, Shipman K. HbA1c: a review of non-glycaemic variables. J Clin Pathol. 2019;72(1):12–9. doi:.https://doi.org/10.1136/jclinpath-2017-204755
- Jaisson S, Leroy N, Guillard E, Desmons A, Gillery P. Analytical performances of the D-100TM hemoglobin testing system (Bio-Rad) for HbA1c assay. Clin Chem Lab Med. 2015;53(9):1473–9. doi:.https://doi.org/10.1515/cclm-2015-0288
- Kameya M, Sakaguchi-Mikami A, Ferri S, Tsugawa W, Sode K. Advancing the development of glycated protein biosensing technology: next-generation sensing molecules. J Diabetes Sci Technol. 2015;9(2):183–91. doi:.https://doi.org/10.1177/1932296814565784
- Nansseu JR, Fokom-Domgue J, Noubiap JJ, Balti EV, Sobngwi E, Kengne AP. Fructosamine measurement for diabetes mellitus diagnosis and monitoring: a systematic review and meta-analysis protocol. BMJ Open. 2015;5(5):e007689. doi:.https://doi.org/10.1136/bmjopen-2015-007689
- Selvin E, Rawlings AM, Lutsey PL, Maruthur N, Pankow JS, Steffes M, et al. Fructosamine and Glycated Albumin and the Risk of Cardiovascular Outcomes and Death. Circulation. 2015;132(4):269–77. doi:.https://doi.org/10.1161/CIRCULATIONAHA.115.015415
- Akatsuka J, Mochizuki M, Musha I, Ohtake A, Kobayashi K, Kikuchi T, et al.; Japanese Study Group of Insulin Therapy for Childhood and Adolescent Diabetes. The ratio of glycated albumin to hemoglobin A1c measured in IFCC units accurately represents the glycation gap. Endocr J. 2015;62(2):161–72. doi:.https://doi.org/10.1507/endocrj.EJ14-0066
- Cohen RM, Holmes YR, Chenier TC, Joiner CH. Discordance between HbA1c and fructosamine: evidence for a glycosylation gap and its relation to diabetic nephropathy. Diabetes Care. 2003;26(1):163–7. doi:.https://doi.org/10.2337/diacare.26.1.163
- Zafon C, Ciudin A, Valladares S, Mesa J, Simó R. Variables involved in the discordance between HbA1c and fructosamine: the glycation gap revisited. PLoS One. 2013;8(6):e66696. doi:.https://doi.org/10.1371/journal.pone.0066696
- Nayak AU, Singh BM, Dunmore SJ. Potential Clinical Error Arising From Use of HbA1c in Diabetes: Effects of the Glycation Gap. Endocr Rev. 2019;40(4):988–99. doi:.https://doi.org/10.1210/er.2018-00284
- Rodríguez-Segade S, Rodríguez J, García Lopez JM, Casanueva FF, Camiña F. Estimation of the glycation gap in diabetic patients with stable glycemic control. Diabetes Care. 2012;35(12):2447–50. doi:.https://doi.org/10.2337/dc11-2450
- Shipman KE, Jawad M, Sullivan KM, Ford C, Gama R. The glycation gap and estimated glomerular filtration rate in individuals without diabetes mellitus. Clin Chem. 2014;60(10):1346–7. doi:.https://doi.org/10.1373/clinchem.2014.223545
- Wu L, Parhofer KG. Diabetic dyslipidemia. Metabolism. 2014;63(12):1469–79. doi:.https://doi.org/10.1016/j.metabol.2014.08.010
- Keane KN, Cruzat VF, Carlessi R, de Bittencourt PI, Jr, Newsholme P. Molecular Events Linking Oxidative Stress and Inflammation to Insulin Resistance and β-Cell Dysfunction. Oxid Med Cell Longev. 2015;2015:181643. doi:.https://doi.org/10.1155/2015/181643
- Medina Escobar P, Moser M, Risch L, Risch M, Nydegger UE, Stanga Z. Impaired glucose metabolism and type 2 diabetes in apparently healthy senior citizens. Swiss Med Wkly. 2015;145:w14209.
- FOPH. Swiss Nutrition Report. In.; 2012.
- Braga F, Panteghini M. Standardization and analytical goals for glycated hemoglobin measurement. Clin Chem Lab Med. 2013;51(9):1719–26. doi:.https://doi.org/10.1515/cclm-2013-0060
- Rodriguez-Segade S, Rodriguez J, García-López JM, Casanueva FF, Coleman IC, Alonso de la Peña C, et al. Influence of the glycation gap on the diagnosis of type 2 diabetes. Acta Diabetol. 2015;52(3):453–9. doi:.https://doi.org/10.1007/s00592-014-0666-z
- Genest J, McPherson R, Frohlich J, Anderson T, Campbell N, Carpentier A, et al. 2009 Canadian Cardiovascular Society/Canadian guidelines for the diagnosis and treatment of dyslipidemia and prevention of cardiovascular disease in the adult - 2009 recommendations. Can J Cardiol. 2009;25(10):567–79. doi:.https://doi.org/10.1016/S0828-282X(09)70715-9
- Inker LA, Eckfeldt J, Levey AS, Leiendecker-Foster C, Rynders G, Manzi J, et al. Expressing the CKD-EPI (Chronic Kidney Disease Epidemiology Collaboration) cystatin C equations for estimating GFR with standardized serum cystatin C values. Am J Kidney Dis. 2011;58(4):682–4. doi:.https://doi.org/10.1053/j.ajkd.2011.05.019
- Inker LA, Schmid CH, Tighiouart H, Eckfeldt JH, Feldman HI, Greene T, et al.; CKD-EPI Investigators. Estimating glomerular filtration rate from serum creatinine and cystatin C. N Engl J Med. 2012;367(1):20–9. doi:.https://doi.org/10.1056/NEJMoa1114248
- Salazar J, Martínez MS, Chávez M, Toledo A, Añez R, Torres Y, et al. C-reactive protein: clinical and epidemiological perspectives. Cardiol Res Pract. 2014;2014:605810. doi:.https://doi.org/10.1155/2014/605810
- American Diabetes Association. Standards of medical care in diabetes--2014. Diabetes Care. 2014;37(Suppl 1):S14–80. doi:.https://doi.org/10.2337/dc14-S014
- Heianza Y, Arase Y, Fujihara K, Tsuji H, Saito K, Hsieh SD, et al. Screening for pre-diabetes to predict future diabetes using various cut-off points for HbA1c and impaired fasting glucose: the Toranomon Hospital Health Management Center Study 4 (TOPICS 4). Diabet Med. 2012;29(9):e279–85. doi:.https://doi.org/10.1111/j.1464-5491.2012.03686.x
- Heianza Y, Arase Y, Hsieh SD, Saito K, Tsuji H, Kodama S, et al. Development of a new scoring system for predicting the 5 year incidence of type 2 diabetes in Japan: the Toranomon Hospital Health Management Center Study 6 (TOPICS 6). Diabetologia. 2012;55(12):3213–23. doi:.https://doi.org/10.1007/s00125-012-2712-0
- Kashino I, Nanri A, Kurotani K, Akter S, Yasuda K, Sato M, et al. Association of dietary patterns with serum adipokines among Japanese: a cross-sectional study. Nutr J. 2015;14(1):58. doi:.https://doi.org/10.1186/s12937-015-0046-8
- Malmström H, Walldius G, Grill V, Jungner I, Gudbjörnsdottir S, Hammar N. Fructosamine is a useful indicator of hyperglycaemia and glucose control in clinical and epidemiological studies--cross-sectional and longitudinal experience from the AMORIS cohort. PLoS One. 2014;9(10):e111463. doi:.https://doi.org/10.1371/journal.pone.0111463
- Nayak AU, Nevill AM, Bassett P, Singh BM. Association of glycation gap with mortality and vascular complications in diabetes. Diabetes Care. 2013;36(10):3247–53. doi:.https://doi.org/10.2337/dc12-1040
- Bartlett WA, Braga F, Carobene A, Coşkun A, Prusa R, Fernandez-Calle P, et al.; Biological Variation Working Group, European Federation of Clinical Chemistry and Laboratory Medicine (EFLM). A checklist for critical appraisal of studies of biological variation. Clin Chem Lab Med. 2015;53(6):879–85. doi:.https://doi.org/10.1515/cclm-2014-1127
- Mosca A, Lapolla A, Gillery P. Glycemic control in the clinical management of diabetic patients. Clin Chem Lab Med. 2013;51(4):753–66. doi:.https://doi.org/10.1515/cclm-2012-0594
- Sartore G, Chilelli NC, Burlina S, Di Stefano P, Piarulli F, Fedele D, et al. The importance of HbA1c and glucose variability in patients with type 1 and type 2 diabetes: outcome of continuous glucose monitoring (CGM). Acta Diabetol. 2012;49(S1, Suppl 1):S153–60. doi:.https://doi.org/10.1007/s00592-012-0391-4
- Cohen RM, Franco RS, Khera PK, Smith EP, Lindsell CJ, Ciraolo PJ, et al. Red cell life span heterogeneity in hematologically normal people is sufficient to alter HbA1c. Blood. 2008;112(10):4284–91. doi:.https://doi.org/10.1182/blood-2008-04-154112
- Khera PK, Smith EP, Lindsell CJ, Rogge MC, Haggerty S, Wagner DA, et al. Use of an oral stable isotope label to confirm variation in red blood cell mean age that influences HbA1c interpretation. Am J Hematol. 2015;90(1):50–5. doi:.https://doi.org/10.1002/ajh.23866
- Steele AM, Wensley KJ, Ellard S, Murphy R, Shepherd M, Colclough K, et al. Use of HbA1c in the identification of patients with hyperglycaemia caused by a glucokinase mutation: observational case control studies. PLoS One. 2013;8(6):e65326. doi:.https://doi.org/10.1371/journal.pone.0065326
- Donath MY, Shoelson SE. Type 2 diabetes as an inflammatory disease. Nat Rev Immunol. 2011;11(2):98–107. doi:.https://doi.org/10.1038/nri2925
- Liu CT, Merino J, Rybin D, DiCorpo D, Benke KS, Bragg-Gresham JL, et al. Genome-wide Association Study of Change in Fasting Glucose over time in 13,807 non-diabetic European Ancestry Individuals. Sci Rep. 2019;9(1):9439. doi:.https://doi.org/10.1038/s41598-019-45823-7
- Gayoso-Diz P, Otero-González A, Rodriguez-Alvarez MX, Gude F, García F, De Francisco A, et al. Insulin resistance (HOMA-IR) cut-off values and the metabolic syndrome in a general adult population: effect of gender and age: EPIRCE cross-sectional study. BMC Endocr Disord. 2013;13(1):47. doi:.https://doi.org/10.1186/1472-6823-13-47
- Klonoff DC. Hemoglobinopathies and Hemoglobin A1c in Diabetes Mellitus. J Diabetes Sci Technol. 2019:1932296819841698. doi:.https://doi.org/10.1177/1932296819841698
- Johnson AMF, Olefsky JM. The origins and drivers of insulin resistance. Cell. 2013;152(4):673–84. doi:.https://doi.org/10.1016/j.cell.2013.01.041
- Lenters-Westra E, English E. Evaluating new HbA1c methods for adoption by the IFCC and NGSP reference networks using international quality targets. Clin Chem Lab Med. 2017;55(9):1426–34. doi:.https://doi.org/10.1515/cclm-2017-0109
- Danese E, Montagnana M, Nouvenne A, Lippi G. Advantages and pitfalls of fructosamine and glycated albumin in the diagnosis and treatment of diabetes. J Diabetes Sci Technol. 2015;9(2):169–76. doi:.https://doi.org/10.1177/1932296814567227
- Dunmore SJ, Al-Derawi AS, Nayak AU, Narshi A, Nevill AM, Hellwig A, et al. Evidence That Differences in Fructosamine-3-Kinase Activity May Be Associated With the Glycation Gap in Human Diabetes. Diabetes. 2018;67(1):131–6. doi:.https://doi.org/10.2337/db17-0441
- Rawshani A, Rawshani A, Franzén S, Sattar N, Eliasson B, Svensson AM, et al. Risk Factors, Mortality, and Cardiovascular Outcomes in Patients with Type 2 Diabetes. N Engl J Med. 2018;379(7):633–44. doi:.https://doi.org/10.1056/NEJMoa1800256
- Sacks DB, Nathan DM, Lachin JM. Gaps in the glycation gap hypothesis. Clin Chem. 2011;57(2):150–2. doi:.https://doi.org/10.1373/clinchem.2010.158071
- Perry RJ, Samuel VT, Petersen KF, Shulman GI. The role of hepatic lipids in hepatic insulin resistance and type 2 diabetes. Nature. 2014;510(7503):84–91. doi:.https://doi.org/10.1038/nature13478
- Tamura Y, Izumiyama-Shimomura N, Kimbara Y, Nakamura K, Ishikawa N, Aida J, et al. β-cell telomere attrition in diabetes: inverse correlation between HbA1c and telomere length. J Clin Endocrinol Metab. 2014;99(8):2771–7. doi:.https://doi.org/10.1210/jc.2014-1222
- Dubowitz N, Xue W, Long Q, Ownby JG, Olson DE, Barb D, et al. Aging is associated with increased HbA1c levels, independently of glucose levels and insulin resistance, and also with decreased HbA1c diagnostic specificity. Diabet Med. 2014;31(8):927–35. doi:.https://doi.org/10.1111/dme.12459
- Chaudhuri J, Bains Y, Guha S, Kahn A, Hall D, Bose N, et al. The Role of Advanced Glycation End Products in Aging and Metabolic Diseases: Bridging Association and Causality. Cell Metab. 2018;28(3):337–52. doi:.https://doi.org/10.1016/j.cmet.2018.08.014