@article {144783, title = {Albumin Oxidation and Albumin Glycation Discordance During Type 2 Diabetes Therapy: Biological and Clinical Implications.}, journal = {Metab Syndr Relat Disord}, volume = {22}, year = {2024}, month = {2024 Jun}, pages = {372-384}, abstract = {

Cys34 albumin redox modifications (reversible "cysteinylation" and irreversible "di/trioxidation"), besides being just oxidative stress biomarkers, may have primary pathogenetic roles to initiate and/or aggravate cell, tissue, and vascular damage in diabetes. In an exploratory "proof-of-concept" pilot study, we examined longitudinal changes in albumin oxidation during diabetes therapy. Mass spectrometric analysis was utilized to monitor changes in human serum albumin (HSA) post-translational modifications {glycation [glycated albumin (GA)], cysteinylation [cysteinylated albumin (CA) or human non-mercaptalbumin-1; reversible], di/trioxidation (di/trioxidized albumin or human non-mercaptalbumin-2; irreversible), and truncation (truncated albumin)} during ongoing therapy. Four informative groups of subjects were evaluated [type 1 diabetes (T1DM), type 2 diabetes (T2DM), prediabetes-obesity, and healthy controls] at baseline, and subjects with diabetes were followed for a period up to 280 days. At baseline, T2DM was associated with relatively enhanced albumin cysteinylation (CA\% total) compared with T1DM ( = 0.004), despite comparable mean hyperglycemia ( values: hemoglobin A1c = 0.09; GA = 0.09). T2DM, compared with T1DM, exhibited selectively and significantly higher elevations of all the "individual" glycated cum cysteinylated ("multimodified") albumin isoforms ( values: CysHSA+1G = 0.003; CysHSA+2G = 0.007; and CysHSA+3G = 0.001). Improvements in glycemic control and decreases in albumin glycation during diabetes therapy in T2DM were not always associated with concurrent reductions of albumin cysteinylation, and in some therapeutic situations, albumin cysteinylation worsened (glycation-cysteinylation discordance). Important differences were observed between the effects of sulfonylureas and metformin on albumin molecular modifications. T2DM was associated with higher oxidative (cysteinylation) and combined (cysteinylation plus glycation) albumin molecular modifications, which are not ameliorated by improved glucose control alone. Further studies are required to establish the clinical significance and optimal therapeutic strategies to address oxidative protein damage and resulting consequences in diabetes.

}, keywords = {Adult, Aged, Biomarkers, Blood Glucose, Case-Control Studies, Cysteine, Diabetes Mellitus, Type 1, Diabetes Mellitus, Type 2, Female, Glycated Hemoglobin, Glycated Serum Albumin, Glycation End Products, Advanced, Glycosylation, Humans, Hypoglycemic Agents, Male, Metformin, Middle Aged, Oxidation-Reduction, Oxidative Stress, Pilot Projects, Protein Processing, Post-Translational, Serum Albumin, Serum Albumin, Human}, issn = {1557-8518}, doi = {10.1089/met.2023.0275}, author = {Vaishnav, Madhumati S and Kumari, Namita and Srikanta, Sathyanarayana and Simha, Vinaya and Krishnaswamy, Patnam R and Balaram, Padmanabhan and Bhat, Navakanta} } @article {131301, title = {Differential Spectrum of Albumin Glycation, Oxidation, and Truncation in Type 2 and Type 1 Diabetes: Clinical and Biological Implications.}, journal = {Metab Syndr Relat Disord}, year = {2023}, month = {2023 Jul 20}, abstract = {

Albumin, the most abundant and physiologically vital serum protein, accumulates a range of chemical modifications, as consequence of encounters with large number of reactive molecules whose concentrations increase in serum under pathological conditions. In a "proof of concept" study, mass spectrometric analysis was utilized to quantitate albumin post-translational modifications (glycation, oxidation, and truncation; individual isoforms and total) in four informative subject groups [type 1 diabetes (T1DM), type 2 diabetes (T2DM), prediabetes-obesity and healthy; all with estimated glomerular filtration rate >=60 mL/(min{\textperiodcentered}m)]. Besides glycated albumin (GA/mass spectrometry), glycated serum protein (GSP/nitro blue tetrazolium colorimetry), and glycated hemoglobin (HbA1c/high-performance liquid chromatography) were also measured. A wide spectrum of albumin molecular modifications was identified in diabetes, with significant differences between T2DM and T1DM. GA correlated more strongly with HbA1c in T1DM, compared to T2DM. Higher albumin glycation isoforms (human serum albumin +3G/2G) were more stable and discriminative markers of mean glycemia. T2DM, in comparison with T1DM, showed enhanced oxidative and dual (glycation plus oxidation) modifications, representing extreme molecular pathology. There was dramatic reduction ("deficiency") of truncated albumin isoforms in T2DM, and significant reduction in T1DM. Albumin truncation negatively correlated with severity of albumin glycation (mean glycemia) and albumin oxidation (cysteinylation). Possible mechanisms of insulin resistance, with associated increased free fatty acids binding to albumin, in stimulating albumin oxidation and inhibiting albumin glycation ("metabolic cross talks") are reviewed. Albumin molecular modifications in diabetes, together with significant differences between T2DM and T1DM, suggest possible role for insulin resistance in their genesis and consequent cell, tissue, and vascular dysfunction/damage. Albumin molecular fingerprinting can provide valuable insights into pathogenesis, diagnosis, monitoring, and future therapies for diabetes. Identification of biomarker battery ("albuminomics," "diabetomics") driven diverse "healthy," prediabetes, obesity, and T2DM phenotypes represents additional novel step toward precision medicine in diabetes and related disorders.

}, issn = {1557-8518}, doi = {10.1089/met.2023.0079}, author = {Vaishnav, Madhumati S and Kumari, Namita and Srikanta, Sathyanarayana and Krishnaswamy, Patnam R and Balaram, Padmanabhan and Bhat, Navakanta} } @article {94388, title = {Glycation of Albumin and its Implication in Diabetes: A Comprehensive Analysis using Mass Spectrometry.}, journal = {Clin Chim Acta}, year = {2021}, month = {2021 Jun 02}, abstract = {

AIM: To understand the mechanism of glycation of albumin and effects on cysteinylation and methionine oxidation.

METHODS: The in vitro glycation of HSA and BSA was studied with varying concentrations of glucose. Clinical blood samples of diabetic subjects with varying HbA1c values, were analyzed to assess in vivo glycation. All samples and their tryptic digests were analyzed using liquid chromatography/mass spectrometry. Glycation sites were mapped on to the three-dimensional structure of the HSA and BSA.

RESULTS: A total thirty-one sites for glycation and eight sites of N-carboxymethyl-lysine (CML) modification were identified on albumin. The site selectivity of glycation was correlated with the environment of the reactive residue in the three-dimensional structure.

CONCLUSIONS: The maximum percentage glycation under extreme conditions was in the range of \~{}55 to 88\% in four weeks. Two major glycation sites K-233 and K-525 were identified, which together accounted for 40-50\% of total glycation. A correlation was observed between glycation and oxidation of methionine residues in samples glycated in vitro. The role of spatially proximate residues in facilitating the glycation process is evident. The tri- and tetra-glycated isoforms of albumin can serve as biomarkers for the severe uncontrolled diabetic state.

}, issn = {1873-3492}, doi = {10.1016/j.cca.2021.06.001}, author = {Kumari, Namita and Bandyopadhyay, Debarati and Kumar, Vinay and Venkatesh, D B and Prasad, Sujay and Prakash, Sunita and Krishnaswamy, P R and Balaram, P and Bhat, Navakanta} }