Comprehensive overview of human serum albumin glycation in diabetes mellitus

Table 1 Review of the in vivo glycation sites of human serum albumin

Ref.	Glycation sites reported so far	Analysis tools
Iberg et al[63]	HSA from a diabetic patient: Lys-12, Lys-199, Lys-233, Lys-281, Lys-317, Lys-351, Lys-439, Lys-525, Lys-534	Amino acid analysis after hydrolysis in HCl
Garlick et al[64]	Freshly purified human serum albumin: Lys-525	Cation exchange chromatography
Frolov et al[55]	HSA from five T2DM patients: Lys-12, Lys-51, Lys-64, Lys-162, Lys-174, Lys-181, Lys-233, Lys-262, Lys-276, Lys-351, Lys-359, Lys-378, Lys-414, Lys-475, Lys-525, Lys-545	Q-TOF-MS
Kisugi et al[56]	HSA from a female diabetic patients: Lys-64/Lys-73, Lys-199, Lys-136/ Lys-137, Lys-233, Lys-274/Lys-276, Lys-317, Lys-389, Lys-439, Lys-534, Lys-525	QSTAR Pulsar-i mass spectrometer
Frolov et al[57]	HSA from 5 T2DM patients and 4 healthy subjects: Lys-12, Lys-511, Lys-641, Lys-73, Lys-93, Lys-137, Lys-162, Lys-1741, Lys-1811, Lys-205, Lys-2331, Lys-2621, Lys-274, Lys-351, Lys-3591, Lys-3781, Lys-414, Lys-475, Lys-525, Lys-5451, Lys-5571 (detected only in diabetic samples), Lys-574	Nano-ESI-LTQ Orbitrap XL MS with ETD
Bai et al[10]	HSA from a healthy subject and a diabetic patient: Lys-64, Lys-93, Lys-190, Lys-199, Lys-205, Lys-225, Lys-233, Lys-240, Lys-262, Lys-274, Lys-281, Lys-317, Lys-323, Lys-351, Lys-372, Lys-378, Lys-413, Lys-432, Lys-475, Lys-525, Lys-545, Lys-557, Lys-557/ Lys-560/ Lys-564, Lys-564, Lys-573/ Lys-574	IT-TOF-MS/MS
Zhang et al[7]	HSA from clinical T2DM, IGT, NGT and 389 volunteers: Lys-12/ Lys-201, Arg-144, Arg-186/ Lys-1901, Arg-222/ Lys-225, Lys-240, Arg-336, Lys-372, Lys-414/ Arg-4281. (8 glucose sensitive sites)	Agilent MSD trap
Anguizola et al[59]	HSA from individual clinical plasma samples: Arg-10, Lys-12, Arg-10/Lys-121, Arg-981, Arg-160, Lys-162, Lys-190, Lys-199, Lys-276, Lys-281, Lys-276/Lys-2811, Lys-2861, Lys-313, Lys-317, Lys-372, Lys-428, Lys-432, Arg-484, Arg-485, Arg-484/ Arg-4851, Lys-545, Lys-557, Lys-560, Lys-5641, Lys-573/ Lys-5741	MALDI-TOF-MS
Priego-Capote et al[12]	HSA from human Plasma: Lys-64, Lys-73, Lys-93, Lys-106, Lys-136, Lys-137, Lys-159, Lys-174, Lys-181, Lys-195, Arg-218, Lys-233, Lys -240, Lys-262, Lys-274, Lys-323, Lys-359, Lys-372, Lys-378, Lys-389, Lys -402, Lys-413, Lys-432, Lys-436, Lys-439, Lys-444, Lys-466, Arg-472, Lys-475, Lys-500, Lys-519, Lys -525, Lys-573	Hybrid linear ion trap-Orbitrap MS
Korwar et al[65]	HSA from clinical plasma samples: Lys-12, Lys -641, Lys -136, Lys-137, Lys-1591, Lys-4021, Lys-4141, Lys-4661, Lys-5251	Hybrid quadruple Q-Exactive Orbitrap MS
Zhang et al[60]	HSA from 12 NGT, 11 IGT and 8 T2DM: Lys-41, Lys-12, Lys-51, Lys-641, Lys-73, Lys-136, Lys-137, Lys-159, Lys-162, Lys-1811, Lys-1901, Lys-195, Lys-1991, Lys-205, Lys-225, Lys-2331, Lys-262, Lys-274, Lys-276, Lys-3171, Lys-351, Lys-378, Lys-414, Lys-4321, Lys-4361, Lys-475, Lys-525, Lys-538, Lys-545, Lys-5621, Lys-573, Lys-574	Ion Trap LC-MS
Miyamoto et al[66]	HSA from 8 diabetic patients: Lys-51, Lys-64/ Lys-73, Lys-136/ Lys-137, Lys-159/ Lys-162, Lys-190/ Lys-195/ Lys-199/ Lys-205, Lys-233, Lys-262, Lys-274/ Lys-276, Lys-313/ Lys-317, Lys-351, Lys-378/ Lys-389, Lys-432/ Lys-436/ Lys-439, Lys-525, Lys-534/ Lys -536/ Lys-538/ Lys-541, Lys -545, Lys-573/ Lys-574	QSTAR Pulsar-i MS
Brede et al[67]	HSA from plasma: Lys-12, Lys-137, Lys-414, Lys-5251	Q-TOF MS
Spiller et al[68]	HSA from 48 T2DM patients and 48 non-diabetic: Lys-64, Lys-73, Lys-93, Lys-174, Lys-181, Lys-233, Lys-262, Lys-359, Lys-378, Lys-414, Lys-525, Lys-545, Lys-574	QTRAP 4000
Spiller et al[69]	HSA from 5 T2DM patients and 5 non-diabetic individuals: Lys-641, Lys-731, Lys-1811, Lys-2621, Lys-3781, Lys-5741	ESI-QqLIT-MS (4000
Takátsy et al[70]	HSA from diabetic patients and healthy individuals: Arg-81, Lys-93, Arg-98, Lys-106, Arg-114, Lys-190, Lys-199, Arg-218, Arg-257, Lys-276, Lys-317, Arg -348, Lys-372, Lys-378, Lys-389, Lys-413, Lys-436, Lys-439, Lys-444, Lys-466, Arg-484, Arg-485, Lys-500, Lys-519, Arg-521, Lys-564, Lys-536, Lys-538, Arg-445, Lys-541, Lys-560, Lys-573	MALDI TOF MS
Greifenhagen et al[71]	HSA from 5 diabetic patients: Lys-12, Lys-64, Lys-137, Lys-190, Lys-199, Lys-274, Lys-276, Lys-525	ESI-Orbitrap-MS
Qiu et al[53]	HSA from 4 diabetic patients and 4 healthy subjects: Lys-4, Lys-12, Lys-511, Lys-641, Lys-73, Arg-81, Lys-931, Arg-98, Arg-117, Lys-136, Lys-137, Lys-1621, Lys-174, Lys-181, Arg-186, Lys-1991, Lys-205, Lys-2331, Lys-240, Arg-257, Lys-2621, Lys-274, Lys-276, Lys-281, Lys-286, Lys-3131, Lys-317, Lys-3231, Lys-351, Lys-359, Lys-372, Lys -3781, Lys-389, Lys-4021, Lys-410, Lys-4141, Lys-436, Lys-439, Lys-4661, Lys-4751, Lys-519, Lys-5251, Lys-538, Lys-541, Lys-5451, Lys-5571, Lys-5641, Lys-573, Lys-5741	LTQ Orbitrap Velos Pro MS

¹Represents glycation sites detected at higher quantities in diabetic patients than in healthy individuals. HSA: Human serum albumin; ESI: Electrospray ionization; NGT: Normal glucose tolerance; T2DM: Type 2 diabetes mellitus; MS: Mass spectrometry.

Table 2 Effects of glycation on the binding of human serum albumin to various ligands

Ref.	Ligands	In vivo/ vitro/ex vivo	Glycation level of HSA	Binding affinity
Nakajou et al[75]	Warfarin	In vitro	HSA glycated with 2.5 mmol/L, 12.5 mmol/L, and 50 mmol/L glucose	↑
Baraka-Vidot et al[35]	Warfarin	In vitro and Ex vivo	HSA purified from blood and HSA glycated with 25 mmol/L or 100 mmol/L glucose	↓
Joseph et al[76]	Warfarin	In vitro	HSA glycated with 0.5 mol/L glucose	→
Qiu et al[53]	Warfarin	In vivo	HSA from diabetic patients	↑
Joseph et al[76]	Tryptophan	In vitro	HSA glycated with 0.5 mol/L glucose	↑4.7-5.8-fold
Nakajou et al[75]	Dansylsarcosine	In vitro	HSA glycated with 2.5 mmol/L, 12.5 mmol/L, and 50 mmol/L glucose	↓
Qiu et al[53]	Heparin	In vitro and in vivo	HSA from diabetic patients	→
Guerin-Dubourg et al[81]	Copper	In vivo	HSA purified from diabetic patients and control individuals	↓16%
Koizumi et al[82]	Furosemide	In vitro	Prepared from HSA, and commercial HSA	↓
Okabe et al[83]	Phenylbutazone	In vitro	Each mole of HSA contains 1.94 moles of glucose	↓
Yamazaki et al[84]	Fatty acids	In vitro	HSA glycated with 100 mmol/L glucose	↓
Karp et al[85]	Diazepam	In vitro	HSA glycated with 140 mmol/L glucose	→
Karp et al[85]	Bilirubin	In vitro	HSA glycated with 140 mmol/L glucose	↓30%
Okabe et al[83]	Ibuprofen	In vitro	Each mole of HSA contains 1.94 moles of glucose	↓20
Okabe et al[83]	Dansylproline	In vitro	Each mole of HSA contains 1.94 moles of glucose	↓25%
Okabe et al[83]	Flufenamic acid	In vitro	Each mole of HSA contains 1.94 moles of glucose	↓
Koizumi et al[82]	Naproxen	In vitro	Prepared from HSA, and commercial HSA	→

“→”: No change; “↑”: Increase; “↓”: Decrease; HSA: Human serum albumin.