Fendo 12 756581

REVIEW
published: 26 October 2021

doi: 10.3389/fendo.2021.756581
The Utility of Exosomes in Diagnosis

and Therapy of Diabetes Mellitus and
Associated Complications
Yaoxiang Sun 1†, Qing Tao 2†, Xueqin Wu 1, Ling Zhang 1, Qi Liu 1* and Lei Wang 2*
1 Department of Clinical Laboratory, Yixing People’s Hospital, Yixing, China, 2 Center for Translational Medicine and Jiangsu
Key Laboratory of Molecular Medicine, Medical School of Nanjing University, Nanjing, China
Diabetes mellitus and the associated complications are metabolic diseases with high
morbidity that result in poor quality of health and life. The lack of diagnostic methods for
Edited by: early detection results in patients losing the best treatment opportunity. Oral
Ping Wang, hypoglycemics and exogenous insulin replenishment are currently the most common
Michigan State University,
therapeutic strategies, which only yield temporary glycemic control rather than curing the
United States
disease and its complications. Exosomes are nanoparticles containing bioactive
Reviewed by:
Alok Raghav, molecules reflecting individual physiological status, regulating metabolism, and repairing
Ganesh Shankar Vidyarthi Memorial damaged tissues. They function as biomarkers of diabetes mellitus and diabetic
Medical College, India
Anwar Abdullah Borai, complications. Considering that exosomes are bioactive molecules, can be obtained
King Saud bin Abdulaziz University for from body fluid, and have cell-type specificity, in this review, we highlight the multifold
Health Sciences, Saudi Arabia
effects of exosomes in the pathology and therapy of diabetes mellitus and
*Correspondence:
diabetic complications.
Qi Liu
staff1177@yxph.com
Keywords: exosomes, biomarkers, diabetes mellitus, therapy, diagnosis, mesenchymal stem cells
Lei Wang
Wlei@nju.edu.cn
†
These authors have contributed
equally to this work 1 INTRODUCTION
Specialty section: Exosomes are membranous extracellular vesicles (EVs) first discovered in 1983; for several years,
This article was submitted to they have been described as organelles removing metabolic waste out of cells (1). Exosomes can be
Clinical Diabetes, isolated from body fluids such as blood, urine, cerebrospinal fluid (CSF), amniotic fluid, and saliva,
a section of the journal and from different cell types in vitro such as stem cells, dendritic cells, mast cells, and T cells (2, 3).
Frontiers in Endocrinology Recent studies on exosomes extracted from body fluid in vivo and culture media in vitro have shown
Received: 10 August 2021 that they can provide information about the tissues or cells of their origin and that they act as
Accepted: 01 October 2021 messengers in cell–cell communication and deliver bioactive molecules such as proteins and nucleic
Published: 26 October 2021 acids, apart from removing cellular waste (4, 5). These studies suggest that exosomes play important
Citation: roles in non-invasive diagnosis (6) and impaired tissue repair (7).
Sun Y, Tao Q, Wu X, Zhang L, Liu Q Diabetes mellitus (DM) is a metabolic disease with high morbidity. It significantly deteriorates
and Wang L (2021) The Utility of
the quality of health and life. Early diagnostic methods for diabetes remain lacking, resulting in
Exosomes in Diagnosis and
Therapy of Diabetes Mellitus and
patients losing the optimal treatment opportunity, which increases the risk of diabetic complications
Associated Complications. (8). Current therapeutic options include oral hypoglycemic drugs or insulin injections, which
Front. Endocrinol. 12:756581. provide temporary blood glucose level control; however, these therapies cannot prevent diabetic
doi: 10.3389/fendo.2021.756581 complications and are associated with adverse effects such as hypoglycemia (9). In this review, we
Frontiers in Endocrinology | www.frontiersin.org 1 October 2021 | Volume 12 | Article 756581

Sun et al. Exosomes in Diabetes Diagnosis and Therapy
summarize the recent evidence on exosomes as biomarkers and 3 EXOSOMES AS THE POTENTIAL
therapeutic factors for DM and its complications in BIOMARKERS OF DIABETES MELLITUS
clinical practice.
AND DIABETIC COMPLICATIONS
3.1 Introduction to Diabetes Mellitus
2 INTRODUCTION TO AND DM mainly includes type 1 DM (T1DM) and type 2 DM
CHARACTERIZATION OF EXOSOMES (T2DM). Under physiological conditions, fasting blood glucose
levels should be 3.9–6.1 mM given normal secretion of insulin
Exosomes are microvesicles released by cells into the
and tissue insulin sensitivity. Various factors such as genetic
extracellular space, sized around 30–200 nm. Generally, the
inheritance, viral infection, unhealthy lifestyle, and other
size of exosomes is at the nanometer level, and the unit for
physical or chemical damages lead to b-cell destruction,
detecting the concentration of exosomes is units/microliter. They
impaired insulin secretion, and loss of peripheral tissue insulin
can be recognized as a heterogeneous population of membrane-
sensitivity, finally resulting in a high blood glucose level (28).
bound structures (“cup-like” or “dish-like”) under a transmission
T1DM accounts for 10% of DM cases and is characterized by
electron microscope (10). Chemical or physical stimulations
absolute insufficiency of insulin, often presenting with symptoms
such as cytokines, unesterified cholesterol, thrombin, tobacco
such as thirst, weight loss, and polyuria. T2DM, characterized by
smoke extract (11, 12), hypoxia, and shear stress activate or
insulin resistance in target tissue, relatively insufficient insulin
induce cell apoptosis, which results in the budding of the
secretion, and subsequent b-cell dysfunction, is often non-
endosomal membrane, forming multivesicular bodies (MVBs).
symptomatic; and patients with T2DM seek medical care only
MVBs and the plasma membrane fuse and finally lead to the
for complications such as vision loss, heart attack, or limb
release of exosomes (13, 14). Exosomes can be released by most
gangrenes (28, 32). The frequently used diagnostic methods for
cell types such as cancer cells, stem cells, skeletal muscles cells,
diabetes include fasted or random blood glucose level
mast cells, dendritic cells, and lymphocytes. The most common
measurement for preliminary screening, homeostatic model
components in the evaluation of exosomes are the following
assessment—insulin resistance (HOMA-IR), oral glucose
categories: functional miRNA, a small amount of mRNA, long
tolerance tests (OGTTs), intraperitoneal glucose tolerance test
non-coding RNA (lncRNA), and specific proteins (such as
for detecting the sensitivity of peripheral tissues to glucose and
cytokines and growth factors) and other biologically active
insulin, serum insulin level, homeostatic model assessment b
substances, which are protected from hydrolase activity by the
(HOMA-b) and insulin release tests for determining the function
lipid from the original cells and the membrane structures,
of b cells, and glycated hemoglobin (HbA1c) for indicating the
allowing exosomes to act as cell communication messengers
blood glucose level for the previous 8–12 weeks (28, 33).
and influence biological function in target cells by fusion,
endocytosis, and receptor–ligand interaction (6, 14–17). These
are not total components and just one of the components. 3.2 Introduction to Diabetic Complications
Exosomes can be extracted from the serum, urine, cerebral A chronic high blood glucose level disrupts homeostasis, causes
spinal fluid, saliva, and bronchiolar lavage fluid (2, 18). The oxidant stress, and induces microvessel, nervous, and immune
level of exosomes is generally through the detection of their system damage, finally exacerbating the development of diabetic
morphology, namely, particle size and concentration. Three complications (34). Cardiomyopathy is induced by an increased
main methods are used: morphology (electron microscopy), fatty acid metabolism, reduced myofilament Ca+ sensitivity,
particle size (diameter particle analysis), and marker protein mitochondrial dysfunction, oxidative stress, apoptosis, and
(WB) (19). Exosome density ranges from 1.13 to 1.21 g/ml, fibrosis of diabetic cardiomyocytes (35–37). Pathologic glucose
allowing the use of the sucrose-deuteroxide density gradient metabolism also damages the blood vessels structurally and
separation method to isolate them (20). In addition, exosomes functionally, resulting in apoptosis and fibrosis in microvessels,
can also be extracted using ultra-centrifugation or the ExoQuick inducing diabetic nephropathy, glomerular atrophy, renal
exosome precipitation solution (8, 21). CD9, CD63, and CD81 fibrosis, renal dysfunction, and renal failure (29, 38). In the
are the accepted surface markers on exosomes for identification retina, microvessel apoptosis and paraplasm may also result in
using Western blotting (20), quantitative RT-PCR, nucleic acid microaneurysms and hemorrhage, which are diagnosed as
sequencing, enzyme-linked immunosorbent assay (ELISA), and diabetic retinopathy and finally cause vision loss (30). Poor
flow cytometry (FCM). glucose control induces peripheral neuropathy and peripheral
As exosomes are stable and cell-type specific and can be vascular disease combined with structural deformities, and
isolated non-invasively/minimally invasively, they have been environmental factors and compromised immunity lead to the
extensively studied, particularly in tumorigenesis (22–25) and development of diabetic foot (31).
diagnosis of DM and diabetic complications. Physiologically, Furthermore, heart attack, vision loss, renal dysfunction, and
exosomes can repair tissue damage, particularly exosomes refractory wound healing are often apparent before DM
derived from stem cells (7, 20, 26, 27). Pancreatic, vascular, diagnosis, and these symptoms indicate significant organ
kidney, nervous, and skin injuries are commonly associated with injury. Therefore, early detection of DM and diabetic
DM onset and diabetic complications (28–31). Exosomes can complications is crucial; however, no definitive methods of
physiologically contribute to the repair of such injuries. early diagnosis exist (28).

3.3 Potential of Exosomes in Non-Invasive/ magnetic bean sorting, filter device, and flow sorting; in this
Minimally Invasive Diagnosis manners, exosomes can be captured accurately depending on the
Exosomes are a medium of cell–cell communication and carry expensive equipment and consumables and will be the mainstream
several bioactive substances from the original cells including approach in the future (48, 52–54).
proteins, RNA, DNA, and lipid derivatives (6, 39, 40); they have Herein, we present a review of the recent advances in the use of
been studied in both physiological and pathological circumstances exosomes as potential early diagnostic biomarkers (Table 2) of DM
such as exercise, cancer, neurodegenerative disorders, and and diabetic complications in different ways, particularly of the
metabolic diseases (41–44). DM and diabetic complications are recent ones, and the detailed information will be described,
systemic diseases and affect several organs. The following factors as follows.
allow the potential use of exosomes in the diagnosis of systemic
diseases: 1) exosomes can be derived from the serum, urine, and CSF 3.3.1 Diabetes Mellitus and Diabetic Complications
and contain several bioactive materials like proteins, nucleic acids, Result in a Change in Exosome Count
and lipids, which can provide information about almost the entire The count of exosomes derived from circulating cells differs
body (14, 45–47). Urine and serum are the common specimen significantly between those with diabetes and those without, as
sources of exosomes in DM and associated complication diagnosis; chronic high glucose levels result in inflammatory cell activation
the collection of urine is quite convenient, which can be operated by and endothelial cell apoptosis (74). Meta-analyses have revealed a
patients themselves non-invasively; and the collection of blood or notable increase in circulating exosomes released by platelets,
CSF is minimally invasive, which can cause no obvious discomfort; monocytes, and endothelial cells in diabetes; however, exosomes
2) exosomes are relatively stable and allow prolonged storage given from leucocytes do not differ between patients with diabetes and
their membranous structures, which provide structural integrity to controls (57, 58). A high glucose concentration can induce a
bioactive molecules; this feature makes sure of the authenticity and threefold increase in exosomes from endothelial cells (59). A
accuracy of results in subsequent tests in that the bilayer structure study reported that the count of total exosomes isolated from
can avoid the degradation of different kinds of enzyme such as gingival crevicular fluid of pregnant women who developed
proteolytic enzyme or RNase (48); 3) analysis techniques such as gestational DM (GDM) later in pregnancy was significantly
liquid chromatography–mass spectrometry (LC/MS), protein or higher than in normoglycemic pregnant women (75). In diabetic
gene chip analysis, liquid biopsy, FCM, and magnetic bead-based nephropathy, urinary podocyte exosome counts are higher in
analysis have sufficiently matured to allow using exosomes or tests. patients with T2DM, preceding changes in other biomarkers such
The LC/MS can be used to analyze the type and quantity of proteins as urine albumin or nephrin (an early biomarker of glomerular
or metabolites, and genetic sequencing is an important tool of injury) (76). The exosome counts can be assessed using NanoSight
nucleic acid analysis, are which contained in exosomes derived from or FCM. Both NanoSight and FCM are experimental methods used
body fluid of DM or related patients. Besides, Western blotting and to evaluate exosomes. NanoSight technology can detect the size
qRT-PCR can be used to verify the correlated data in different distribution and concentration of purified exosomes through
groups (48–51); 4) several methods for isolation of exosomes exist nanoparticle tracking analysis (NTA) (77–79). FCM can be used
with acceptable costs (Table 1). Ultra-centrifugation is the gold to observe the number of exosomes and their surface markers (80).
standard method for exosomes isolation, which can promise the It also can be used to identify various exosomal subpopulations (81).
highest purity; however, the facility request and operating steps are The detection of exosomes in the disease through the above
quite tedious, and the output is quite low; these characteristics result techniques may be the most easily accessible method for early
in the low inspection efficiency, which is not clinically applicable screening of DM or diabetes complications.
(44–46). Sucrose/heavy water density gradient is the improved
method of ultra-centrifugation, which increases the output of 3.3.2 Differences in Exosome Contents Between
exosomes, but the steps are still very cumbersome (51). Exosome Individuals With or Without Diabetes
isolation kit is the most common and convenient method, which Although the contents of exosomes between patients with DM
has high yield, but the high yield is built on the sacrificing purity have also been reported to vary, the difference is significant in case
(44). In addition, several other methods develop gradually such as of diabetic complications. Exosomal proteins derived from body
TABLE 1 | Methods of exosome isolation and evaluation.
Method Principle Advantage Disadvantage Reference
Ultra-centrifugation Special density Gold standard for vesicle isolation, effective, low cost Laborious, low yield (45–47)
Sucrose/heavy water density gradient Special density Effective, low cost Laborious, low yield, (20, 52)
Exosomes isolation kit Special density Convenient, efficient Low purity and high cost (45, 47, 50)
Magnetic beans Immunoreaction High precision, direct analysis target molecular Laborious, high cost (49)
sorting
Filter device Special diameter High precision, direct analysis of target molecules High cost (53)
Flow sorting Immunoreaction High precision, direct analysis of target molecule Laborious, high cost (54, 55)
PEG (polyethylene glycol) Special density Effective Low purity, high cost (56)

TABLE 2 | Exosomes derived from body fluid can act as novel biomarkers for early diagnosis of DM and diabetic complications.
Disease Target Sample Method Scientific mechanism Reference

content in
exosome
T2DM Counts of cell Serum Flow 1. Total annexin V-positive blood cell microparticles—procoagulant activity could be involved (57–59)
derived cytometry in vascular complications 2. Endothelial microparticles stimulated by elevated glucose change
exosomes ↑ meta- their molecular composition and increase their biological activity, which may lead to
analysis progressive endothelial damage and subsequent cardiovascular complications in diabetes
Diabetes Counts of cell Urinary Flow MiR-26a-5p from adipose-derived mesenchymal stem cell-derived EVs protect against DN
nephropathy derived cytometry
exosomes ↑
Dipeptidyl Urinary ELISA The urinary level of microvesicle-bound microvesicle-dipeptidyl peptidase-IV is associated with (38)
peptidase-IV ↑ the severity of diabetic kidney disease
Wilms tumor-1 Urinary Western Among podocyte‐derived signal transduction factors in urinary exosomes, WT1 mRNA levels (60)
↑ blotting reflected damage of diabetic glomeruli in the patients
AMBP, MLL3 Urinary LC-MS/MS Comparing DN urine exosomes and healthy controls, it was discovered in a panel of three (61)
↑VDAC1 ↓ proteins (AMBP, MLL3, and VDAC1) that they were differentially found in urinary exosomes
from DN patients
MiR-130, miR- Urinary TaqMan High glucose will stimulate mesangial cells and increase the content of miR-145 in mesangial (62)
145, miR-155, qPCR cells and their derived exosomes
miR-424 ↑
Mitochondrial Urinary Intrarenal Urine exosomes from patients with diabetes and CKD had less mitochondrial DNA, and (63)
DNA ↓ Gene kidney tissues from patients with diabetic kidney disease had lower gene expression of
Expression PGC1a
Analysis
Elf3 ↑ Urinary Western AGE treatment induced the secretion of Elf3-containing exosomes from cultured podocytes, (64)
blotting which was dependent on the activation of the TGF-b-Smad3 signaling pathway
MiR-16 ↓ Urinary RT-qPCR MiR-16 identified as the most stable endogenous reference gene in data set, making it a (65)
suitable endogenous reference gene for miRNA studies of urinary exosomes derived from
CKD patients
Gelatinase Urinary ELISA Gelatinase (decreased activity) and ceruloplasmin (increased levels), in the urinary exosomes (66)
↓ceruloplasmin of diabetic kidney patients were in agreement with the alterations of these two proteins in the
↑ kidney tissue
Diabetic Counts of Blood Flow Exosomes from diabetic rats no longer activated the ERK1/2 and HSP27 cardioprotective
cardiomyocytes exosomes ↑ cytometry 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 (67)
release of instrumental exosomes
MiR-320 ↑ Serum TaqMan Cardiomyocytes exert an anti-angiogenic function in type 2 diabetic rats through exosomal (68)
qPCR transfer of miR-320 into endothelial cells
MiR-126 ↓ Serum TaqMan MiR-126 targets insulin receptor substrate (IRS)-1 expression via PI3K/Akt signaling pathways (69)
qPCR suggests that it is involved in IR modulation
MiR-7 ↑ Serum RT-qPCR MiR-7 was demonstrated to be involved in b-cell dysfunction and insulin secretion (70)
Diabetic Charcot Counts of Plasma Flow The concentration of EVs is related to elevation of markers of inflammation (CRP and foot (71)
neuroarthropathy exosomes ↑ cytometry temperature difference) in acute diabetic CN
(CN)
Gestational Counts of Serum, Western Exosomal Ang2 secretion is regulated by the PI3K/Akt/eNOS and syndecan-4/syntenin (72, 73)
diabetes endothelial cell plasma blotting, pathways
exosomes ↑ RT-qPCR
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.
fluids of patients with DM differ; for example, dipeptidyl diabetic complications. For example, Lange et al. found that the
peptidase-IV (DPP IV) that activates glucagon-like peptide-1 level of miR-16 was lower in the urine of patients with diabetic
(GLP-1) is associated with DM. In addition, the microvesicle- nephropathy than of healthy controls (65). Individuals with
bound type is the major form of DPP IV in urine, which is T2DM and T2DM-associated microvascular complications have
significantly higher among those with T2DM than among a significantly higher level of miR-7 in serum-derived exosomes
controls (38). The levels of Wilms tumor protein 1 in urinary than do individuals without. Accordingly, the changes in these
exosomes are significantly higher in patients with diabetes with biomarkers in exosomes precede organ-level changes and provide
proteinuria, which implies that exosomes can be early biomarkers more specificity than whole urine or blood, which further
of podocyte injury (60). The changes in miRNA levels can be consolidates the potential role of exosomes in early diagnosis of
detected also in exosomes in diabetes patients with and without DM and diabetic complications (Figure 1).

FIGURE 1 | Analysis of exosomes from patients with diabetes mellitus. Diabetes mellitus and diabetic complications have pathological change before organic
damage in exosomes derived from body fluids. We can collect the serum, plasma, and urine non-invasively and analyze the counts and contents such as DNA,
RNA, and protein depending on the differences between healthy control by choosing the significant biomarker for early diagnosis of diabetes mellitus and
diabetic complications.
4. EXOSOMES AS A POTENTIAL the treatment of DM and diabetic complications. However, if its

THERAPEUTIC TARGET FOR DIABETES dose is not precisely controlled, it can induce life-threatening
hypoglycemia (32, 97). Oral hypoglycemic drugs also play key
MELLITUS AND DIABETIC roles in blood glucose level management. Hypoglycemics have
COMPLICATIONS been divided into several types depending on their mechanism of
blood glucose regulation. For instance, metformin can increase
4.1 The Disadvantages of Traditional peripheral tissue insulin sensitivity, whereas sulfonylureas can
Treatment for Diabetes Mellitus and stimulate insulin secretion. Of relevance, these hypoglycemic
Diabetic Complications drugs have adverse effects depending on the mechanism of blood
Herein, we focus on common therapeutic strategies for the glucose regulation, such as gastrointestinal tract response,
treatment of DM and its complications (Table 3) apart from hypoglycemia, hypoleucocytosis, hemolytic anemia, increased
lifestyle optimizations such as diet control and physical exercise. risk of major cardiovascular events, and weight gain (83–85).
Insulin injection is the most important therapeutic approach in There is a correlation between exosomes and traditional
TABLE 3 | The common therapeutic strategies and disadvantages for the DM and its complications.
Disease Therapy Treatment principle Adverse effect Reference
T1DM Insulin Exogenous insulin improves glucose metabolism Substandard dose control can induce (82)
hypoglycemia, ketoacidosis
T2DM Insulin Exogenous insulin improves glucose metabolism Substandard dose control induces (82)
hypoglycemia, ketoacidosis
Metformin Improving peripheral tissue glucose uptake Gastrointestinal tract response (83)
Sulfonylureas/meglitinides Stimulating insulin secretion Hypoglycemia, hypoleucocytosis, hemolytic (84, 85)
anemia, increased risk of major cardiovascular
events, weight gain
DPP-4 inhibitors/GLP-1/GIP Stimulating insulin secretion, suppressing glucagon Renal impairment, hypoglycemia (86–90)
receptor agonist secretion, slowing gastric emptying, increasing b-cell
mass and function
a-Glucosidase inhibitor Delaying food decomposition, enhancing GLP-1 Flatulence, diarrhea (91–94)
secretion
Diabetic Antianginal therapy, Reduce myocardial fibrosis, revascularization Surgical risk, little benefit, other risk factors (95, 96)
cardiomyopathy percutaneous intervention,
surgical revascularization
DM, diabetes mellitus; T1DM, type 1 diabetes mellitus; T2DM, type 2 diabetes mellitus.

diagnostic test results. For example, a study showed that bone cells (NT-ES) into C-peptide-positive cells and achieved an
marrow mesenchymal stem cell (BM-MSC)-derived exosomes average efficiency of 55% in vitro, which indicates that this
can regulate aging-related insulin resistance. When BM-MSC- approach could address the challenges of b-cell donation.
derived exosomes are administered to old mice, young wild-type However, the risk of teratomas remains. Sui et al. (110) found
C57/BL6J mouse fasting glucose, fasting serum insulin, and that neuropeptide Y (NPY) family members can activate the Y
HOMA-IR increased, suggesting that BM-MSC-derived receptor that inhibits glucagon-like peptide 1 (GLP-1) signaling
exosomes in old mice can damage the body’s insulin sensitivity in b cells and induces insulin secretion. Using Y receptor
(98). Further clinical data showed that after measuring total inhibitors can increase insulin secretion from transplanted
plasma and EV-related microRNA (miRNA)-15a by real-time islets; however, little is known about Y receptor inhibitors
PCR, it was found that the circulating levels of miRNA-15a were (111), which precludes its immediate extensive clinical use.
significantly different. And miRNA-15a has a significant
connection with markers of altered glucose metabolism (e.g., 4.2.2 The Advantages and Disadvantages of
HbA1c, plasma glucose, insulin, and HOMA-IR) (99). However, Mesenchymal Stem Cell Transplantation
so far, no specific association mechanism between exosomes and Currently, MSCs are regarded as a potent regenerative source in
HOMA, fasting glucose, OGTT, HbA1c, and other diagnostic repairing injured tissue (26, 50, 112, 113), including in DM and
indicators has been found. associated diseases. This hypothesis was verified in both animal
Currently, effective drugs to treat diabetic complications are models and among patients with diabetes. Human umbilical cord
lacking, apart from invasive surgery or conventional methods to MSC (hucMSC) infusion decreased high-fat diet and
relieve symptoms such as anti-inflammatory and wound care streptozotocin (STZ)-induced T2DM in rats. Blood glucose level
(95, 96, 100–102). decrease was affected by increasing insulin sensitivity and
Glycemic control encompasses the management of not only restoring insulin secretion (114–116). hucMSC injection can
DM but also the associated complications. However, oral also help decrease insulin dependency in patients with T2DM
hypoglycemic drugs and insulin can only resolve symptoms and in early stages and hence reduce the insulin dosage at later stages
cannot prevent disease development. Therefore, novel strategies (117). The characteristics of MSCs such as low immunogenicity,
for effective treatment, which are non-invasive or minimally proliferation, and multilineage differentiation may partly solve the
invasive with minimal or no adverse effects, are urgently required. challenges associated with pancreas or islet transplantation (118,
119). Moreover, genetic editing techniques such as lentivirus and
4.2 Cell Transplantation for the CRISPER/Cas9 in MSCs, which overexpress exendin-4, can be
Treatment of Diabetes Mellitus and used for pancreatic duodenal homeobox-1-induced MSC
Diabetic Complications: Opportunities differentiation into insulin secretion cells, which may help
and Challenges overcome the shortage in islet donors (120, 121). Besides, MSCs
Promoting insulin secretion and ameliorating insulin resistance also show remarkable effects in diabetic complications. BM-MSCs
are the most important approaches in preventing DM and its seeded in collagen scaffolds can augment angiogenesis in diabetic
complications. Pancreas/islet and stem cell transplantations ulcers in rabbits (122). Placenta-derived MSCs can accelerate foot
could be effective and have seen remarkable advancements. We ulcer repair by inhibiting NF-kB expression and promoting
discuss the current research on tissue/cell transplantation for the secretion of the anti-inflammatory factor IL-10 (123) in T2DM
treatment of DM and diabetic complications. rat models. In diabetic nephropathy, MSCs derived from several
tissues can reverse glomerular injury by inhibiting oxidation,
4.2.1 The Limitations of Pancreas proinflammatory cytokines, and macrophage infiltration (124–
or Islet Transplantation 127). MSCs also can reverse diabetic neuropathy, cardiopathy,
Pancreas or islet transplantation has been applied in both T1DM and retinopathy; the underlying mechanism mainly involves
and T2DM and has proved successful in restoring functional b improving revascularization, inhibiting fibrosis, controlling
cells (103, 104). However, even after several years since first use, inflammation, and regulating oxidation (128–130). Given this
these have not been applied extensively for the following reasons. body of evidence, MSCs could be the best treatment choice
1) Pancreas or islet transplantation requires surgical for diabetes and diabetic complications. However, MSC
intervention. Although islet transplantation is minimally transplantation also presents challenges. First, in vivo MSC
invasive, the risk of portal vein hypertension, thrombosis, or injection has tumorigenic potential (131–136). Second, the
infarction of the liver exists (105–107). 2) Post-transplant infusion of a large number of MSCs may cause thrombosis
autoimmune reactions can cause graft loss and eventual failure (137, 138), headache, and fever (139). Third, the low survival
(108). 3) To reduce donor antigens, using islets from a single time and efficiency of MSCs in vivo may limit their therapeutic
donor (>5,600 islets equivalents/kg) is the best approach; efficiency (140). Fourth, although several studies have attempted
however, this cannot meet the demand, and post-transplant to improve MSC therapy with techniques such as transfecting
management is complex (109). Patients with glucose lability, CDR1 (141) and hepatocyte nuclear factor-4 alpha (HNF-4a) to
insulin resistance, obesity, and donor sensitization are not good regulate the biological characteristics of MSCs directly (142), no
candidates for islet transplantation (109). To solve these practical strategy is applicable in clinical practice and increases
problems, Sui et al. induced nuclear transfer embryonic stem the risk of MSC application.

4.3 The Advantages of Exosomes offspring (156). Early screening and timely intervention are
in Regulating the Glucose Metabolism critical to improve the maternal and child outcomes in GDM
in Diabetes Mellitus and Resolving (157–159). Exosomes can be potential biomarkers for disease
diagnosis and early prediction (160, 161), can carry miRNA,
Diabetic Complications
lncRNA, protein, and so forth, which act on recipient cells (162)
Glucose metabolism regulation by exosomes was first discovered
and play a key role in intercellular signal transmission (163).
in the setting of physical exercise. Physical exercise is critical in
Previous studies have found that in different stages of pregnancy,
DM care and has proved to increase insulin sensitivity in
the levels and biological activities of exosomes in the circulation
peripheral tissues and preserve b-cell function (143, 144).
differ between women with GDM and without (164); however,
Physical exercise or training can also induce rapid release of
the miRNA expression changes in exosomes in GDM. The
small EVs from skeletal muscle into circulation, which indicates
underlying mechanisms are yet to be fully clarified. GDM is
a connection between exercise-induced exosome release and
associated with proinflammatory processes, oxidative stress, and
reversal of insulin resistance and b-cell destruction (145, 146).
endothelial cell dysfunction in the placental microvascular
Furthermore, exosomes released by muscles may contribute to
system (165). Fetal–placental endothelial dysfunction is
DM management. Glucose-deprived cardiomyocytes released
characterized by changes in the L-arginine-adenosine signaling
exosomes containing glucose transporter 1 (GLUT1) and
pathway and inflammation (165, 166). The mechanisms involved
GLUT4, and other glucose metabolism enzymes, which can
in these changes are hypothesized to be hyperglycemia,
increase glucose uptake and subsequent glycolysis in
hyperinsulinemia, and oxidative stress (167, 168). These
neighboring endothelial cells (147). Exosomes released
conditions increase the release of exosomes. Because exosomes
during exercise contain miR-455, miR-29b, miR-323-5p, and
can regulate vascular function, they play an important role in the
miR-466, which can downregulate the expression of matrix
fetal–placental endothelial dysfunction in pregnancy in women
metalloproteinase (MMP9) by binding to its 3′ region to
with GDM (165). Increasing evidence shows that miRNAs rich
inhibit MMP9-induced cardiac fibrosis, which may reverse
in nanovesicles called exosomes are important regulators of gene
diabetic cardiopathy (15, 148). Previously, our team has used
expression. Compared with a normal pregnancy, a GDM
exosomes derived from hucMSCs to treat T2DM rat models,
pregnancy is associated with skeletal muscle insulin resistance
achieved good curative effects in the early stage, and explained
and increased levels of circulating placental exosomes. Placental
the relevant mechanisms (149). In addition, exosomes secreted
exosomes from women with GDM pregnancy suppressed
from INS-1 cells can deliver neutral ceramidase to inhibit
insulin-stimulated migration and glucose uptake in primary
palmitic acid (PA)-induced INS-1 cell apoptosis and increase
skeletal muscle cells obtained from patients with normal
insulin sensitivity in the PA-induced insulin-resistant cell model
insulin sensitivity. Of interest, placental exosomes from
H4IIEC3 (150). These data showed the potential of physical
normoglycemic women increased insulin migration and
exercise associated exosomes in regulating glucose metabolism.
glucose uptake in skeletal muscle of women with diabetes (73).
Exosomes have also been reported to be effective in the
Although DM and diabetic complications are metabolic
treatment of diabetic complications. For instance, Davidson
diseases, one of the essential causes is tissue injury. For
et al. found that exosomes derived from diabetic rats are not
example, auto-antibodies destroy b cells, causing insulin
capable of activing the ERK1/2 and HSP27 cardioprotective
secretion deficiency; lipid mediates activation of macrophages
pathway to protect rat cardiomyocytes from hypoxia and re-
to prominent proinflammatory cytokines and induces insulin
oxygenation injury (151); however, exosomes derived from non-
resistance (169, 170); chronic high glucose levels and insulin
diabetic plasma were effective. In addition, human endothelial
resistance cause increased fatty acid metabolism; the reduced
progenitor cell-derived exosomes contained angiogenesis-related
myofilament Ca + sensitivity, mitochondrial dysfunction,
molecules, including FGF-1, VEGFA, VEGFR-2, ANG-1, E-
oxidative stress, apoptosis, and fibrosis induce endothelial cell
selectin, CXCL-16, eNOS, and IL-8, to accelerate cutaneous
apoptosis, cardiomyopathy (30, 31, 34–36), and neuropathy; and
wound healing in diabetic rats by improving proliferation,
chronic high glucose levels and working strength induce
migration, and angiogenic tubule formation in endothelial cells
glomerular injury and renal fibrosis (29, 76). Based on
(152); the Erk1/2 signaling pathway was also involved (153).
reported evidence, exosomes can potentially repair tissue injury.
These reports indicate that the contents of exosomes
derived from patients with DM or diabetic complications
are dysfunctional and incapable of regulating cell–cell 4.4 Therapeutic Advantages of
communications; however, the use of exogenous exosomes Mesenchymal Stem Cell-Derived
overcomes these limitations. Exosomes in Diabetes Mellitus and
GDM is the first occurrence or diagnosis of abnormal glucose Diabetic Complications
tolerance during pregnancy; this condition occurs during Exosomes can be derived from several tissues and cells; however,
pregnancy when the pancreatic b-cell function is insufficient to exosomes can be derived from MSCs (MSC-ex) most
overcome the insulin resistance (154). The incidence of GDM is conveniently. MSCs can be isolated from the bone marrow,
increasing every year (155). It is associated with various short- umbilical cord, and adipose tissue, which can be used in
term and long-term adverse effects in pregnant women and autotransplantation. Low immunogenicity ensures low

immunoreactions in such transplantation. The proliferation treatment, various tumor-derived exosomes have been identified
potential of MScs ensures sufficiency of exosomes. that harbor several specific molecules from different types of
Currently, the repair of injured tissue by MSCs does not rely on tumors in patients with cancer (182, 183). In addition, exosomes
proliferation potential but on paracrine activity, because only <1% are associated with neurodegenerative diseases, such as
MSCs can reach the target tissue, and evidence shows that MSCs Alzheimer’s disease (AD) and Parkinson’s disease. A recent
differentiated into target cells are lacking (114, 171–173). study found that AD caused by the accumulation of b-amyloid
Exosomes are one of the most important approaches for (Ab) peptides in senile plaques is related to an exosome-
paracrine regulation. Our previous research showed that associated protein called ALIX, which suggests a significant
exosomes are an excellent replacement for MSCs and played an role of exosomes in the pathogenesis of AD (184). Exosomes
important role in the repair of injured tissue or organs by can participate in the occurrence and development of
delivering bioactive molecules such as Wnt4 (7) and Wnt11 to cardiovascular diseases. Scientists found that exosomes
regulate b-catenin and ameliorate scalded wound, and 14-3-3z carrying endothelial differentiation signals affect the formation
and glutathione peroxidase 1 to regulate YAP signaling in of new blood vessels, indicating the effectiveness of exosomes in
inhibiting excessive repair and recovering hepatic oxidant injury the treatment of angiogenesis (185, 186). In addition, our
(8, 50, 112). MSC-ex can also mediate the repair of osteochondral findings indicated that DIM promoted the stemness of
defects by increasing cellular proliferation and infiltration, hucMSCs by increasing exosomes derived from hucMSCs to
enhancing matrix synthesis, and a regenerative immune activate Wnt11 autocrine signaling, which provides a novel
phenotype (174). The present studies not only explain the strategy for improving the therapeutic effects of hucMSCs on
mechanism underlying MSC-driven repair of tissue injury but skin wound healing (112).
also prove that exosomes are key to the paracrine activity of MSCs. Some studies have shown that exosomes derived from MSCs
In DM, MSC-ex could be the key element in protecting the can also increase ATP levels, reduce oxidative stress through
pancreatic islets in patients with T1DM from autoimmune the PI3K/Akt pathway, enhance the vitality of myocardial cells,
targeting, slowing disease progression (175). MSC-ex can and prevent adverse remodeling after myocardial ischemia and
promote angiogenesis and survival of transplanted pancreatic reperfusion (187). In a study of intervertebral disc degeneration,
islets and can enhance the efficiency and success rate of the exosomes can significantly inhibit the inflammatory response of
treatment, for example, by carrying siFas and anti-miR-375 and apoptotic nucleus pulposus cells (188).
inhibiting immune reaction to improve islet transplantation Exosomes are also involved in the occurrence and
(176, 177). MiR-29b-3p in MSC-derived exosomes significantly development of liver diseases. Karamichali et al. found that
ameliorated the insulin resistance in aged mice and helped exosomes can mediate the transfer of in-frame deletion
regulate the blood glucose level (98). Exosomes from the mutants to regulate HCV virus replication and make the virus
hucMSCs can downregulate blood glucose level in T2DM by continue to infect (189). The concentration of exosomes in the
reversing peripheral insulin resistance and inhibiting b-cell peripheral blood of pregnant women is closely related to the
destruction (149). In diabetic complications, MSC-ex can process of pregnancy and pregnancy complications. Abnormal
induce proliferation and migration of normal and chronic concentration of exosomes in the peripheral blood of pregnant
wound fibroblasts and enhance angiogenesis to accelerate women can reflect the risk of pregnancy complications to a
cutaneous wound healing (178). Diabetes-induced cognitive certain extent (190).
impairment and nephropathy can be improved by bone
marrow stem cell-derived exosomes too (179, 180). 4.6 The Future Application Prospects of
Besides ordinary MSC-ex, exosomes from modified MSCs Exosomes in the Treatment of Diabetes
can carry special molecules, like exosomes from 3,3′- and Complications
diindolylmethane (DIM)-stimulated human hucMSCs contain Nowadays, the application of MSC exosomes is becoming more
higher levels of Wnt 11 and enhanced the wound healing and more extensive, and the corresponding application technology
potential of hucMSCs (112). Exosomes from hypoxia-inducible is relatively mature. In autologous therapy, currently, the main
factor 1a (HIF-1a) modified BM-MSCs were much more cell-free therapy is MSC-ex. It contains a variety of functional
effective in attenuating early steroid-induced avascular necrosis proteins, mRNAs, miRNAs, and signaling lipids (191–193). In
of the femoral head in rabbits than exosomes from the wild-type non-autologous therapy, researchers are moving towards a new
MSCs (181). These studies indicate that the potency of exosomes strategy based on loading MSC-ex by patches, injectable
can be increased by modifying MSCs, which may be safer than microcarriers, or hydrogels, aimed at maintaining the function
using MSCs directly and can promote the use of exosomes in the of exosomes at the function site and enhancing efficiency and
treatment of DM and diabetic complications (Figure 2). safety. Chitosan and relevant compounds are ideal carriers for the
sustained release of nanoparticles including exosomes (183, 194,
4.5 The Utility of Exosomes in 195). Shi et al. prepared the chitosan/silk hydrogel sponge by
Other Diseases freeze-drying method to be a scaffold for exosomes (196). Since
As a communication messenger between cells, the potential role chitosan is a hydrophilic polymer, this hydrogel sponge shows
of exosomes in the clinical treatment and prevention of diseases good swelling behavior, creates a moist environment, and
has gradually emerged. First, in early diagnosis or targeted tumor enhances the angiogenesis and neuronal ingrowth. Alginate-

FIGURE 2 | Potential approach of exosomes derived from mesenchymal stem cell in diabetes mellitus and diabetic complication repair. Exosome derived from
mesenchymal stem cell may downregulate blood glucose through reversing peripheral tissue (liver and muscle) insulin resistance and increasing b-cell survival during
remission of diabetes mellitus; exosome derived from mesenchymal stem cell can inhibit apoptosis, oxidative stress, and immune reaction to reduce vascular or
neuron injury and carry growth factors to increase damaged tissue or cell repair, which may participate in alleviating diabetic complications.
based hydrogels have been designed to encapsulate adipose- Further study is needed before extensive clinical use of
derived mesenchymal stem cell exosomes (ADSC-Exos) to exosomes can be recommended.
fabricate a bioactive scaffold (133), which is tested to be
biodegradable and biocompatible, reflecting its potential as a
cell-free therapy (197). In general, the exosome-carrier
compound displays better treatment outcomes than the
AUTHOR CONTRIBUTIONS
exosomes or carrier materials alone, suggesting a synergistic YS and QT: conception and design, collection and/or assembly of
effect through the sustained release of MSC-ex. Not only that, data, data analysis and interpretation, visualization, manuscript
for better delivery of exosomes, MSC exosomes that deliver writing, and final approval of the manuscript; these authors
biological scaffolds have also been invented and used and were contributed equally to this work. XW: collection and/or assembly
fabricated in a 3D-printed cartilage extracellular matrix (ECM)/ of data. LZ: collection and/or assembly of data. QL and LW:
gelatin methacrylate (GelMA)/exosome scaffold (198). conception and design, financial support, administrative
Besides, in the future, with the help of mass spectrometry and support, provision of study material, supervision, collection
high-throughput sequencing (199, 200), a pathological molecular and/or assembly of data, data analysis and interpretation,
spectrum of exosomes derived from body fluids of diabetic visualization, manuscript writing, and final approval of the
patients will be formed, covering molecules such as proteins, manuscript. All authors reviewed the manuscript. All authors
nucleic acids, and metabolites, which can provide new ideas and contributed to the article and approved the submitted version.
research for early diagnosis and prognosis of diabetes. This
direction can also provide more options for the treatment
of diseases.
FUNDING
This work was supported by the Natural Science Youth
5 SUMMARY Foundation of the Jiangsu Province (Grant BK20210074),
the Introduction program of high-level innovative and
Exosomes can function not only as biomarkers for early entrepreneurial talents in Jiangsu province, Wuxi first
diagnosis of DM but also as potential therapeutic tools in DM “Double hundred” Young and middle-aged Top-notch
and its complications. However, some key challenges exist. The Medical and health talents Program (HB2020108), Wuxi
cost of exosome isolation for high volume use is high; no Health Commission scientific research project youth project
diagnostic and therapeutic standards have been established; (Q202059), and the National Key R&D Program of
and most supporting studies were animal model studies. China (2020YFC2005300).

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published: 26 October 2021

The Utility of Exosomes in Diagnosis

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TABLE 1 | Methods of exosome isolation and evaluation.

Method Principle Advantage Disadvantage Reference

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Disease Target Sample Method Scientiﬁc mechanism Reference

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4. EXOSOMES AS A POTENTIAL the treatment of DM and diabetic complications. However, if its

Disease Therapy Treatment principle Adverse effect Reference

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