Table 2.

Exosomes derived from body fluid can act as novel biomarkers for early diagnosis of DM and diabetic complications.

Disease	Target content in exosome	Sample	Method	Scientific mechanism	Reference
T2DM	Counts of cell derived exosomes ↑	Serum	Flow cytometry meta-analysis	1. Total annexin V-positive blood cell microparticles—procoagulant activity could be involved in vascular complications 2. Endothelial microparticles stimulated by elevated glucose change their molecular composition and increase their biological activity, which may lead to progressive endothelial damage and subsequent cardiovascular complications in diabetes	(57–59)
Diabetes nephropathy	Counts of cell derived exosomes ↑	Urinary	Flow cytometry	MiR-26a-5p from adipose-derived mesenchymal stem cell-derived EVs protect against DN
	Dipeptidyl peptidase-IV ↑	Urinary	ELISA	The urinary level of microvesicle-bound microvesicle-dipeptidyl peptidase-IV is associated with the severity of diabetic kidney disease	(38)
	Wilms tumor-1 ↑	Urinary	Western blotting	Among podocyte‐derived signal transduction factors in urinary exosomes, WT1 mRNA levels reflected damage of diabetic glomeruli in the patients	(60)
	AMBP, MLL3 ↑VDAC1 ↓	Urinary	LC-MS/MS	Comparing DN urine exosomes and healthy controls, it was discovered in a panel of three proteins (AMBP, MLL3, and VDAC1) that they were differentially found in urinary exosomes from DN patients	(61)
	MiR-130, miR-145, miR-155, miR-424 ↑	Urinary	TaqMan qPCR	High glucose will stimulate mesangial cells and increase the content of miR-145 in mesangial cells and their derived exosomes	(62)
	Mitochondrial DNA ↓	Urinary	Intrarenal Gene Expression Analysis	Urine exosomes from patients with diabetes and CKD had less mitochondrial DNA, and kidney tissues from patients with diabetic kidney disease had lower gene expression of PGC1α	(63)
	Elf3 ↑	Urinary	Western blotting	AGE treatment induced the secretion of Elf3-containing exosomes from cultured podocytes, which was dependent on the activation of the TGF-β-Smad3 signaling pathway	(64)
	MiR-16 ↓	Urinary	RT-qPCR	MiR-16 identified as the most stable endogenous reference gene in data set, making it a suitable endogenous reference gene for miRNA studies of urinary exosomes derived from CKD patients	(65)
	Gelatinase ↓ceruloplasmin ↑	Urinary	ELISA	Gelatinase (decreased activity) and ceruloplasmin (increased levels), in the urinary exosomes of diabetic kidney patients were in agreement with the alterations of these two proteins in the kidney tissue	(66)
Diabetic cardiomyocytes	Counts of exosomes ↑	Blood	Flow cytometry	Exosomes from diabetic rats no longer activated the ERK1/2 and HSP27 cardioprotective pathway and were no longer protective in a primary rat cardiomyocyte model of hypoxia and reoxygenation injury. Exosomes from diabetic plasma have lost the ability to protect cardiomyocytes, but protection can be restored with exosomes from non-diabetic plasma
	Hsp20 ↓	Serum	LC-MS/MS	Elevation of Hsp20 in cardiomyocytes can offer protection in diabetic hearts through the release of instrumental exosomes	(67)
	MiR-320 ↑	Serum	TaqMan qPCR	Cardiomyocytes exert an anti-angiogenic function in type 2 diabetic rats through exosomal transfer of miR-320 into endothelial cells	(68)
	MiR-126 ↓	Serum	TaqMan qPCR	MiR-126 targets insulin receptor substrate (IRS)-1 expression via PI3K/Akt signaling pathways suggests that it is involved in IR modulation	(69)
	MiR-7 ↑	Serum	RT-qPCR	MiR-7 was demonstrated to be involved in β-cell dysfunction and insulin secretion	(70)
Diabetic Charcot neuroarthropathy (CN)	Counts of exosomes ↑	Plasma	Flow cytometry	The concentration of EVs is related to elevation of markers of inflammation (CRP and foot temperature difference) in acute diabetic CN	(71)
Gestational diabetes	Counts of endothelial cell exosomes ↑	Serum, plasma	Western blotting, RT-qPCR	Exosomal Ang2 secretion is regulated by the PI3K/Akt/eNOS and syndecan-4/syntenin pathways	(72, 73)

DM, diabetes mellitus; T2DM, type 2 diabetes mellitus; EV, extracellular vesicle; DN, diabetic nephropathy; LC-MS/MS, liquid chromatography–tandem MS; CKD, chronic kidney disease; AGE, advanced glycation end-product; CRP, C-reactive protein.