Table 1.

Potential immunometabolic biomarkers in type 1 diabetes.

Target proteins	Involved pathways	Relevant PTMs and pathological roles	References
GLUT1	glucose intake	reduces diabetogenic CD8+ T cells by GLUT1 blockade	(16)
SGLT2	glucose intake	maintains blood glucose level by SGLT2 inhibitors	(17)
GK	glycolysis	alters GK activity by ubiquitination, SUMOylation and citrullination diminishes insulin secretion by citrullination increased citrullinated GK in islets before the onset of hyperglycemia autoantibodies against GK and citrullinated GK in NOD and T1D serum autoreactive T cells against citrullinated GK peptide in T1D patients	(10, 18, 19) (10) (10) (10) (10)
PFKFB3	glycolysis	inhibits diabetogenic CD4+ T cells response to beta cell antigens by PFKFB3 inhibitor, PFK15 delays diabetic onset in adoptive transfer model of T1D by PFKFB3 inhibitor, PFK15 increased PFKFB3 expression in T1D beta cells	(20) (20) (21)
Enolase	glycolysis	loss expression of neuron-specific enolase in T1D decreased α-enolase expression in T1D renal glomeruli	(22) (23)
PK	glycolysis	alters PK activity by phosphorylation, acetylation, citrullination, methylation, succinylation and glycosylation decreased PKM1 and PKM2 expression in T1D renal glomeruli protects diabetes by PKM2 activation	(24–26) (23) (27)
PDH	TCA cycle	alters PDH activity by phosphorylation, acetylation and succinylation beta cell-specific PDH knockout mouse develops increased blood glucose level and decreases GSIS	(28, 29) (30)
PC	TCA cycle	overexpression of PC in INS-1 cells increases insulin secretion and cell proliferation protects human beta cells from inflammation and nitrosative stress	(31) (32, 33)
PDIA1/P4Hb	protein folding	ablation of the thioredoxin activity prevents the refolding of denatured and reduced proinsulin increased carbonylated PDIA1/P4Hb in islets before the onset of hyperglycemia autoantibodies against PDIA1/P4Hb and carbonylated PDIA1/P4Hb in NOD and T1D serum autoreactive T cells against carbonylated PDIA1/P4Hb peptide in T1D patients increased PDIA1/P4Hb level in NOD and T1D plasma	(34) (35) (35) (35) (36)
GRP78	protein folding	autoantibodies against GRP78 and citrullinated GRP78 in NOD and T1D serum autoreactive T cells against citrullinated GRP78 peptide in T1D patients	(37, 38) (37)
Insulin	glucose homeostasis	PTMs, citrullination, deamidation, chlorination and oxidation, increase HLA-A*02:01- binding affinity to insulin-B-derived epitopes autoantibodies against oxidized insulin in T1D serum autoreactive T cells against deamidated insulin B30-C13 in T1D patients	(39–41) (42–44) (45)
GAD65	glutamate metabolism	autoantibodies against citrullinated and deamidated GAD65 peptides in T1D patients autoreactive T cells against citrullinated and deamidated GAD65 peptides in T1D patients	(46–49) (49–52)
IGRP	glucose metabolism	autoreactive T cells against citrullinated IGRP peptides in T1D patients	(50)
IAPP	glycemic regulator	autoreactive T cells against IAPP and citrullinated IAPP peptides in NOD and T1D serum	(51–53)
IA2	insulin-signaling pathway regulator	autoantibodies against IA2 and deamidated IA2 in T1D serum autoreactive T cells against IA2 and deamidated IA2 peptides in T1D patients	(54) (50, 55)

GLUT1, glucose transporter 1; SGLT2, sodium-glucose co-transporter-2; GK, glucokinase; PFKFB3, 6-phosphofructo-2-kinase/fructose-2,6- biphosphatase 3; PK, pyruvate kinase; PDH, Pyruvate dehydrogenase; PC, Pyruvate carboxylase; PDIA1/P4Hb, Protein disulfide isomerase A1 (PDIA1)/prolyl-4-hydroxylase beta; GRP78, glucose-regulated protein 78; GAD65, glutamic acid decarboxylase 65; IGRP, islet-specific glucose-6-phosphatase catalytic subunit-related protein; IAPP, islet amyloid polypeptide; IA-2, islet antigen-2.