Discrepancies between HbA1c and glucose management indicator (GMI) may reflect individual variations in glycation rate, independent of mean glycemia, and could influence complication risk stratification in type 1 diabetes (T1D). We evaluated the phenotype of individuals with T1D using continuous glucose monitoring (CGM), identified as high glycators based on HbA1c/updatedGMI ratio, and assessed retrospectively their risk of diabetic retinopathy (DR) and the time to DR diagnosis. The secondary aim was to identify clinical correlates of high glycation. Primary outcome: time to first diagnosis of DR. Secondary outcomes: clinical factors associated with high glycation.
Methods:
A retrospective study of 411 individuals with T1D using CGM and concurrent HbA1c values. Patients with conditions affecting red blood cell (RBC) lifespan were excluded. Participants were divided into 3 subgroups based on current HbA1c/updatedGMI ratio ≤0.95 (low glycators), >0.95 and <1.05 (concordant glycators), and ≥1.05 (high glycators). Time to diagnosis of DR was retrieved.
Results:
High glycation is associated with shorter time to first diagnosis of DR (adjusted hazard ratio 1.60). Non-HDL-C, RBC indices, and metformin were associated with high glycation.
Conclusion:
Among individuals with T1D, an HbA1c/updatedGMI ratio ≥1.05 is associated with higher odds of DR. Non-HDL-C and RBC indices are correlates of high glycation. These results underscore the relevance of HbA1c and updatedGMI discrepancy in cardiometabolic risk assessment, but cutoffs remain to be set.
BattelinoTDanneTBergenstalRM, et al. Clinical targets for continuous glucose monitoring data interpretation: recommendations from the international consensus on time in range. Diabetes Care. 2019;42(8):1593-1603.
2.
SacksDBNathanDMLachinJM.Gaps in the glycation gap hypothesis. Clin Chem. 2011;57(2):150-152.
3.
Puig-JoveCVinalsCCongetI, et al. Association between the GMI/HbA1c ratio and preclinical carotid atherosclerosis in type 1 diabetes: impact of the fast-glycator phenotype across age groups. Cardiovasc Diabetol. 2025;24(1):75.
4.
MaranAMorieriMLFalaguastaDAvogaroAFadiniGP.The fast-glycator phenotype, skin advanced glycation end products, and complication burden among people with type 1 diabetes. Diabetes Care. 2022;45(10):2439-2444.
5.
Sager-La GangaCArranz-MartinJAJimenez-DiazJ, et al. The GMI/HbA1c ratio does not independently predict diabetic retinopathy in adults with Type 1 diabetes. Sci Rep. 2025;15(1):35825.
6.
McCarterRJHempeJMGomezRChalewSA.Biological variation in HbA1c predicts risk of retinopathy and nephropathy in type 1 diabetes. Diabetes Care. 2004;27(6):1259-1264.
7.
FelipeDLHempeJMLiuS, et al. Skin intrinsic fluorescence is associated with hemoglobin A(1c)and hemoglobin glycation index but not mean blood glucose in children with type 1 diabetes. Diabetes Care. 2011;34(8):1816-1820.
8.
JiXLYinMDengC, et al. Hemoglobin glycation index among adults with type 1 diabetes: association with double diabetes features. World J Diabetes. 2025;16(4):100917.
9.
ShahVNKanapkaLGKarakusKEKollmanCBeckRW.The association of high and low glycation with incident diabetic retinopathy in adults with type 1 diabetes. J Diabetes Sci Technol. 2024;19:1481-1485.
10.
OriotPViryCVandelaerA, et al. Discordance between glycated hemoglobin A1c and the glucose management indicator in people with diabetes and chronic kidney disease. J Diabetes Sci Technol. 2023;17(6):1553-1562.
11.
Gomez-PeraltaFChoudharyPCossonEIraceCRami-MerharBSeiboldA.Understanding the clinical implications of differences between glucose management indicator and glycated haemoglobin. Diabetes Obes Metab. 2022;24(4):599-608.
12.
BergenstalRMBeckRWCloseKL, et al. Glucose management indicator (GMI): a new term for estimating A1C from continuous glucose monitoring. Diabetes Care. 2018;41(11):2275-2280.
13.
AzcoitiaPRodríguez-CastellanoRSaavedraP, et al. Age and red blood cell parameters mainly explain the differences between HbA1c and glycemic management indicator among patients with type 1 diabetes using intermittent continuous glucose monitoring. J Diabetes Sci Technol. 2024;18(6):1370-1376.
14.
PerlmanJEGooleyTAMcNultyBMeyersJHirschIB.HbA1c and glucose management indicator discordance: a real-world analysis. Diabetes Technol Ther. 2021;23(4):253-258.
15.
BergenstalRMBeckRWCloseKL, et al. Response to comment on Bergenstal et al. Glucose management indicator (GMI): a new term for estimating A1C from continuous glucose monitoring. Diabetes Care2018;41:2275-2280. Diabetes Care. 2019;42(2):e29-e30.
16.
MontaserEAbadSEShahVN.Changes in A1C versus GMI across glycemic categories in clinical trials of type 1 diabetes. J Clin Endocrinol Metab. 2025;110(12):e4182-e4187.
17.
ShahVNVigersTPyleLCalhounPBergenstalRM.Discordance between glucose management indicator and glycated hemoglobin in people without diabetes. Diabetes Technol Ther. 2023;25(5):324-328.
18.
BrownleeM.The pathobiology of diabetic complications: a unifying mechanism. Diabetes. 2005;54(6):1615-1625.
19.
LachinJMGenuthSNathanDMRutledgeBN.The hemoglobin glycation index is not an independent predictor of the risk of microvascular complications in the Diabetes Control and Complications Trial. Diabetes. 2007;56(7):1913-1921.
20.
DunnTCXuYBergenstalRMOgawaWAjjanRA.Personalized glycated hemoglobin in diabetes management: closing the gap with glucose management indicator. Diabetes Technol Ther. 2023;25(S3):S65-S74.
21.
Lenters-WestraEFokkertMKilpatrickES, et al. Managing discordance between HbA(1c) and glucose management indicator. Diabet Med. 2025;42(6):e70023.
22.
FreckmannGWehrstedtSEichenlaubM, et al. A comparative analysis of glycemic metrics derived from three continuous glucose monitoring systems. Diabetes Care. 2025;48:1213-1217.
23.
YooJHMoonSJParkCYKimJH.Differences between glycated hemoglobin and glucose management indicator in real-time and intermittent scanning continuous glucose monitoring in adults with type 1 diabetes. J Diabetes Sci Technol. 2024;20:103-112.
24.
ShahVNXuYDabiriYMohanadasHPChengADunnTC.Association of HbA(1c) and an updated glucose management indicator (uGMI) with incident diabetic retinopathy in adults with type 1 diabetes: a longitudinal study. Diabetologia. 2025;69:610-617.
25.
XuYDunnTCAjjanRA.A Kinetic model for glucose levels and hemoglobin A1c provides a novel tool for individualized diabetes management. J Diabetes Sci Technol. 2021;15(2):294-302.
26.
XuYGrimsmannJMKargesB, et al. Personal glycation factors and calculated hemoglobin a1c for diabetes management: real-world data from the diabetes prospective follow-up (DPV) registry. Diabetes Technol Ther. 2021;23(6):452-459.
27.
Kidney Disease: Improving Global Outcomes Diabetes Work Group. KDIGO 2020 clinical practice guideline for diabetes management in chronic kidney disease. Kidney Int. 2020;98(4S):S1-S115.
28.
LimJIKimSJBaileyST, et al. Diabetic retinopathy preferred practice pattern(R). Ophthalmology. 2025;132(4):P75-P162.
29.
ChalewSHempeJMcCarterR.Comment on: Lachin et al. (2007) The hemoglobin glycation index is not an independent predictor of the risk of microvascular complications in the diabetes control and complications trial: Diabetes 56:1913-1921, 2007. Diabetes. 2008;57(2):e4; author reply e5.
30.
WuWZBaiYP.Endothelial GLUTs and vascular biology. Biomed Pharmacother. 2023;158:114151.
31.
KaiserNSassonSFeenerEP, et al. Differential regulation of glucose transport and transporters by glucose in vascular endothelial and smooth muscle cells. Diabetes. 1993;42(1):80-89.
32.
TakagiHKingGLAielloLP.Hypoxia upregulates glucose transport activity through an adenosine-mediated increase of GLUT1 expression in retinal capillary endothelial cells. Diabetes. 1998;47(9):1480-1488.
33.
CohenRMFrancoRSKheraPK, et al. Red cell life span heterogeneity in hematologically normal people is sufficient to alter HbA1c. Blood. 2008;112(10):4284-4291.
34.
KheraPKJoinerCHCarruthersA, et al. Evidence for interindividual heterogeneity in the glucose gradient across the human red blood cell membrane and its relationship to hemoglobin glycation. Diabetes. 2008;57(9):2445-2452.
35.
XuYOriotPDunnTC, et al. Evaluation of continuous glucose monitoring-derived person-specific HbA1c in the presence and absence of complications in type 1 diabetes. Diabetes Obes Metab. 2022;24(12):2383-2390.
36.
ZafonCCiudinAValladaresSMesaJSimóR.Variables involved in the discordance between HbA1c and fructosamine: the glycation gap revisited. PLoS ONE. 2013;8(6):e66696.
37.
NakasoneYMiyakoshiTSakumaT, et al. Hemoglobin glycation index: a novel risk factor for incident chronic kidney disease in an apparently healthy population. J Clin Endocrinol Metab. 2024;109(3):e1055-e1060.
38.
FiorentinoTVMariniMASuccurroE, et al. Association between hemoglobin glycation index and hepatic steatosis in non-diabetic individuals. Diabetes Res Clin Pract. 2017;134:53-61.
39.
MariniMAFiorentinoTVSuccurroE, et al. Association between hemoglobin glycation index with insulin resistance and carotid atherosclerosis in non-diabetic individuals. PLoS ONE. 2017;12(4):e0175547.
40.
KhalidMPetroianuGAdemA.Advanced glycation end products and diabetes mellitus: mechanisms and perspectives. Biomolecules. 2022;12(4):542.
41.
Jansson SigfridsFDahlströmEHForsblomC, et al. Remnant cholesterol predicts progression of diabetic nephropathy and retinopathy in type 1 diabetes. J Intern Med. 2021;290(3):632-645.
42.
PanWHanYHuHHeY.The non-linear link between remnant cholesterol and diabetic retinopathy: a cross-sectional study in patients with type 2 diabetic mellitus. BMC Endocr Disord. 2022;22(1):326.
43.
KarimiMAVaeziAAnsariA, et al. Lipid variability and risk of microvascular complications in patients with diabetes: a systematic review and meta-analysis. BMC Endocr Disord. 2024;24(1):4.
44.
MalandrinoNWuWCTaveiraTHWhitlatchHBSmithRJ.Association between red blood cell distribution width and macrovascular and microvascular complications in diabetes. Diabetologia. 2012;55(1):226-235.
45.
LiuSHempeJMMcCarterRJLiSFonsecaVA.Association between inflammation and biological variation in hemoglobin A1c in U.S. nondiabetic adults. J Clin Endocrinol Metab. 2015;100(6):2364-2371.
46.
EngströmGSmithJGPerssonMNilssonPMMelanderOHedbladB.Red cell distribution width, haemoglobin A1c and incidence of diabetes mellitus. J Intern Med. 2014;276(2):174-183.
47.
BaoXWanMGuY, et al. Red cell distribution width is associated with hemoglobin A1C elevation, but not glucose elevation. J Diabetes Complications. 2017;31(10):1544-1548.
48.
HamdanMAHempeJMVelasco-GonzalezCGomezRVargasAChalewS.Differences in red blood cell indices do not explain racial disparity in hemoglobin A1c in children with type 1 diabetes. J Pediatr. 2016;176:197-199.
49.
RapinJRLespinasseCYoaRWiernspergerN.Erythrocyte glucose consumption in insulin-dependent diabetes: effect of metformin in vitro. Diabete Metab. 1991;17(1, Pt 2):164-167.
50.
YoaRGRapinJRWiernspergerNFMartinandABellevilleI.Demonstration of defective glucose uptake and storage in erythrocytes from non-insulin dependent diabetic patients and effects of metformin. Clin Exp Pharmacol Physiol. 1993;20(9):563-567.
51.
SumitaniSMoritaSDeguchiR, et al. Metformin decreases glycated albumin to glycated haemoglobin ratio in patients with newly diagnosed type 2 diabetes. Ann Clin Biochem. 2015;52(Pt 1):76-81.
52.
SikdarJSealPRoyAHaldarR.Cigarette smokers develop altered erythrocyte membrane composition: an investigation unmasking the role of membrane bound integral protein GLUT 1. Free Radic Res. 2017;51(4):375-388.
53.
AdesharaKADiwanAGJagtapTRAdvaniKSiddiquiATupeRS.Relationship between plasma glycation with membrane modification, oxidative stress and expression of glucose transporter-1 in type 2 diabetes patients with vascular complications. J Diabetes Complications. 2017;31(2):439-448.
54.
NayakAUHollandMRMacdonaldDRNevillASinghBM.Evidence for consistency of the glycation gap in diabetes. Diabetes Care. 2011;34(8):1712-1716.
55.
HempeJMGomezRMcCarterRJJrChalewSA.High and low hemoglobin glycation phenotypes in type 1 diabetes: a challenge for interpretation of glycemic control. J Diabetes Complications. 2002;16(5):313-320.
56.
CossonEPrevostGOriotP, et al. 1028-P: how stable is the discrepancy between HbA1c and glucose management index? the multicenter Franco–Belgian concordance study over 2 years. Diabetes. 2025;74(Suppl 1):1028-P.
