Table 1.

Biomarkers for diabetic neuropathy mentioned in this review.

Biomarker Candidate	Sample Source	Quantitative Method	Function	Changes during Neuropathy	Literature
(a) AGEs related
Methylglyoxal	Human serum	HPLC	Post-translational modification of voltage-gated sodium channel Nav 1.8 causes hyperalgesia. In addition, it activates TRPA1 and induces temperature and mechanical hyperalgesia.	When administered to mice, hyperalgesia due to thermal and mechanical stimulation is induced.	[14,15,16,17,18,19,20]
Glyoxalase I (GLO I)	Mouse DRG Human serum	Colorimetric method	A rate-limiting enzyme that decomposes reactive dicarbonyls such as methylglyoxal	The neuropathic symptoms observed in diabetic conditions are significantly suppressed in mice with high GLO I activity. In humans, decreased GLO I activity is also significantly correlated with the frequency of painful neuropathy	[21,22,23,24,25]
(b) Inflammation-related molecules
TNF-α	Human serum	ELISA	Expression of cell adhesion molecules and induction of apoptosis Increased inflammatory mediator	It is elevated in type 2 diabetic patients in the control group and in the diabetic and neuropathy group compared to the diabetic group	[28,29]
TLR4	Human peripheral blood mononuclear cells	qPCR	Receptors involved in innate immunity	It is elevated in type 2 diabetic patients in the control group and in the diabetic and neuropathy group compared to the diabetic group	[30,31,32,33,34]
Adiponectin	Human serum	ELISA	Adipocytokines produced and secreted by adipocytes	There is a significant difference between the control group and the diabetic group with neuropathy compared with the control group in type 2 diabetic patients (the distinction differs depending on the report).	[36,37,38]
miR-146a	Human Serum Mouse DRG	qPCR	Negative feedback on inflammatory response	It is elevated in patients with type 2 diabetes, but its association with neuropathy has not been investigated. In diabetic neuropathy mice, the expression level in the DRG is reduced, and the forced expression in the DRG after culture acquires resistance to hyperglycemia-induced apoptosis.	[40,41]
(c)Molecules associated with nerve damage
Nerve-specificenolase (NSE)	Human serum	ELISA	Glycolytic enzymes specific to nerve tissue (Leakage due to nerve damage)	It is elevated in type 1 and type 2 diabetic patients compared to the control group, especially in the group with neuropathy.	[47,48]
Semaphorin	Mouse sciatic nerve	qPCR	Nerve axon elongation guidance factor	These mRNAs are induced in the sciatic nerve in a rat sciatic nerve ligation model.	[52,53,54,55]
(d) Molecules involved in neuroprotection
NGF	Human serum	ELISA	Neurotrophic factors involved in nerve regeneration	It is lower in type 2 diabetic patients in the control group and in the diabetic and neuropathy group than in the diabetic group	[56,57,58,59]
HSP27	Human serum	ELISA	Cell protective factors in the presence of stress	It is elevated in type 1 and type 2 diabetic patients compared to the control group, especially in the group with neuropathy.	[60,61,62,63,64]