Diabetic Vascular Diseases: Molecular Mechanisms and Therapeutic Strategies

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REVIEW ARTICLE OPEN
Diabetic vascular diseases: molecular mechanisms and

therapeutic strategies
Yiwen Li1, Yanfei Liu1,2, Shiwei Liu3, Mengqi Gao3, Wenting Wang1, Keji Chen1 ✉, Luqi Huang4 ✉ and Yue Liu 1✉
Vascular complications of diabetes pose a severe threat to human health. Prevention and treatment protocols based on a single
vascular complication are no longer suitable for the long-term management of patients with diabetes. Diabetic panvascular disease
(DPD) is a clinical syndrome in which vessels of various sizes, including macrovessels and microvessels in the cardiac, cerebral, renal,
ophthalmic, and peripheral systems of patients with diabetes, develop atherosclerosis as a common pathology. Pathological
manifestations of DPDs usually manifest macrovascular atherosclerosis, as well as microvascular endothelial function impairment,
basement membrane thickening, and microthrombosis. Cardiac, cerebral, and peripheral microangiopathy coexist with
microangiopathy, while renal and retinal are predominantly microangiopathic. The following associations exist between DPDs:
numerous similar molecular mechanisms, and risk-predictive relationships between diseases. Aggressive glycemic control
combined with early comprehensive vascular intervention is the key to prevention and treatment. In addition to the widely
recommended metformin, glucagon-like peptide-1 agonist, and sodium-glucose cotransporter-2 inhibitors, for the latest molecular
mechanisms, aldose reductase inhibitors, peroxisome proliferator-activated receptor-γ agonizts, glucokinases agonizts,
1234567890();,:
mitochondrial energy modulators, etc. are under active development. DPDs are proposed for patients to obtain more systematic
clinical care requires a comprehensive diabetes care center focusing on panvascular diseases. This would leverage the advantages
of a cross-disciplinary approach to achieve better integration of the pathogenesis and therapeutic evidence. Such a strategy would
confer more clinical benefits to patients and promote the comprehensive development of DPD as a discipline.
Signal Transduction and Targeted Therapy (2023)8:152 ; https://doi.org/10.1038/s41392-023-01400-z
INTRODUCTION been proposed and “polyvascular atherosclerotic disease”14 has

Diabetes mellitus (DM) and its complications pose a serious threat been defined considering coronary and non-coronary AS, mainly
to human health and have become a global public health issue.1,2 peripheral arterial and cerebrovascular diseases (peripheral
Over 90% of patients with diabetes have type 2 DM (T2DM).3,4 vascular disease and cerebrovascular disease respectively). This
Diabetic complications can be classified according to the definition indicates that comprehensive management of the
involvement of cardiopathy and encephalopathy, nephropathy, multivessel disease is clinically essential for improving outcomes
retinopathy, and peripheral vasculopathy.5–7 DM increases the risk and prognoses. However, this definition does not consider either
of all these complications, and multiple vasculopathy is associated microvascular disease (especially in vital organs) or multidisciplin-
with a poorer prognosis.8 Recent intensive investigations into ary fusion. To improve this definition, we propose the concept of
diabetic complications have significantly promoted the under- diabetic panvascular disease (DPD). This is a clinical syndrome in
standing of the pathogenesis of this disease. However, the which AS is a common pathology between macrovessels and
increasing division of medical science into various subspecialties, microvessels in the cardiac, cerebral, renal, ophthalmic, and
has resulted in a tendency to focus on localized lesions instead of peripheral systems in patients with diabetes. The main outcomes
integrating overall evidence. Thus, a holistic investigation of would be cardiovascular and cerebrovascular events, and the
diabetic complications involving multiple systems and different prognosis could be improved through aggressive intervention
angiopathies is needed. against metabolic abnormalities.
The pathology of diabetic complications has a high degree of Diabetic complications are usually classified in two dimensions:
commonality at the vascular level; that is, complications manifest macro/microvascular disease, or complications classified by target
mostly as endothelial dysfunction and atherosclerosis (AS).9 DM organs. DPDs synthesize these concepts. This article systematically
being a risk factor for vascular disease, the several vascular reviews general pathological manifestations of vascular lesions
comorbidities seriously affect the prognosis and treatment of and differences in the etiology of macro/microvascular lesions;
patients, leading to the concept of “panvascular disease”.10–12 pathological manifestations and molecular mechanisms of differ-
Since the late 20th century, the concept of a “vessel tree”13 has ent target organs in DPDs; common molecular mechanisms and
1
National Clinical Research Center for Chinese Medicine Cardiology, Xiyuan Hospital, Chinese Academy of Chinese Medical Sciences, Beijing 100091, China; 2The Second
Department of Gerontology, Xiyuan Hospital, China Academy of Chinese Medical Sciences, Beijing 100091, China; 3Department of Nephrology and Endocrinology, Wangjing
Hospital, China Academy of Chinese Medical Sciences, Beijing 100102, China and 4China Center for Evidence-based Medicine of TCM, China Academy of Chinese Medical
Sciences, Beijing 100010, China
Correspondence: Keji Chen ([email protected]) or Luqi Huang ([email protected]) or Yue Liu ([email protected])
These authors contributed equally: Yiwen Li, Yanfei Liu, Shiwei Liu
Received: 5 November 2022 Revised: 19 February 2023 Accepted: 28 February 2023
© The Author(s) 2023

Diabetic vascular diseases: molecular mechanisms and therapeutic strategies
Li et al.
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Fig. 1 Schematic overview of panvasculopathy in diabetes mellitus. Diabetic panvasculopathy involves the cardiac, cerebral, renal, ophthalmic
and peripheral systems. The macrovascular lesions are in black text. The microvascular lesions are in red. The microvascular system varies in
different organs, which affects vascular function
therapeutic targets in DPDs; time course characteristics of sympathetic nervous system (SNS) directly or indirectly causes
pathological changes in organs and mutual predictive effects widespread vascular damage throughout the body, leading to the
among DPDs to provide clues for early diagnosis. Our findings development of panvascular complications of DM15 (Fig. 1). SNS
should promote the establishment of a multidisciplinary DPD dominates vasoconstriction and RAAS regulates of blood volume,
management system. vascular tone, and blood pressure.16 The vascular system in target
organs is tightly regulated by surrounding tissues that regulate
Diabetes and panvasculopathy microvascular units through physical and signal transduction. As
The vasculature comprises endothelial cells (EC), smooth muscle DM progresses, patients are more likely to develop various
cells (SMC), pericytes, fibroblasts, and various other types of cells. vascular complications and experience many pathological
AS, endothelial barrier damage, loss of pericytes, capillary changes, such as endothelial dysfunction, AS, and microcirculatory
thinning, and angiogenic disorders are common pathologies of disorders that interact with each other, consequently leading to
systemic vascular disease. Blood vessels, together with nerves and the development of DPD.
lymphatic vessels, are wrapped in connective tissue membranes Diabetic vasculopathy is classified as macroangiopathy and
to form vascular nerve bundles. Differences in perivascular tissues, microangiopathy. Macroangiopathy includes AS of large and
vascular nerve bundles, and intravascular structures result in medium arteries (aorta, coronary, renal, basilar, and peripheral
altered vascular function. When imbalanced homeostasis is arteries), whereas microangiopathy includes endothelial damage
characterized by abnormal glucose and lipid metabolism, activa- to vessels between primary arterioles and venules, vascular
tion of the renin-angiotensin-aldosterone system (RAAS) and basement membrane thickening, microthrombosis, platelet and
Signal Transduction and Targeted Therapy (2023)8:152

Li et al.
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red blood cell adhesion aggregation, and microcirculatory Cells.27 Hyperglycemic states can further promote autoimmune
disorders. Due to differences in hemodynamics, vascular structure, responses. In addition to glycemic control and statins, monoclonal
and the affected cells, macro/microangiopathy present with antibodies to proprotein convertase subtilisin/kexin type 9
different pathological manifestations. AS often occurs in sites of (PCSK9), heat shock proteins60/65 (HSP60/65), and ApoB are
hemodynamic disturbances (preferably in elastic arteries). It expected to improve AS by targeting.28
manifests as macrophage foaming and EC lesions as well as The mechanisms by which diabetes promotes cardiomyopathy
mesangial SMC lesions. Microvessels are more hemodynamically have received attention, especially due to abnormal cardiac
stable, with a few cell layers, accompanying abundant plexus. On metabolism (Cardiac Metabolism), glycotoxicity and lipotoxicity,
the other hand, differences in energy metabolic status, and organ- and abnormal mitochondrial function causing oxidative stress and
specific growth factors or cytokines in different target organs are inflammation.29 Unlike other target organs, the myocardium has
also important components of the differences. Most target organs high energy and oxygen requirements, and fatty acid oxidation
(heart, brain, peripheral vasculature) are affected by both diabetic (FAO) and aerobic oxidation of glucose are the main sources of
macrovasculopathy and microvasculopathy; the retina and kidney energy for cardiac metabolism. Insulin resistance increases lipid
are mainly affected by microvasculopathy (Fig. 1). synthesis in hepatocytes and lipolysis in adipocytes, leading to
elevated circulating fatty acids and triglyceride levels. Lipid
DPDs accumulation and fatty acids-induced lipotoxicity can affect
Diabetic heart disease (DHD). DHD includes all kinds of cardio- myocardial FAO processes, promote endoplasmic reticulum (ER)
vascular diseases secondary to DM, including coronary artery stress, autophagy, and apoptosis, and cause ventricular remodel-
disease (CAD) and cardiomyopathy. Cardiomyopathy and CAD are ing.20,30 The most important metabolites of diabetic glycotoxin are
often treated separately as microvascular and macrovascular advanced glycation end-products (AGEs) that are involved in the
diseases, DM can increase the risk of both. They are often formation and evolution of DCM. These end-products bind cellular
combined in clinical settings and ultimately lead to adverse receptors of AGEs (RAGEs) that promote the production of reactive
outcomes and risk of death in patients with cardiovascular oxygen species (ROS), nuclear factor kappa-B (NF-κB), and pro-
disease.17 inflammatory cytokines such as interleukin (IL)-1β, IL-6, IL-18,
Myocardial microvascular functional changes precede structural tumor necrosis factor-alpha (TNF-α) that induce the intracellular
changes in patients with diabetes. These changes finally lead to production of abundant ROS, and initiate oxidative stress/
extensive macrovascular AS.18 DM complicated with coronary inflammation cascade.31,32 AGEs/RAGE causing structural changes
atherosclerotic heart disease manifests as the segmental distribu- in the myocardium. Advanced glycation end-products also
tion of numerous vascular branches throughout the entire activate inflammatory signals through RAGEs on EC macrophages,
process, with obvious AS. Diabetic cardiomyopathy (DCM) refers and smooth muscle cells. This activation leads to increased ROS
to specific myocardial structural and functional abnormalities that production and reduced nitric oxide synthesis, thus promoting the
occur in patients without CAD and cardiac risk factors such as development of DCM.33,34 Hyperglycemia mediates a decrease in
hypertension, with heart failure (HF) as the main manifestation of the expression of jund proto-oncogene subunit (JunD) and of free
chronic cardiovascular complications of DM. The main pathologi- radical scavenger superoxide dismutase 1 and aldehyde dehy-
cal features are left ventricular hypertrophy, myocardial fibrosis, drogenase 2. It also mediates increased expression of inflamma-
cell necrosis, and other myocardial structural changes.19,20 tory mediators such as NF-κB and Mcp-1, IL-6, and TNF-α that
Myocardial involvement in vasoactive metabolite secretion or cause myocardial dysfunction and lead to the development of
neuromodulation causes changes in the coronary artery wall HF.35 Hyperglycemia promotes the increased expression of
pressure or endothelial shear stress. Pericoronary adipose tissue lncDACH1, which in turn promotes mitochondrial oxidative stress
can secrete adipokines and other vasoactive mediators and/or and apoptosis through increased ubiquitination-mediated degra-
oxidative products that can directly alter the phenotypes of dation of NAD-dependent deacetylase sirtuin-3 (SIRT3), mitochon-
perivascular adipocytes. drial in mouse hearts, consequently aggravating DCM.36 Protein
Investigations of biomarkers of DHD and their applications have kinase C (PKC) is an effector in the G protein-coupled receptor
significantly progressed. Cardiovascular events as outcomes are system, and vascular SMC maintains vascular tone. PKC can be
more beneficial for the clinical application of biomarkers from the activated by excess ROS, AGEs, and diacylglycerol (DAG) to impair
aspect of panvascular diseases. The severity of cardiovascular VSM function; this leads to vascular hyperresponsiveness and
disease in patients with diabetes positively correlates with the remodeling and accelerated development of DHD.37,38 Hypergly-
ratio of oxidized low-density lipoprotein to low-density lipopro- cemia triggers classical inflammatory pathways and oxidative
tein-cholesterol (Ox-LDL/LDL-C). This is considered a potential stress.39,40 Hyperglycemia causes upregulates membrane cofactor
biomarker for the early identification and intervention of CAD in protein-1 (MCP-1) and NLR family pyrin domain containing 3
patients with diabetes.21 Osteopontin (OPN) is a multifunctional inflammasome (NLPR3) expression, causing myocardial fibrosis
phosphorylated glycoprotein, that functions as an inflammatory and cardiac dysfunction, and exacerbated DCM development.41
cytokine and pro-atherosclerotic factor. High levels of OPN Several molecular mechanisms synergistically act to impair the
expression in the circulation and tissues are associated with structural function of the heart and promote the development of
cardiovascular complications in DM, and OPN is an independent DHD (Fig. 2).
predictor of cardiovascular disease in DM.22 Serum homocysteine Various interventions have conferred clinical benefits on
levels are elevated in patients with T2DM and CAD and are closely patients with DHD (Table 1). Treatment of DHD should be
related to the severity of coronary artery lesions.23 Plasma-free comprehensive, with aggressive control of risk factors such as
fatty acids also comprise an independent risk factor for CAD in blood glucose, blood pressure, and lipids. Basic pharmacological
patients with DM.24 Novel biomarkers are useful for providing therapy for CAD in patients with diabetes includes antiplatelet,
insights into associations between DM and cardiovascular risk and cholesterol-lowering, anti-myocardial ischemia strategies, and
developing treatment strategies for CAD associated with DM. RAAS inhibitors. Aggressive blood sugar control is necessary for
Coronary AS exists in diabetic patients, and the signal treating DHD to avoid direct hyperglycemic damage. When
transduction of AS is similar in DPDs. Chronic inflammation, treating T2DM complicated with cardiovascular disease, metfor-
abnormal lipid metabolism, and secondary autoimmunity are the min should be combined with glucose-lowering drugs that have a
main mechanisms.25 ApoB-specific CD4 T cells have been proven cardiovascular benefit. When treating T2DM complicated
identified in humans and mice, and treg can be induced with with atherosclerotic cardiovascular disease, the preferred combi-
ApoB peptides.26 Hsp60/65 is the target antigen of autoimmune T nation of metformin with either glucagon-like peptide-1 receptor

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Fig. 2 Pathology and molecular mechanisms of DHD. The mechanisms of diabetic heart disease are complex, including oxidative stress,
inflammation, and altered metabolic pathways (advanced glycosylation end product (AGE) formation, PKC pathway), which intersect and work
together to ultimately lead to myocardial remodeling and dysfunction
agonist (GLP-1RA) or sodium/glucose cotransporter-2 inhibitors neuronal activity, maintains the interstitial environment, and
(SGLT-2i) can reduce cardiovascular events (Table 1). When reduces and stabilizes blood flow.54 Diabetic macroangiopathy
treating T2DM complicated with HF, metformin should be and microangiopathy mutually promote each other, and the
combined with SGLT-2i, as this leads to a 39% reduction in the occlusion of macrovessels can cause chronic perfusion insuffi-
risk of HF hospitalization and a 46% reduction in the composite ciency in the brain and microvascular disorders.55 Microvascular
endpoint of HF hospitalization with all-cause death.42 Although function can affect collateral circulation in macrovessels56,57 and
GLP-1RA and dipeptidyl peptidase-4 inhibitors (DPP-4i) also confer increase the risk of stroke58 as well as a poor prognosis.59–61
some cardiovascular benefits, they do not offer a significant Neurons injury,62 Alzheimer’s like pathologies,63 and abnormal
advantage for reducing the hospitalization of HF in patients with activity of neurotransmitter receptors64 are also closely associated
diabetes (Table 1).43,44,45 with cerebrovascular lesions, and jointly cause brain function
impairment in patients.
Diabetic encephalopathy (DE). DM is significantly associated with Elevated blood glucose is a risk factor for pathological changes
an increased risk of several intracranial diseases, including cerebral in the brain and brain function impairment.65,66 Not only DM but
macro- and microangiopathy.46–48 Broadly speaking, the intracra- also pre-DM can promote the development of dementia.67
nial complication of DM includes stroke, which can also manifest However, the imaging changes do not correspond to the degree
as depression, mild cognitive impairment (MCI), and demen- of cognitive impairment, and its mechanism deserves further
tia.46,49–51 Such vascular lesions can involve large carotid and exploration.68 Diabetic cerebral microangiopathy has multiple
vertebral arteries, small intracerebral perforating arteries, micro- complex changes in images (cerebral atrophy, subcortical micro-
arteries, capillaries, micro-venules, and small veins. They are also infarcts, cerebral white matter hyperintensity, lacunar infarction,
involved in disrupting the integrity of the blood-brain barrier (BBB) perivascular space, and cerebral microhemorrhage),69 with diffuse
and neurodegeneration.52,53 The cerebral microvasculature facil- adverse effects.70,71 Meanwhile, advances are being made in the
itates intracranial nutrient delivery and waste removal, supports measurement of cerebral microangiopathy, along with more

Table 1. Cardiovascular outcomes trials (including stroke) in diabetes mellitus (2013–2022)
Clinical trial Clinical trials’ number Year Phase Participants (n) Intervention Follow-up Main outcome
Dipeptidyl peptidase-4 (DPP-4) inhibitors

CARMELINA475 NCT01897532 2013–2016 3 6991 I: Iinagliptin 2.2 years Cardiovascular death, nonfatal myocardial infarction,
C: placebo nonfatal stroke
NA476 NCT01703208 2012–2016 3 4202 I: Omarigliptin 1.84 years Major adverse cardiovascular event, hospitalization for heart
C: placebo failure
SAVOR-TIMI 5345 NCT01107886 2010-2011 3 16492 I: Saxagliptin 2.1 years Composite of cardiovascular death, myocardial infarction, or
C: placebo ischemic stroke
TECOS477 NCT00790205 2008–2012 3 14671 I: Sitagliptin 3 years Composite of cardiovascular death, nonfatal myocardial
C: placebo infarction, nonfatal stroke, or hospitalization for unstable angina
Glucagon-like peptide-1 receptor (GLP-1) agonists
REWIND478 NCT01394952 2011 3 9901 I: Dulaglutide 5.4 years Nonfatal myocardial infarction, nonfatal stroke, and death from
C: placebo cardiovascular
SUSTAIN-644 NCT01720446 2013 3 3297 I: Semaglutide 2.1 years Cardiovascular death, nonfatal myocardial infarction, or

C: placebo nonfatal stroke
PIONEER 6479 NCT02692716 2017 3 3183 I: oral Semaglutide 1.25years Death from cardiovascular causes, nonfatal myocardial
C: placebo infarction, nonfatal stroke
EXSCEL480 NCT01144338 2010-2015 3 14752 I: Exenatide 3.2 years Death from cardiovascular causes, nonfatal myocardial
LEADER481 NCT01179048 2010–2012 3 9340 I: Liraglutide 3.8 years Death from cardiovascular causes, nonfatal myocardial
ELIXA482 NCT01147250 2010–2013 3 6991 I: Lixisenatide 2.2 years Death from cardiovascular causes, nonfatal myocardial
C: placebo infarction, nonfatal stroke, hospitalization for unstable angina
Sodium-glucose cotransporter-2 (SGLT2) inhibitors
Li et al.
EMPA-REG NCT01131676 2015 3 7020 I: Empagliflozin 3.1 years MACE, cardiovascular, all-cause death, hospitalization for heart
OUTCOME483 C: placebo failure
CANVAS NCT01032629 2017 3 10142 I: Canagliflozin 3.61 years Cardiovascular death or hospitalized Heart failure
program484,485 NCT01989754 C: placebo
DAPA-HF486 NCT03619213 2018–2022 3 3131 I: Dapagliflozin 2.3 years Composite of worsening heart failure, cardiovascular death
C: placebo
Empa-HF100 NCT03485092 2018 3 150 I: Empagliflozin 0.69 year Left ventricular volumes
C: placebo
CREDENCE487 NCT02065791 2014–2017 3 4401 I: Canagliflozin 2.62 years Reduces the risk of kidney failure and cardiovascular events
C: placebo
DECLARE–TIMI 58488 NCT01730534 2013–2018 3 17160 I:Dapagliflozin 4.2 years MACE, composite of cardiovascular death, hospitalization for
C: placebo heart failure
EMPA-REG489 NCT01131676 2010–2013 3 7020 I:Empagliflozin 3.1 years Death from cardiovascular causes, nonfatal myocardial
Others
SAVOR-TIMI 53490 NCT01107886 2010-2011 / 4894 I: Metformin 2.1 years Composite of cardiovascular death, myocardial infarction, or
C:Other antidiabetic drugs ischemic stroke
TOSCA.IT491 NCT00700856 2008–2014 3 3028 I: pioglitazone add on 5 years All-cause death, nonfatal myocardial infarction, nonfatal stroke,
metformin or urgent coronary revascularization
C: sulfonylurea add on
metformin
5
6
Table 1. continued
Clinical trial Clinical trials’ number Year Phase Participants (n) Intervention Follow-up Main outcome
492
PROactive NCT00013208 2015 / 3606 I: Pioglitazone 7.8 years All-cause mortality, nonfatal myocardial infarction, stroke,
C: placebo cardiovascular mortality, cardiac intervention, et al
PROFIT-J493 UMIN000000846 2007–2011 3 481 I: Pioglitazone 1.53/ Composite of all-cause death, nonfatal cerebral infarction, and
C: Other antidiabetic drugs 1.64 years nonfatal myocardial infarction
DEVOTE494 NCT01959529 2013–2014 3 7637 I: Insulin Degludec 1.99 years Death from cardiovascular causes, nonfatal myocardial
C: Insulin Glargine infarction, nonfatal stroke
ORIGINALE495,496 NCT00069784 2012–2014 3 4718 C: Glargine 2.7 years Death from cardiovascular causes or myocardial infarction or
I: Standard care stroke and any of these three outcomes or hospitalization for
heart failure or carotid, coronary, or peripheral revascularization
ACCORD497 NCT00000620 2001–2005 3 10251 I: intensive glycemic control 3.7 years Composite cardiovascular outcome, cardiovascular and total
C: standard glycemic control mortality, nonfatal myocardial infarction
Steno-2498,499 NCT00320008 1993–2006 3 160 I: intensive glycemic control 13.3 years Death from any cause
C: standard glycemic control Stroke
VADT500 NCT00032487 2000–2008 3 1791 I: intensive glycemic control 5.6 years Composite of major cardiovascular events
C: standard glycemic control
Look AHEAD77 NCT00017953 2001–2012 3 5145 I: intensive lifestyle 9.6 years Composite cardiovascular outcome
intervention
C: receive diabetes support
and education
AleCardio501 NCT01042769 2010–2012 3 7226 I: Aleglitazar 2.5 years Composite of cardiovascular mortality, nonfatal myocardial
Li et al.

MACE major adverse cardiovascular events, NA no official trial name

Li et al.
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precise MRI interpretations and artificial intelligence that have glitazones can activate peroxisome proliferator-activated receptor-
revealed more DM-induced cerebrovascular pathologies.72 γ (PPAR-γ),118 which can improve cell adhesion factors and
Intracranial pathological changes of microangiopathy include inflammatory factors in brain cells. This receptor can also act on
endothelial dysfunction, platelet aggregation impairment, and other tissues and regulate glucose metabolism and overall energy
increased inflammation.73–75 The expression of vascular endothe- homeostasis.119 Abundant GLP-1α is expressed in the brain, and
lial growth factor (VEGF) and endothelin nitric oxide synthase GLP-1 receptor agonizts have a good safety profile, neuroprotec-
(eNOS) are decreased in DE, which impairs cerebral artery tive effects, and can improve cognitive impairment. The new
endothelial function and results in decreased vascular autoregu- glucose-lowering agent SGLT-2i has cardio-renal protective
latory response.76 Disorders of platelet aggregation and inflam- effects, but it might increase the risk of stroke, which makes its
mation reduce cerebral blood flow and increase the risk of DE.77 use controversial.120–122 Furthermore, the mechanism of SGLT-2i
Central nervous system is highly dependent on glucose for energy actions is unknown. Meanwhile, new benefits have been
supply.78–80 Disturbance of carbohydrate metabolism can cause confirmed for some traditional hypoglycemic agents, such as
an intracranial energy metabolism imbalance and promote lesion glibenclamide, which can reduce hemispheric edema after stroke
development.81,82 Aldose reductase activity is significantly and when intravenously injected.123,124 Among non-hypoglycemic
systemically increased with hyperactivation of the sorbitol path- drugs, phosphodiesterase type III inhibitor Cilostazole125 improves
way in diabetes.83 This leads to insulin resistance, resulting in oxidative stress and regulates cerebrovascular damage. NMDA
widespread oxidative stress and increased inflammatory cytokines. receptor agonizts, neurotrophic factors, and mitochondrial func-
The insulin receptor signaling system plays an important role in tion modifiers are also under development.126
maintaining normal brain and cognitive functions84 by regulating Imaging modalities such as MRI are significantly more important
GLP-1 receptors,84,85 insulin receptor substrate (IRS) receptors.86,87 than serum markers for identifying encephalopathy compared
In other tissues, insulin activates the glucose transporter (GLUT) with other diabetic vascular lesions. However, current imaging
family of glucose transport proteins, but in the skull GLUT is protocols for diagnosing DE are not sufficiently specific. The
directly regulated by glucose or cAMP. Activation of IRS or GLUT correlation between imaging and corresponding molecular
promotes glucose utilization in the Phosphatidylinositide mechanisms is not yet clear. To overcome this limitation, large
3-kinases (PI3K), protein kinase B (Akt), and β-arrestin/ extracellular clinical trials targeted other vascular lesions and glycaemic control
regulated protein kinases (ERK) pathways. Insulin resistance causes need to be conducted, to identify the population with diabetes
chronic inflammation and increased oxidative stress, imbalanced that is at high risk of developing cerebrovascular lesions.82
energy metabolism.88–92 This leads to neuroinflammation and the
apoptosis of pericytes and microglial cells,88,89,92–96 thus disrupt- Diabetic kidney disease (DKD). Between 5 and 40% of patients
ing vascular endothelial tight junctions and causing damage to with diabetes eventually develop diabetic kidney disease (DKD),127
the BBB. The accumulation of AGEs also affects various cellular and the number of those with chronic DKD is increasing by 2.62
constituents of the BBB, resulting in increased BBB permeability million annually, with chronic DKD being the leading cause of
and cognitive impairment.97–99 Vascular endothelial dysfunction end-stage renal disease.128 DKD is a microvascular complication
further promotes the production of inflammatory mediators that characterized by glomerular hypertrophy, basement membrane
disrupt the BBB,59,63,64,100 which exposes the brain parenchyma to thickening, and damage.129 The complex renal vascular system,
potentially neurotoxic proteins.101 Classical inflammatory media- including the renal arteries and their branches, as well as
tors such as IL-1β, IL-6, IL-10, TNF-α, vascular cell adhesion protein- glomerular and peritubular capillary networks, form the basis for
1 (VCAM-1), and matrix metalloproteinases (MMP)-2 and -9 suggest maintaining normal renal function. The mechanism through which
vascular neuroinflammation. Intracranial-specific inflammatory DM causes kidney damage is complex and might involve
signals, estrogen receptors promote increased expression of hemodynamic, metabolic, and inflammatory pathways and
membrane Rα and ERβ in the hippocampus and promote targets130,131 (Fig. 4). A hyperglycemic environment induces
hippocampal apoptosis;102 P38 activates mitogen-activated pro- hypertension, which increases the disturbed renal perfusion
tein kinase (MAPK) pathway to promote neuronal cell death, and pressure and indirectly causes microvascular damage in renal
microglia activation.103,104 Hyperglycemia stimulates inflammatory arteries, glomerular and tubulointerstitial capillaries.132–134 AS
signals and adaptive signals, accelerating ER stress and mitochon- causes thickening of renal artery walls and lumen narrowing.135,136
drial dysfunction.105 In addition, glutamate is a key excitatory Upregulated SGLT expression promotes glucose uptake, which
neurotransmitter in the central nervous system. Glutamate affects the tubular-glomerular feedback mechanism, leading to
receptors, including N-methyl-D-aspartic acid receptors (NMDA), glomerular hypertension.137,138 Plasma levels of kallikrein, throm-
may regulate neurogenesis and synaptic plasticity.106,107 Upregu- bin, and coagulation factors are elevated in hyperglycemic states.
lation of NMDA receptors had beneficial effects on learning and A chronically activated coagulation system is closely associated
memory in diabetic rats108 (Fig. 3). with a vascular injury in patients with DKD.139
The main therapeutic approaches target brain microvascular The most prevalent diagnostic markers for DKD are the
endothelium and the BBB, microvascular function, neuroinflam- estimated glomerular filtration rate (eGFR) and proteinuria
mation, and antiplatelet agents.109,110 Maintaining normal blood calculated based on serum creatinine or cystatin C.140 However,
glucose levels is essential, but no evidence supports intensive tissue damage is often irreversible by the time a diagnosis is
glucose-lowering regimens for patients with diabetes and confirmed, and new biomarkers are needed to diagnose DKD
cognitive impairment or dementia.111–113 Moreover, the risk of earlier and to stratify risk factors. Current new biomarkers mainly
hypoglycemic events is associated with cognitive decline and target diagnoses of inflammation, endothelial damage, fibrosis,
increased risk of dementia.81,82,114 Although lowering glucose is endothelial dysfunction, and kidney damage,141 including TNF-α
generally ineffective for preventing stroke and cognitive impair- receptor,142 intercellular adhesion molecule-1,143 endostatin,144
ment,113 some drugs do provide these benefits in addition to copeptin,145 kidney injury molecule-1,146,147 monocyte chemoat-
controlling glucose levels. Metformin, pioglitazone, and GLP-1 tractant protein-1,148 and neutrophil gelatinase-associated lipoca-
agonizts that can cross the BBB are of interest in the treatment of lins.149 Extracellular vesicles have recently attracted interest,150
DE.115 Metformin might improve cognitive impairment associated because they are essentially exosomes and particles151 that
with stroke or Alzheimer’s disease,116,117 and prevent dementia in transport miRNA,152 mRNA,153,154 and proteins,155 and might
persons aged <75 years more effectively than sulfonylurea serve as early biomarkers of DKD. In addition to individual
hypoglycemic agents.111 Pioglitazone might reduce the risk of biomarkers, other approaches such as proteomics,156 genomics,157
dementia by 47% in populations with diabetes.48 Pioglitazone and and metabolomics158 all play roles in screening, especially in

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Fig. 3 Pathology and molecular mechanisms of DE. (1) Structural brain changes from MRI studies in diabetes are the primary diagnostic basis
of DE, including microinfarcts and microbleeds, perivascular spaces, white matter hyperintensities, white matter microstructure, lacunes, and
atrophy; (2) Pathologies related to imaging findings include blood-brain barrier permeability, perfusion defects, hypoxia, and increased
angiogenesis that can involve brain microvessels, multiple nerve cells, and the blood-brain barrier; (3) Microvascular dysfunction manifested
by impaired neurovascular coupling and impaired neuronal function. Neurovascular coupling links transient local neural activity to
subsequently increased blood flow; (4) The molecular pathways of hyperglycemic damage to brain microvasculature are closely related to
oxidative stress, inflammation, abnormal lipid metabolism, and insulin resistance. RAS rat sarcoma protein, GTP guanosine triphosphate, GDP
guanosine diphosphate, TLR4 Toll-like receptor 4, MEK mitogen-activated protein kinase, PI3K phosphoinositide 3-kinase, Akt protein kinase B,
TSC tuberous sclerosis complex, MAPK mitogen-activated protein kinases, mTOR mammalian target of rapamycin, RHEB Ras homolog protein
enriched in brain, PKC protein kinase C, PGC1-α PPAR-gamma co-activator-1 alpha, PIP2,3 phosphatidylinositol bisphosphate2, 3, IRS-1,2
insulin receptor substrate1, 2, NFκB nuclear factor kappa-B
studies of chronic kidney disease (CKD)159 which can predict the renal tubular capillaries, the absence of specific VEGFA expression
development of proteinuria.160 Despite many studies of novel leads to a significant decrease in peritubular capillary density in
biomarkers, only eGFR and proteinuria are routinely applied to mice.168 However, overexpression causes dilation of peritubular
clinically diagnose DKD, and the specificity and accuracy of these capillaries.169
awaits clarification in future controlled clinical trials with large Inflammatory mediators (chemokines, cytokines, and adhesion
samples. molecules)170,171 are often released due to hyperglycemia and
In addition, imbalanced pro- and anti-angiogenic factors can hemodynamic abnormalities, which lead to nephron damage
disrupt the vascular network in DKD. Hyperglycemia increases through ultrafiltration, mechanical stress, oxidative stress, glyco-
glomerular capillary pressure through a RAAS-mediated increase calyx dysfunction, and endothelial activation.172,173 These media-
in angiotensin II.161,162 Hyperglycemia-mediated changes in tors cause renal microvascular dilation or altered permeability
glomerular capillary autoregulation can cause endothelial dys- through thylakoid proliferation, podocyte or tubular injury,174 and
function and inflammation by increasing transforming growth inflammatory cell infiltration.175 In addition, oxidative stress is
factorβ-1 (TGFβ-1) mediated ROS that dilates glomerular afferent closely associated with inflammation and causes endothelial
and efferent arterioles.163 Lipid metabolism is often abnormal in dysfunction by activating NF-κB176,177 and adapter protein
patients with diabetes, and this can also contribute to glomerular complex-1178,179 to induce pro-inflammatory factors and, in turn,
and tubulointerstitial vascular injury through mediators such as mediate the inflammatory response, thus inducing renal fibro-
cytokines, ROS, and hemodynamic changes.164,165 Hypoxia in renal sis.180 Therefore, the main causes of vasculopathy in DKD are
tissues due to reduced density of tubulointerstitial capillaries is inflammation, hemodynamic, and metabolic disorders. Lesions are
also a major cause of renal disease progression.166,167 Although mostly concentrated on the glomerular and tubulointerstitial
scant vascular endothelial growth factor A (VEGFA) is expressed in microvasculature and also in other vessels such as renal arteries,

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Fig. 4 Pathology of the glomerulus and tubules in DKD. a The classical pathological mechanisms of DKD. It mainly includes hemodynamic,
metabolic disturbances, and inflammation, which often interact with each other. (1). Hemodynamic disturbances lead to dysregulation of
tubulobulbar feedback balance. (2). Metabolic disorders are crucial to the pathogenesis of DKD. Hyperglycemia affects pathways such as
TGFβ1-RhoA/Roa pathway, RAAS, proximal tubular sodium and glucose reabsorption, and intracellular metabolism; abnormal lipid
metabolism can affect the release of mediators such as cytokines and ROS; in the presence of nutrient overload in the organism, endoplasmic
reticulum autophagy leads to a chronic unfolded protein response, and mTOR also disturbs the podocytes leading to oxidative stress. (3).
Inflammation promotes the release of inflammatory mediators such as adhesion molecules, chemokines, cytokines, and growth factors,
causing renal infiltration of inflammatory cells. b Schematic representation of the pathological damage of DKD. Differences in structural
changes of glomeruli and tubules in the diabetic setting and in the healthy state. Diabetic glomerulopathy is characterized by arterial
hyalinization, thylakoid stromal deposition, basement membrane thickening, glomerular thylakoid cell hypertrophy and proliferation,
podocytosis, proteinuria, tubular epithelial atrophy, activated myofibroblasts, and stromal accumulation. NFκB nuclear factor kappa-B, TGFβ
transforming growth factor-β, ROS reactive oxygen species, RAAS renin-angiotensin-aldosterone system, ANG2 angiotensin II, SGLT2 sodium-
dependent glucose transporters 2, mTOR mammalian target of rapamycin, NADPH nicotinamide adenine dinucleotide phosphate, NOX
NADPH oxidase, ICAM-1 intercellular cell adhesion molecule-1, VCAM-1 vascular cell adhesion molecule-1, VAP-1 vascular adhesion protein-1,
CCL CC chemokine ligand, CXCL C-X-C motif chemokine ligand, TNF tumor necrosis factor, IL interleukin, TWEAK tumor necrosis factor-like
weak inducer of apoptosis, MIF macrophage migration inhibitory factor, MIP-1 macrophage inflammatory protein-1, VEGF vascular endothelial
growth factor, PDGF platelet-derived growth factor, BMP bone morphogenetic protein, FGF fibroblast growth factor, M-CSF macrophage
colony-stimulating factor
and glomerular afferent and efferent arterioles. The pathogenesis patients mainly through post-glomerular vasodilation to normalize
and therapeutic strategies need further exploration. the eGFR.189 In addition to stimulating insulin secretion from
The current strategies for treating DKD mainly comprise pancreatic β-cells to control blood glucose, incretin might also
controlling blood sugar and blood pressure and blocking the bind to GLP-1 receptors to inhibit endothelial damage and thus
RAAS140 (Table 2). After controlling various risk factors such as exert positive effects.190 The large FIDELIO-DKD clinical trial found
hyperglycemia, hyperlipidemia, hypertension, and uric acid,181,182 that finerenone, a novel nonsteroidal mineralocorticoid receptor
the risk of DKD is reduced, but the vascular disease continues to antagonist combined with a RAAS inhibitor, reduced the risk of
progress. Blood pressure control and fenofibrate can increase the cardiac and renal outcomes while reducing the incidence of
risk of renal adverse events such as decreased eGFR, suggesting a hyperkalemia.191 MiRNAs play an important role in maintaining
need to explore more effective treatment modalities.183,184 Novel optimal vascular homeostasis and regulating microvasculature
hypoglycemic agents might protect the kidney through combined disorders.192 The miR-132 inhibitor CDR132L improves HF and
actions against hyperglycemia, hypertension, lipotoxicity,185 affects cardiac fibrosis biomarkers193 and might also have a
abnormal tubuloglomerular feedback,186 hypoxia,187 endothelial therapeutic effect on renal fibrosis. Anticoagulants might hamper
dysfunction, and renal fibrosis.188 The SGLT-2i dapagliflozin exerts the progression of DKD,194 but the clinical application requires
renoprotective effects, possibly by affecting the hemodynamics of further validation and tests, as some anticoagulants such as

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Table 2. Renal outcomes trials in diabetes mellitus
Clinical trials Clinical trials’ number Year Phase Paticipants (n) Intervention Follow-up Main outcome
Dipeptidyl peptidase-4 (DPP-4) inhibitors

CARMELINA502 NCT01897532 2013–2018 4 6991 I: Linagliptin 2.2 years Reduced proteinuria, control blood
C: Placebo glucose.
Glucagon-like peptide-1 receptor (GLP-1) agonizts
REWIND503 NCT01394952 2011–2018 3 9901 I: Dulaglutide 5.4 years Reduced compound renal outcome.
C: placebo
PIONEER 5504 NCT02827708 2016–2018 3 424 I: Semaglutide 0.54 years Effective in patients with type 2
C: Placebo diabetes and moderate renal
impairment, but with higher adverse
events.
BETENT-4505 NCT03730662 2018–2021 3 2002 I: Tirzepatide 2 years Slowed down eGFR decline rate,
C: Insulin reduced UACR (urinary albumin
Glargine creatinine ratio).
DAPA-CKD506 NCT03036150 2017–2020 3 4304 I: Dapagliflozin 3.2 years Reduced the risk of GFR and major
C: Placebo renal and cardiovascular adverse
events in diabetic and non-diabetic
patients with chronic kidney disease.
CREDENCE487 NCT02065791 2014–2018 3 4401 I: Canagliflozin 2.62 years Reduced the risk of kidney failure and
C: Placebo cardiovascular events.
SCORED507 NCT03315143 2017–2020 3 10584 I: Sotagliflozin 1.3 years Reduced risk of cardiovascular-related
C: Placebo hospitalization and death from
diabetes and CKD, but associated with
adverse events.
VERTIS CV508 NCT01986881 2013–2019 3 8223 I: Ertugliflozin 3.5 years Ertugliflozin reduced the risk of
C: Placebo composite renal end points and was
associated with reduced eGFR
and UACR.
Mineralcorticoid receptor antagonists
FIDELIO-DKD191 NCT02540993 2015–2021 3 5734 I: Finerenone 2.6 years Reduced the risk of the cardio-renal
C: Placebo outcome.
PRIORITY509 NCT02040441 2014–2018 2/3 209 I: Spironolactone 2.5 years Can’t prevent disease progression of
C: Placebo high-risk patients with DKD.
Standard care
SONAR510 NCT01858532 2013–2018 3 2648 I: Atrasentan 4.4 years Reduced the risk of renal events in
C: Placebo patients with diabetes and CKD.
Standard care
Others
CKD-FIX181 ACTRN12611000791932 2014–2016 3 369 I: Allopurinol 2.17 years Decreased serum urate but did not
C: Placebo affect the renal outcome and did not
Standard care alleviate the decline in eGFR.
ALBUM197 NCT02358096 2015–2017 2 125 I:ASP8232 2 years Reduced albuminuria in DKD patients,
C: Placebo safe and well tolerated.
NA196 NCT01683409 2012–2017 2 130 I: Baricitinib 0.46 years Reduced albuminuria.
C: Placebo
NA NCT03804879 2018–2021 2 83 I: Nidufexor 0.54 years UACR and 24-hour urinary albumin
C: Placebo were decreased in DKD patients.
NA201 NCT03016832 2017–2021 1 413 I: HuangKui 0.46 years The combination of Huangkui capsule
capsule and irbesartan had the best effect on
C: Irbesartan reducing ACR in DKD patients.
tablets
NA no official trial name
vorapaxar might increase bleeding risk (Table 2).195 ASP8232, reduce proteinuria through local effects on glomeruli
Some pathways associated with kidney injury have emerged as and podocytes, offering potential multi-target interventions.197
novel targets for treating DKD. For example, baricitinib is an oral Another promising therapeutic target is gut flora, as the renal
small-molecule inhibitor that selectively inhibits the Janus kinase disease causes the dysbiosis of various gut microbes. Inhibiting
(JAK) protein tyrosine kinase family members JAK1 and JAK2,196 phenyl sulfate (a metabolite derived from gut microbiota) reduces
which inhibits the JAK-mediated inflammatory pathways and proteinuria in mice with DKD.198 Supplementing patients with
reduces proteinuria. Small-molecule inhibitors associated with diabetes who are on hemodialysis with probiotics improves
kidney damage, such as the vascular adhesion protein-1 inhibitor glucose and lipid metabolism, as well as biomarkers of

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inflammation and oxidative stress.199 Orally administered Faeca- to automatically measure and analyze the characteristic biological
libacterium exerts both anti-inflammatory and renoprotective structures of the eyes of patients with DR to assist with diagnosis.
effects on patients with CKD through butyrate-mediated G We found different features of Hematoxylin-eosin-stained retinal
protein-coupled receptor-43 signaling.200 Moreover, traditional sections from diabetic mouse models based on changes in nerve
Chinese medicine has also achieved considerable progress in DKD fiber layers and ganglion cells during the early stage of the
treatment, as a combination of Huangkui capsules and irbesartan disease. We then identified these features using image recognition
was found to be more effective than either of the medications and DL, and consequently identified changes in ganglion cells and
alone in reducing albumin-to-creatinine ratio in patients with the nerve fiber layer that could be applied to the early quantitative
DKD,201 suggesting the potential role of Chinese medicine in diagnosis of DR.213 Another AI-based study by our team quantified
future DKD therapy. the pathological changes of retinal neurons and synapses in mice
Renal microvasculature is an important target of DPD. Intensive with diabetes induced by monosodium glutamate (MSG). We
management of DM, including controlling blood sugar and blood found that MSG-induced DR was closely associated with
pressure and blocking the RAAS, will reduce the incidence of CKD neurotransmitter abnormalities and had important features of
and delay its progression. Current and future health resource retinal neurodegeneration, providing an effective animal model
requirements for DKD treatment are difficult to estimate. Thus and technique for quantifying retinal neuron pathology.214
innovative therapeutic strategies are needed to prevent, block, A thorough knowledge of the mechanism of DR is essential for
treat, and reverse DKD. its prevention and treatment. Hyperglycemia can lead to
inflammation, oxidative stress, and increased glycosylation pro-
Diabetic retinopathy (DR). DR is one of the most common duct and VEGF contents during the late stages. These can increase
microvascular complications of DM.202,203 Pathological changes of retinal permeability and alter retinal hemodynamics, leading to
DR start with the loss of retinal neuronal. The series of events retinal leakage and the development of DR. Serine racemase (SR)
include early loss of neurovascular coupling, retinal neurodegen- promotes the formation of D-serine, which activates NMDA
eration, and subsequent gliosis, finally leading to retinal vasculo- receptors and has multiple effects on neuron.215 Overexpression
pathy. Microvasculopathy in the DR retina are manifested as loss of SR in diabetic retinopathy leads to retinal neurodegeneration.
of retinal capillary epithelial cells, decreased capillary elasticity, Hyperglycemia subsequently leads to vascular EC damage, and in
and increased vascular permeability, exudation, local inflamma- turn, leukocyte aggregation/adhesion to vessel walls.216 Leukocyte
tion, and growth factors promoting neovascularization.204,205 DR is adhesion and aggregation activate a massive amount of
clinically classified as non-proliferative (NPDR) or proliferative neutrophils that adhere to EC and form a reticular network and
(PDR) in the absence or presence of retinal neovascularization, aggravate tissue hypoxia, causing vascular remodeling and
respectively. The NPDR type progresses to PDR and eventually neovascularization.217 The main protein that mediates intercellular
develops into macular edema, with the latter being an important adhesion is intercellular cell adhesion molecule-1 (ICAM-1).218
cause of vision loss or blindness in patients with diabetes.206,207 Under inflammation, ICAM-1 is abundantly expressed in retinal EC,
Such patients must undergo regular fundus examinations to where it binds to receptors. This induces leukocytes to penetrate
detect vision-threatening stages of DR, such as PDR and diabetic the endothelium and become adherent, indicating that ICAM-1 is
macular edema, as early as possible to treat them before vision an important mediator of the inflammatory response in DR.219,220
loss becomes irreversible. The inflammatory response of the retina in DR involves the
Delayed diagnosis and treatment are the most common causes production and release of various inflammatory factors.221 In
of visual impairment in patients with diabetes. Therefore, the early particular, the release of massive amounts of IL-1β can lead to the
detection and prevention of lesions in DR is the key to stop DR apoptosis of retinal pigment epithelial cells, which damages the
progression. Biomarker-related biomic and artificial intelligence integrity of photoreceptors. IL-1β activates NF-κB and oxidative
(AI) investigations will play increasingly important roles in the risk stress, leading to the apoptosis of capillary EC and increasing EC
assessment, early diagnosis, and treatment of the disease. permeability.222 IL-1β also promotes IL-6 secretion and induces
Homocysteine levels are significantly high in the serum of patients capillary angiogenesis by activating the NF-κB pathway and p38/
with diabetes and should become a screening and diagnostic MAPK.223 The pro-inflammatory factor TNF-α can cause EC
indicator of DR, as its prevention and treatment can be targeted damage and increase EC permeability, resulting in vascular
by increasing homocysteine clearance.208 The main factor leakage.224 Inflammatory factors induce each other via cascade
controlling neovascularization is VEGF, levels of which increase amplification, mediating the inflammatory response and exacer-
in vitreous and tear fluids from patients with DR and correlate bating DR. Oxidative stress leads to nerve, vascular, and retinal
positively with DR severity. Retinol-binding protein 3 (RBP3) is a tissue damage and, in turn, the development of DR.225,226 Chronic
retinol transporter protein secreted by photoreceptors, and high hyperglycemia causes oxidative stress mainly through PKC, polyol,
levels of RBP3 in the vitreous body of patients with diabetes slow hexosamine, and AGEs formation pathways.225 Hyperglycemia can
DR progression.209 Elevated RBP3 expression can alleviate regulate vascular cell permeability, the extracellular matrix, cell
hyperglycemia-induced DR by inhibiting glucose uptake by growth, neovascularization, cytokine response, and leukocyte
glucose transporter protein-1 and reducing the expression of adhesion through the diacylglycerol-PKC pathway, leading to
inflammatory cytokines and VEGF.210 Therefore, RBP3 could serve structural and functional changes of the retinal vasculature.227,228
as a biomarker and therapeutic strategy in preventing the Activation of the polyol pathway produces oxidative stress, which
progression of DR. MiRNAs are involved in retinal neovasculariza- increases the consumption of reduced coenzyme II (NADPH)
tion and the inflammatory response in DR. The relative expression oxidase through the production of sorbitol by aldose reductase
of serum miRNAs was measured in 80 patients with T2DM (AR), thus affecting the production of the antioxidant reduced
comprising an NPDR group with normal, mild, moderate, or severe glutathione and causing an oxidative-antioxidative imbal-
symptoms and a PDR group. The results showed that the relative ance.229–231 The production and accumulation of sorbitol under
expression of serum miR-146a and miR-21 increased, whereas that hyperglycemic conditions increases retinal osmotic pressure, cell
of miR-34a decreased with worsening DR severity.211 miR-125a-5p edema, metabolic disorders, and microvascular damage,232,233
significantly attenuated vascular leakage in DR.212 These findings consequently aggravating DR. Advanced glycation end-products
suggested that miR-146a, miR-21, miR-34a, and miR-125a-5p could promote NF-kB activation by interacting with the cellular RAGEs
serve as promising biomarkers for DR.211 AI has recently become a on the cell surface.234 This leads to retinal pericyte apoptosis and
research hotspot in auxiliary medical diagnosis. Ophthalmic AI elevated expression of VEGF, inflammatory cytokines, and adhe-
integrates imaging databases with deep learning (DL) technology sion molecules.235 Inhibition of ACEs can improve hyperglycemia-

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Fig. 5 Pathology and molecular mechanisms of DR. Multiple mechanisms are involved in the pathogenesis of DR. Hyperglycemia can promote
oxidative stress through the polyol pathway, accumulation of advanced glycosylation end-products (AGEs), the protein kinase C (PKC)
pathway, and the hexosamine pathway, and exacerbate inflammation and abnormal angiogenesis by stimulating the secretion of
inflammatory factors and vascular endothelial growth factor, inducing retinal dysfunction until vision loss
induced blood-retinal barrier leakage and reduce retinal EC Diabetic peripheral vasculopathy (DPVD). DPVD is often over-
proliferation, migration, and neovascularization,236 thus alleviating looked, yet it is one of the most important and common vascular
DR. The main hallmark of PDR is neovascularization. The most complications in patients with T2DM.251 In such patients, DPVD
important inflammatory factor that stimulates neovascularization increases the risk of not only coronary atherosclerotic events,252
and causes vascular leakage is VEGF.209 Hypoxia-inducible factor- but also major adverse limb events such as amputation.253 DPVD
1α is activated under hyperglycemic and hypoxic conditions, can manifest as diabetic foot syndrome and peripheral arterial
which leads to increased secretion of VEGF, and overexpressed disease (PAD), which seriously affect the quality of life of patients
VEGF, in turn promotes neovascularization through activation of with diabetes. Peripheral arterial disease is traditionally considered
the PI3K/Akt,237–239 PKC,240,241 and NF-κB242,243 signal pathways. to be dominated by large artery AS.254 In fact, PAD is often
The expression of ICAM and nitric oxide synthase induced by VEGF accompanied by local and systemic microangiopathy.255,256
promotes leukocyte adhesion and causes changes in vascular Multivessel endothelial dysfunction can manifest as microangio-
permeability and pathological neovascularization.244–246 The pathy (either exclusively or with other diseases), such as capillary
pathogenesis of DR is complex, with numerous factors that basement membrane thickening, endothelial hyperplasia, oxygen
synergistically interact with each other during the development tension reduction, and hypoxia, affecting peripheral nerve
and progression of DR (Fig. 5). function.257 Pre-DM can affect blood vessels and accompanying
DR can be treated mainly by laser photocoagulation and vitreous nerves.258,259 The chronic course of DM might have further
injections of antibodies.247 Retinal laser photocoagulation can adverse effects under poor glycemic control.260,261 An increase in
prevent further vision deterioration, but cannot restore damaged postprandial glucose plays an important role in the development
vision. Intravitreally injected ranibizumab and bevacizumab reduce of peripheral vascular disease in DM.262
the recurrence of active neovascularization and risk of retinal The pathogenesis of DPVD overlaps with that of other AS and
detachment. However, frequent intraocular administrations due to microvascular endothelial injuries. IL-6, high-sensitivity C-reactive
a short half-life increase the risk of retinitis, retinal obstruction, and protein, lipoprotein-associated phospholipase A2, and high-
patient pain and might facilitate the development of drug molecular-weight lipocalin biomarkers serve as indicators of the
resistance.248,249 Intraocular glucocorticoid injection is often used to risk of cardiovascular disease and peripheral vascular dis-
treat persistent and refractory diabetic macular edema, which ease.263–267 Specific markers for DPVD are unknown, but many
improves vision but increases the incidence of cataracts and biomarkers of vascular injury are available.268,269 For example,
glaucoma.250 Drugs such as ranibizumab, aflibercept, and fenofibrate circulating levels of ICAM and sE-selectin indicate EC activation
have been included in clinical trials to evaluate their effectiveness and vascular inflammation, and thus have potential as diagnostic
and safety (Table 3), thus providing new ideas for treating DR. markers of DPVD.270,271

Table 3. Interventional trials in diabetic retinopathy
Clinical trials Clinical Year Phase Participants (n) Intervention Follow-up Main outcome Adverse events
trials’ number

Dapagliflozin511 NCT02919345 2017 / 97 I: Dapagliflozin 12 weeks Central retinal thickness Not reported
(Completed) C: glibenclamide
Dapagliflozin plus another NCT05310916 2022 3 60 I:Dapagliflozin 10 mg Tab plus another 12 weeks Severity of retinopathy /
oral hypoglycemic agent (Ongoing) oral hypoglycemic agent
C:Two oral hypoglycemic agents other
than dapagliflozin
Others
Faricimab512 NCT03622580 2018 3 1891 I:faricimab 1 year Mean change in best-corrected Intraocular
(Completed) C:faricimab per personalized treatment visual acuity inflammation
interval or aflibercept
Brolucizumab513 NCT03321513 2017 3a 270 (312 eyes) I:Brolucizumab 2 years Mean best-corrected visual Retinal vasculitis and
(Completed) C: aflibercept acuity; Retinal central subfield retinal vascular

thickness and visual acuity occlusion
Abicipar514 NCT02462928 2015 3 1888 I: Abicipar 52 weeks Stable vision, best-corrected Intraocular
NCT02462486 C: ranibizumab visual acuity, central retinal inflammation
(Completed) thickness
Fenofibrate515 NCT01927315 2013 4 41 I: Fenofibrate 12 weeks Change in the levels of Ischaemic stroke
(Completed) C: placebo circulating hematopoietic stem/ related to pre-existing
progenitor cells conditions
PDS implant pre-filled with NCT04503551 2020 3 174 I: PDS implant pre-filled with ranibizumab 52 weeks Early treatment diabetic /
ranibizumab (Ongoing) C: Intravitreal ranibizumab retinopathy study, diabetic
retinopathy severity scale
Li et al.
OPL-0401 NCT05393284 2022 2 120 I: OPL-0401 24 weeks Improvement in diabetic /

(Ongoing) C: Placebo retinopathy severity scale
Calcium Dobesilate NCT04283162 2020 4 1200 I:Calcium dobesilate + conventional 12 months The rate of the progression of /
(Ongoing) treatment diabetic retinopathy
C:conventional treatment
Sinemet CR NCT05132660 2022 1 244 I:Sinemet CR 24 months Electroretinogram /
(Ongoing) C:placebo
Aflibercept NCT04708145 2021 4 150 Eyes without panretinal photocoagulation 112 weeks Improvement in diabetic /
(Ongoing) (PRP) and eyes with PRP, Drug: Aflibercept retinopathy severity scale
Injection
13
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The molecular mechanisms of AS in DPVD can be found in the After adjusting for age and the duration of DM, the risk of
section on coronary AS. Microvasculopathy in DPVD is highly peripheral neuropathy is found to be significantly higher in
concomitant with neuropathy, as microvessels form a neurovas- patients with T2DM than in those with T1DM.306 The median
cular network with accompanying nerves.272 Neurons and elapsed time to the onset of microproteinuria is also significantly
Schwann cells are highly susceptible to hyperglycemia.273,274 shorter in adolescents with T2DM than in those with T1DM (1.3 vs.
Energy and inflammation, oxidative stress,275 insulin resistance,276 6.8 years).307
AGEs,277 nerve growth factors,278 activation of the polyol path- The natural course of DPDs in rodents from the same genetic
way,279 and activation of the hexosamine and PKC pathways280 background would provide insights into the pathological changes
are core pathological factors and processes similar to those of in various tissues at the same time. Streptozotocin induced in
other DM vascular complications.281,282 Glucose and fatty acid C57BL/6 mice develop microangiopathy in various organs at 4‒20
metabolism,283 neural metabolism,284 and exosome regulation (mostly 8‒10) weeks after the onset of DM;308–310 db/db mice
have recently attracted attention.285,286 Much more is known simulating type 2 diabetes develop microangiopathy in various
about peripheral neuropathy than about DPVD. Glucose overload organs at 16‒40 (mostly 20) weeks of age.311,312 The temporal
and high fatty acid metabolism lead to decreased ATP production, progression of diabetic microvascular complications in mice are
excessive ROS formation, and impaired mitochondrial function, Concurrent regardless of the modeling modality (Fig. 6). DKD is
which further increases oxidative stress, leading to the formation the earliest to appear, with peripheral motor nerve conduction
of AGEs from the glycosylation of various proteins. The vicious velocity decelerating at 4 weeks of DM (C57BL/6 mice).313
cycle of these events further promotes ROS formation and ER Microvascular function in diabetic mice partially changes around
stress, resulting in DNA damage and apoptosis of various cells. 8–10 weeks after DM onset (C57BL/6 mice)310,314–318 or 20 weeks
Abnormal neurometabolism in DM manifests as changes in of age (db/db mice),268,311,319,320 manifested as pathological
sphingolipid metabolism, wherein sphingolipids are biologically staining of various organs changes. After 8 weeks of hypergly-
active and important structural components of plasma cell cemic state, further pathological changes of diabetic C57B/6 mice
membranes and are important signaling molecules. Abnormal in microvascular structure can occur, including expansion of the
sphingolipid metabolism causes neurotoxicity in patients with mesangial matrix of renal microvasculature and rupture of the
hyperglycemia.287 All of these pathways eventually manifest as renal tubular epithelium321 The retinal ultrastructure changes,
increased pro-inflammatory factors that further induce AGEs infoldings in retinal pigment epithelium layers are decreased, and
production, leading to oxidative stress and endothelial dysfunc- balance or proprioception are impaired due to neurovascular
tion.288 These interactive processes simultaneously place EC and disease.322 At 12‒20 weeks of DM, late panvascular disease can
neurons in a state of oxidative stress and inflammation. occur, with advanced vasculopathy of the heart, retina, or
The endpoint of DPVD is amputation, the occurrence of which is brain.323–325 occurring slightly before that of the kidneys.326
closely associated with infection and trauma. Therefore, care and Diabetic macroangiopathy does not develop spontaneously in rats
lifestyle changes play an important role in its treatment, which after DM modeling; rather, it is generally induced through specific
greatly differs from the preventive measures for other vascular diet control or vascular occlusion of the DM model rats.327 Thus,
pathologies. Normal or near-normal glycemic control is a primary after simply constructing animal models of diabetes, studies on
therapeutic goal. Intensified hypoglycemic therapy reduces the microangiopathy and macroangiopathy in the same models are
incidence of peripheral neuropathy in patients with T1DM but has scant. Rodents have different lipoprotein metabolism from
a little additional benefit for those with T2DM.289,290 Systemic humans and are highly resistant to AS. C57BL/6 mice are relatively
antioxidant and anti-inflammatory therapy might also provide too resistant to intraperitoneal injections of STZ to construct a
some benefits.291 New glucose-lowering drugs can reduce blood model of DKD, and various diabetic complications require
glucose without increasing the risk of amputation. In a subgroup different animals for optimal modeling. Therefore, the optimal
of patients with T2DM combined with PAD, empagliflozin reduced animal model for DPD studies awaits further investigation and
rates of mortality, hospitalization for HF, and the progression of clinical evidence.
kidney disease.252 Patients treated with the new glucose-lowering Relationships among DPDs (Fig. 7) outcomes in vital organs
drugs SGLT-2i, GLP-1RA, and DPP-4i have low risks of amputation (heart, kidney, and brain) are mutually predictive. DR is associated
with a good safety profile.292 Some glucose-lowering agents have with coronary atherosclerotic heart disease, macrovascular events
conferred advantages for patients with DPVD and other multi- (including stroke), and all-cause mortality.328 Screening retinal
vessel diseases. The results of the LEADER trial suggested that microvessels have a potential role in the risk identification of
liraglutide could be used in diabetic multivessel diseases.293 These cerebrovascular and neurodegenerative diseases.329 In T2DM,
treatment options could improve the overall quality of life of retinal parameters and a genome-wide polygenic risk score for
patients. coronary heart disease have independent and incremental
prognostic value compared with conventional cardiovascular risk
Temporal progression of DPDs assessment.330 Risk of macrovascular complications in patients
The time of onset of panvascular complications in patients with with diabetes and retinal artery occlusion for at least 5 years after
diabetes is closely associated with patient age,294 race,295 genetic an obstruction event is increased compared with those who do
background,296 DM staging,297 treatment regimen,298,299 and level not have such occlusion. Therefore, retinopathy can predict
of glycemic control.300,301 The natural course of DPDs is not cardiovascular risk in patients with T2DM.331 DR is closely
completely clear, but diabetic microangiopathy generally pre- associated with stroke332–336 and cerebral microangiopathy.337
cedes diabetic macroangiopathy.302 Clinical trials of patients with During embryonic development, the diencephalon is homologous
insulin-dependent DM have found that DR develops within the to the retina and optic nerve, especially the capillary-linked
first 2 years of DM in conventionally treated patients, and that by microglia and neuronal synapses, which are abundant in the retina
the fifth year, 25–40% of these patients develop retinal, renal, and and brain and sensitive to blood glucose.338 The microvasculature
peripheral microangiopathy.303 A Chinese cohort study has shown of the retina and the axonal function of retinal ganglion cells can
that >20% of patients develop moderate retinopathy and >40% be detected using fundus photography and optical coherence
develop mild proteinuria within 7 years after the onset of DM.304 tomography to assist with the diagnosis of cerebrovascular
According to the ADVANCED study, the incidence of macroangio- neuropathy.339 Retinal microvascular imaging findings closely
pathy at the fifth year of DM does not exceed 10%.305 correlate with cerebral infarction and white matter lesions,
Complications with panvascular disease appear earlier and more parapapillary retinal nerve fiber layer thickness, macular thickness,
frequently in patients with T2DM, than in those with T1DM.306,307 and volume being indicators of stroke risk.340 Changes in the

Li et al.
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Fig. 6 The natural course of diabetic vasculopathy in mice. Streptozotocin induced in C57BL/6 mice simulate type 1 diabetes in human; db/db
mice simulate type 2 diabetes in human. Vasculopathy in different organs appears over a period of time, In C57BL/6 mice Streptozotocin
induced in C57BL/6 mice develop typical microangiopathy mostly at 8‒10 weeks after the onset of DM and develop advanced
microangiopathy at 12–16 weeks. db/db mice develop microangiopathy at about 20 weeks of age and develop advanced microangiopathy at
34 weeks
retinal vasculature can predict various stroke subtypes, suggesting

that retinal vascular changes reflect specific cerebral microangio-
pathy and might even distinguish stroke from other causes of
focal neurological deficits.341 In contrast, qualitative retinal
vascular signs and quantitative retinal vascular measurements of
narrowing small retinal arteries and widening small retinal veins,
might indicate a cognitive decline.342 Compared to that with
stroke, the association of DR with dementia and cognitive decline
is more limited, suggesting a need for further prospective studies.
In addition, because risk factors for stroke differ between patients
with and without diabetes, stroke risk prediction models should
include data on DR and DKD,335 which is a topic for future studies.
DKD increases the risk of stroke, cerebral infarction, and cerebral
hemorrhage.334 However, some subclinical cardiovascular compli-
cations of DM are not associated with stroke.343 Retrospective
studies have shown that DR is associated with the development of
DKD and the decline of renal function.344–346 Subsequent retro- Fig. 7 Predictive relationships among DPDs. CSVD cerebral small
spective studies have found a positive association between DR vessel diseases
and the risk of DKD progression.347,348 Retrospective findings of
narrowing small retinal arteries and widening small veins both DKD.357,358 As discussed, vasculopathy due to various diseases,
suggested the development of DKD,349 and this was later especially DR, is generally predictive of DKD progression,
confirmed by a cross-sectional study350 and several prospective providing evidence supporting the panvascular nature of DM.
studies.351–353 Diabetic macroangiopathy and neuropathy are also
important risk factors for DKD. Prospective studies have shown Molecular mechanism and signaling pathway of DPDs
that carotid plaques and aortic stiffness are associated with DKD Cellular energy metabolism. Cellular energy metabolism requires
progression.354,355 A retrospective cohort study found that energy supply from glucose, fatty acids, amino acids, etc.359,360 In
coronary artery calcification played a similar predictive role.356 the diabetic state, abnormalities in cellular energy metabolism
Two retrospective cohort studies found that peripheral neuro- affect macrovascular and microvascular lesions,361–363 including
pathy and cardiac autonomic neuropathy are strong predictors of abnormalities in substrate delivery to vascular EC or target organ

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Fig. 8 Schematic diagram of cellar sugar metabolic pathways. Cells obtain energy through multiple gluconeogenic pathways. These include
glycolysis, polyol, hexosamine, and pentose phosphate pathways. In the diabetic environment, excessive intracellular glucose causes
abnormal activation of the polyol and hexosamine pathways, and inhibition of the major glycolytic and pentose phosphate pathways,
resulting in continued accumulation of reactive oxygen species, which ultimately leads to increased oxidative stress loss in cells and induces
the development of DPDs. Different metabolic pathways are distinguished by different colors, with pink representing the glycolytic pathway,
purple representing the polyol pathway, blue representing the pentose phosphate pathway, and yellow representing the hexosamine
pathway. All enzymes are indicated in red. Solid arrows indicate that this process is promoted and dashed arrows indicate that this process is
inhibited. IL interleukin, GSH glutathione, GSH-px glutathione peroxidase, AR aldose reductase, SDH sorbitol dehydrogenase, 3DG 3-
deoxyglucosone, AGE advanced glycosylation end, NOX reduced nicotinamide adenine dinucleotide phosphate oxidase, ROS reactive oxygen
species, NLRP3 NOD-like receptor thermal protein domain associated protein 3, GK glucokinase, G6P glucose-6-phosphate, F6P D-fructose-6-
phosphate disodium salt hydrate, F1,6P2 fructose 1,6-bisphosphate, G3P glyceraldehyde 3-phosphate, 1,3BPG 1,3-bisphosphoglycerate,
G6PDH glucose-6-phosphate dehydrogenase, 6PGL 6-phosphogluconolactonase, 6PGDH 6-phosphogluconate dehydrogenase, GFAT
glutamine-fructose-6-phosphate aminotransferase, TCA tricarboxylic acid cycle
cells (e.g., cardiac myocytes, thylakoid cells in glomeruli, and pentose phosphate pathway, glucokinase/hexokinase is involved,
neurons and Schwann cells in peripheral nerves), conversion of and this enzyme also regulates glucose transport into cells, as well
the ratio of cell-specific fuel sources between glucose intermedi- as glycogen metabolism and gluconeogenesis. Activation of
ates, fatty acids, and amino acids, changes in respiratory chain glucokinases (Dorzagliatin, PB-201, AZD-1656, etc.) has a regula-
protein function, and uncoupling of respiratory chains.364–366 The tory effect on glucose homeostasis,372–377 but no additional
hyperosmolar state and abnormal energy metabolism of diabetes vascular protective value has been reported yet.378,379
increase the PKC pathway, endothelial xanthine oxidase, and the Hyperglycemia reduces glucose-6-phosphate dehydrogenase
eNOS uncoupling pathway, promoting increased ROS levels.367,368 (G6PDH)-mediated entry of glucose into the pentose phosphate
The mechanisms of energy metabolism imbalance vary slightly pathway, but rather into the polyol pathway through conversion
between target organs with different mitochondrial content and to sorbitol by the rate-limiting enzyme AR, and these processes
different major energy supply substances.369 are accompanied by a decrease in the rate of NADPH (an
important intracellular reducing agent) production.380 Meanwhile,
Glucose metabolism: Glucose metabolism is the main factor high glucose induces activation of NADPH oxidase (NOX) to
affecting cellular energy metabolism. The “unification hypoth- produce ROS, increases oxidative stress levels, and promotes
esis”226 suggests that several seemingly independent biochemical NLRP3/IL-1β and IL-18 to increase inflammation levels.381 Diabetes
pathways that are overactivated in diabetes are actually caused by promotes the accumulation of fructose-6-phosphate (F6P), which
excessive intracellular glucose flux (Fig. 8). EC are extensively can lead to an increase in the hexosamine (HBP) pathway and
damaged in DPDs, and EC produce ATP mainly by glycolysis.370 In overproduction of UDPn-acetylglucosamine.382 UDPn-
hyperglycemic states, changes in the metabolic pathways of sugar acetylglucosamine is involved in intracellular protein regulation,
(increased flux of the hexosamine pathway, increased flux of the especially for post-translational modifications of proteins such as
polyol pathway, decreased flux of pentose phosphate and O-GlcNAcylation.383 The HBP pathway accounts for a small
glycolytic pathways) lead to decreased production of NADPH percentage of glucose metabolism and does not affect tissue
and increased ROS, exacerbating oxidative stress.371 In the energy supply, but regulates glucose transporter protein and

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insulin signal transduction, regulates glycogen synthesis and of asparagine synthetase (ASNS), and supplementation with
elevates cellular O-glycosylation levels, stimulates cytokines, etc. asparagine and α-ketoglutarate reverses the EC damage caused
The sorbitol/polyol pathway is similarly increased in the high by glutamine deficiency.397,401 Thus, asparagine is also an
glucose state, where sorbitol is, in turn, converted to fructose by important part of amino acid metabolism in DPDs.406
sorbitol dehydrogenase (SDH), resulting in the production of Amino acid metabolism also affects oxidative stress in EC via the
3-deoxyglucosone (3DG), a highly reactive α-oxo-aldehyde, and arginine metabolic pathway.407 Vascular protective NO is pro-
promoting the production of AGEs.384 AR is also a key enzyme in duced via endothelial-type nitric oxide synthase (eNOS).408,409 In
this pathway. AR promotes the conversion of glucose to sorbitol vitro experiments, arginine deficiency leads to EC eNOS dysfunc-
and further to fructose with the participation of NADPH (produced tion.410 Elevated arginase levels lead to L-arginine depletion,
by the pentose phosphate pathway). In the hyperglycemic state, decreased output of NO, increased ROS, and impaired
AR depletes NADPH while increasing the accumulation of F6P, so endothelium-dependent vasodilation.411 On the other hand, EC
there is a close influence between several glucose metabolic can absorb serine directly or produce serine in the reaction
pathways. Not only that, AR decreases glutathione levels and intermediate 3-phosphoglycerate of the glycolytic pathway412 for
glutathione peroxidase activity, and reduces cellular antioxidant nucleotide biosynthesis and redox homeostasis.413 The serine
capacity through amino acid metabolism. Elevated intracellular pathway is activated in the high glucose state and it synergizes
sorbitol also provides excess nicotinamide adenine dinucleotide with the pentose phosphate pathway with single carbon
(NADH) to the mitochondrial electron transport chain, which is a metabolism to alter chromatin status and promote
substrate for complex I (substrate for complex I) in mitochondria inflammation.414
and closely affects mitochondrial function and cellular energy
metabolism.385 Overexpression of AR in mice increases suscept- Fatty acid metabolism: Diabetic patients often have abnormal
ibility to diabetes-induced AS and ischemia/reperfusion lipid metabolism, and hyperlipidemia can lead to increased
injury.386,387 In contrast, aldose reductase inhibitors (ARIs) and cellular uptake of fatty acids through passive diffusion and
AR gene-deficient animals have vascular protective effects in protein-mediated pathways. A cluster of differentiation 36 (CD36)
DPDs.83,388 Some natural compounds and plant extracts have and the fatty acid binding protein (FABP) family mediate fatty acid
shown the inhibitory effect of aldose reductase 2 (ALR2), which uptake into tissues,415 and soluble CD36 expression is increased in
can improve inflammation and protect the vascular endothelium, diabetic patients.416 Fatty acid uptake and transport by EC is
but in recent years ARIs have not been successfully available for extremely important for many cellular processes, including
widespread clinical use.389 membrane synthesis, intracellular signaling, ATP production, and
post-translational modification of proteins.417 Imbalance of fatty
Amino acid metabolism: Amino acid metabolism plays an acid metabolism in EC does not lead to significant abnormalities in
important role in diabetes and complications, and branched- energy supply or disturbance of redox homeostasis, but can
chain amino acids may serve as new biomarkers as well as impair de novo nucleotide synthesis for DNA replication.418 For
signaling pathways suggesting the risk of DPDs.390,391 Glutamine example, DNA repair factors such as Polyadp-ribose polymerase
is a branched-chain amino acid that is synthesized by glutamine (PARP) are involved in fatty acid metabolism.419 In a high glucose
synthetase (GS) and hydrolyzed by glutaminase (GLS).392,393 state, vascular damage can be aggravated by PARP1.420
Glutamine levels were negatively associated with BMI and insulin Fatty acid metabolism plays an important role in high-energy-
resistance index (HOMA-IR) in men with type 2 diabetes.394 demand cells and is closely associated with diabetic heart disease
Glutamine in plasma binds the bridging protein GRB-10394 and in DPDs.421,422 Overexpression of GLUT-1 in the myocardium
improves the insulin resistance of cells. It also promotes the increased glucose levels in cardiomyocytes and revealed that FAO
secretion of GLP-1 and GLP-2 secretion from intestinal cells.395,396 in the heart was inhibited and that a high fatty acid diet failed to
Vascular EC expresses glutaminase (GLS) and break down upregulate FAO in these hearts, while glucose supply was
glutamine, and glutamine deficiency or inhibition of endothelial significantly increased, further leading to activation of p38
GLS1 can cause impaired EC proliferation and reduced vascular mitogen-activated protein kinase and increased oxidative stress
neogenesis.397 Increased glutamine synthetase (GS) transcription in the heart.423
or increased glutamine levels promote macrophage polarization
and atherosclerotic plaque formation.398 Chromosome Mitochondrial dysfunction. An imbalance in energy metabolic
1q25 single nucleotide polymorphism (SNP) variants cause pathways causes impaired mitochondrial function, most often
reduced GS expression in EC. In these populations, patients with manifested as increased mitochondrial autophagy and ROS
diabetes have an increased risk of CAD but not patients with production.424 Mitochondrial function plays an important role in
diabetes, and the causal mechanism remains to be determined.399 cellular energy homeostasis. Alterations in glycolytic pathways,
Glutamine metabolism in cells holds two branches: glutamine fatty acid oxidation, and some amino acid metabolism in the high
catabolism and asparagine synthetase/gamma-aminobutyric acid glucose state can affect mitochondrial oxidative phosphorylation
(ASNS-GABA) shunting. These two pathways independently processes. AGEs production in the hyperglycemic state and AGE-
regulate the AMP-activated protein kinase/mechanistic target of RAGE-induced increase in cytoplasmic ROS promote the produc-
the rapamycin kinase complex (AMPK/mTORC) pathway, mediat- tion of mitochondrial superoxide and the development of diabetic
ing cellular autophagy.400,401 Also, glutamine provides anaplerotic microangiopathy in the condition of hyperglycemia.425,426 Most
substrates for the TCA cycle.397,402 In EC, 30% of the tricarboxylic ROS are derived from complexes I and III in mitochondria.427 In
acid carbon comes from glutamine, comparable to that produced addition to complexes I and III, the NOX family also promotes the
by the glycolytic pathway, and the novel hypoglycemic agent mitochondrial production of ROS.428,429 NOX4 is the highest
SGLT-2i can regulate mitochondrial oxidative phosphorylation and expressed member of the NOX family and is upregulated by a
improve cellular energy metabolism through the above path- variety of agonizts and cellular stress.429,430 Administration of
way.403 Glutamine metabolites are involved in intracellular oxygen novel mitochondria-targeted drugs helps to improve the mito-
reduction regulation. EC produces glutathione via glutamine, chondrial ROS/NLRP3 axis and attenuate mesangial tubular injury
which regulates redox homeostasis, and its depletion makes EC in DKD;431 similar manifestations exist in the myocardium,
vulnerable to ROS-induced damage. Glutamine catabolism pro- attenuating diabetic myocardial ischemia-reperfusion injury68.
duces glutamate that is converted to ornithine404 and aspartate397 The intramitochondrial protein p66Shc can promote increased
and these generated amino acids are also involved in the reactive oxygen species in mitochondria by interfering with Ras
proliferation of EC.405 EC proliferation is reduced after silencing activation or binding to cytochrome C and other.432

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Table 4. List of novel targets with emerging implications related to insulin receptor signaling
Insulin receptor signaling Target tissue Effect/ potential role Reference

516
HCF-1 Hepatocyte (human, mice) HCF-1-dependent pathway regulating Glucose and lipid
metabolism
517
IRS/PTP1B Cerebral microvascular endothelial Hyperinsulinemia affects insulin receptor signaling and
cells (mice) internalization of endothelial cells
518
SMPDL3b/C1P/Cav-1 kidney cortexes (rats), podocytes (human) Inducing glucose and lipid metabolism, protein synthesis
519
IRS/IGF1/SRF Myocardium (mice) Affecting autophagy and apoptosis of cardiomyocytes
520
SDF-1/CXCR4 Primary endothelial cells (human), Affecting immune cell recruitment to the vascular wall or
CD31 + cells (mice) tissue parenchyma
521
miR-15b, miR-16, miR-30b/ Endothelial cells (human) IRS2 and eNOS in ECs are ceRNAs and related to the Akt
IRS2 signal pathway
522
IRS Renal hemodynamics (mice) stimulation of renal functions and renal hemodynamics
523
IRS/p53/KLF4 Vascular smooth muscle cells (mice) IRS-1/p53 affects the progression of atherosclerotic lesions in
hyperglycemia
524
QKI-7 Endothelial cells (human) Promotes mRNA degradation of essential genes for EC
function
525
EPDR1 Endothelial cells (mice) Mediate pathological angiogenesis during hyperinsulinemia
and insulin resistance
526
IRS-1 rs956115 genotypes (Human) IRS-1 CG/GG genotype are at higher risk of major adverse
cardiovascular events
Therapeutic effect
527
Amlexanox inhibition of Serum (human) Lowering HBA1c, fructosamine, ameliorates metabolic
TBK1/IKKe dysfunctions
528
Loganin inhibition of JNK-IRS- Peripheral nerve (rats), SH-SY5Y cell Inhibiting oxidative stress-provoked inflammation, improved
1/Akt/GSK3β (human) Nerve pain behaviors
529
SGLT-2i inhibition of JunD/ Endocardiomyocytes (human) Inhibiting JunD/PPAR-γ overexpression and lipid
PPAR-γ, IRS-1, IRS2 accumulation, ameliorate diabetic cardiomyopathy
C1P ceramide-1-phosphate, IRS insulin receptor substrate, PTP1B protein tyrosine phosphatase, non-receptor type 1, SMPDL3b sphingomyelin
phosphodiesterase acid-like 3b, Cav-1 caveolin-1, IGF1 insulin-like growth factor 1, SRF serum response factor, SDF-1 stromal cell-derived factor-1, CXCR4
CXC receptor 4, CD31 endothelial cell adhesion molecule-1, eNOS endothelial nitric oxide synthase, ECs endothelial cells, ceRNAs competing endogenous RNAs,
Akt protein kinase B, KLF4 Krüppel-like factor 4, QKI-7 quaking-7, EPDR1 ependymin-related protein-1, TBK1 TANK binding kinase 1, IKKe IkappaB kinase, HBA1c
glycated hemoglobin, JNK c-Jun N-terminal kinase, GSK3β glycogen synthase kinase-3β, JunD jund proto-oncogene subunit
Mitochondria can store calcium ions and act in concert with the receptor binding protein-2 (GRB-2), GRB-10, SHC transforming
endoplasmic reticulum and extracellular matrix to control the protein (SHC), and SH2B adapter protein-2 (SH2B-2) through
dynamic balance of calcium ion concentration in cells and induced insulin receptor.439,440 Selective glucose transporters exist
regulate the cell cycle and apoptosis.433 High glucose can affect in different target organs, such as the renal SGLT2 receptor;441 the
myocardial contractile function by upregulating sarcolipin (SLN) distribution of GLUT receptors in different target organs and the
promotes calcium sparks.434 Therapeutically, metformin inhibits pathways also differ.78,442 This paper summarizes the new
mitochondrial respiratory chain complex-1 and regulates cellular advances in insulin signaling receptor pathways and their roles
energy metabolism.435 In addition, metformin and GLP-1 agonizts from 2018 to date (Table 4).
regulate the glucagon-lowering hormone glucagon-like peptide-1
and the bile acid pathway and alter the composition of the gut Glycosylation end-products. As the end-products of dysfunctional
microbiota, which may also indirectly affect mitochondrial EC metabolism, AGEs have profound effects on the immediate
function.362,436 extracellular environment of EC as well as on other cell types. AGEs
Mitochondrial energy metabolism differs among target organs, can bind key proteins (such as laminin, elastin, and collagen) in
and myocardial mitochondrial content is abundant. Diabetic mice the extracellular matrix (ECM) basement membrane, leading to
have altered mitochondrial function in the myocardium earlier increased vascular stiffness promoting DPDs.443–445 AGEs may also
than in the kidney, brain, and liver.437 Further in-depth mechan- affect coagulation and hemodynamics, cause increased vascular
istic exploration is worthwhile in tissues with high mitochondrial permeability and induce tissue factor expression.446,447 The
content. extensive intracellular action of circulating AGEs is mediated
through the attachment of receptors for RAGE, which is expressed
Insulin resistance. Insulin resistance is the most common and in monocytes, smooth muscle cells (SMC), and EC.448,449
widespread molecular mechanism of diabetic complications, not RAGE induces an inflammatory cascade response by activating
only in the high glucose state with extensive activation of insulin the transcription factor NF-κB, which promotes the expression of
receptor signaling pathways, such as the regulation of glucose growth factors and adhesion molecules. On the other hand, RAGE
uptake by GLUT.438 Even in the presence of normal blood glucose, activates NADPH oxidase to increase oxidative stress; RAGE also
insulin resistance is still harmful, and the lack of insulin receptor binds to tissue-specific proteins to promote local vascular
signaling pathways in renal pedal cells induces a disease state injury,450,451 such as binding AGEs or S100/calmodulin or
similar to diabetic nephropathy.439 β-amyloid peptide to exacerbate cerebral hemorrhage;452 RAGE
The most common downstream mechanisms of insulin binds to EC to promote increased NADPH expression leading to
resistance include inhibitory phosphorylation of IRS, growth factor inflammatory responses and a prothrombotic state by activating

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diaphanous-related 1 (DIAPH 1), ERK1, ERK2, and PKC.451,453 AGE/ collaborations among medical and research institutions and
RAGE on mononuclear macrophages increases CD36 expression, academic organizations are needed to narrow gaps among
promotes OX-LDL uptake while decreasing high-density lipopro- research results, new technologies, and clinical applications.
tein (HDL) efflux, and promotes foam cell formation; AGE/RAGE Cross-collaborations among medical institutions at all levels are
action on vascular smooth muscle cells (VSMC) induces autophagy needed to fully integrate the resources of primary- and higher-
through the ERK/Akt pathway454 and increases ROS and NOS level care. Cross-collaborations among doctors, nursing staff,
levels through activation of NOX and NF-κB,455,456 increases and patients are needed to ensure personalized treatment for
oxidative stress, and accelerates atherosclerotic plaque progres- patients. Cross-collaborations among clinical disciplines, includ-
sion.447 Excessive AGE formation and overactivation of the ing endocrinology, cardiovasology, geriatrics, neurology,
hexosamine pathway induce angiopoietin-2 transcription by nephrology, vascular surgery, and nutrition are also needed to
inhibiting transcriptional co-repressor complex binding and integrate comprehensive evidence. Traditional Chinese medi-
silencing the angiopoietin-2 promoter.457 The formation of AGEs cine also has considerable potential for the prevention and
may partially explain the “hyperglycemic memory” of tissue treatment of DPD.473,474 A comprehensive DPD prevention and
damage, i.e., the vascular damage that occurs during hyperglyce- treatment system should be established with Chinese char-
mia can continue into the normoglycemic cycle.458 Hyperglycemia acteristics, promoted cooperation, and accelerated clinical
may alter cellular epigenetics, such as DNA and protein translation to improve the overall prevention and control of
modifications, DNA methylation, non-coding RNA, or histone chronic diseases such as diabetes.
modifications by receptor-mediated mechanisms to alter cellular
function.459 Thus, epigenetics, as well as AGEs, are important
targets for intervention outside of glycemic control. ACKNOWLEDGEMENTS
This work was supported by the National Outstanding Youth Natural Science
Prospects Foundation of China (82022076) and the Young Qihuang Scholar of the “Tens of
DPD has become a major public health problem that requires millions” talent project of China. All figures were created with Biorender.com.
urgent attention, as 11% of patients with T2DM complicated with
AS have a multivessel disease.460 Patients with T2DM complicated
with the multivessel disease have a significantly higher risk of AUTHOR CONTRIBUTIONS
Y.L., L.H., and K.C. designed the manuscript. Y.W.L., Y.F.L., and S.L. did the literature
ischemic events and overall mortality than those with T2DM with
search, wrote the manuscript, and drafted figures. M.G., W.W., and Y.W.L. revised the
single-vessel disease. The significant cardio-renal benefits of manuscript. All authors listed have made a substantial contribution to the work. All
metformin and SGLT-2i beyond glycemic control have led to the authors have read and approved the article.
emergence of an integrated treatment model that can be applied
to manage DPD.461 The pathogenesis of DPD involves insulin
resistance, inflammation, oxidative stress, and AGEs, with a wide ADDITIONAL INFORMATION
prevalence of hyperglycemic “metabolic memory” and some Competing interests: The authors report no commercial or financial relationships
epigenetic alterations in various vascular pathologies.462,463 The that could be construed as a potential conflict of interest.
latest drugs in development are ARIs, tyrosine phosphatase 1B
inhibitors, PPAR-γ agonizts, regulators of the glucagon system,
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Diabetic vascular diseases: molecular mechanisms and

Signal Transduction and Targeted Therapy (2023)8:152 ; https://doi.org/10.1038/s41392-023-01400-z

INTRODUCTION been proposed and “polyvascular atherosclerotic disease”14 has

Received: 5 November 2022 Revised: 19 February 2023 Accepted: 28 February 2023

© The Author(s) 2023

Signal Transduction and Targeted Therapy (2023)8:152

Signal Transduction and Targeted Therapy (2023)8:152

Signal Transduction and Targeted Therapy (2023)8:152

Dipeptidyl peptidase-4 (DPP-4) inhibitors

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C: placebo infarction, nonfatal stroke

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Signal Transduction and Targeted Therapy (2023)8:152

Signal Transduction and Targeted Therapy (2023)8:152

Signal Transduction and Targeted Therapy (2023)8:152

Dipeptidyl peptidase-4 (DPP-4) inhibitors

Signal Transduction and Targeted Therapy (2023)8:152

Signal Transduction and Targeted Therapy (2023)8:152

Signal Transduction and Targeted Therapy (2023)8:152

Sodium-glucose cotransporter-2 (SGLT2) inhibitors

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OPL-0401 NCT05393284 2022 2 120 I: OPL-0401 24 weeks Improvement in diabetic /

Signal Transduction and Targeted Therapy (2023)8:152

retinal vasculature can predict various stroke subtypes, suggesting

Signal Transduction and Targeted Therapy (2023)8:152

Signal Transduction and Targeted Therapy (2023)8:152

Signal Transduction and Targeted Therapy (2023)8:152

Insulin receptor signaling Target tissue Effect/ potential role Reference

Signal Transduction and Targeted Therapy (2023)8:152

Signal Transduction and Targeted Therapy (2023)8:152

Signal Transduction and Targeted Therapy (2023)8:152

Signal Transduction and Targeted Therapy (2023)8:152

Signal Transduction and Targeted Therapy (2023)8:152

Signal Transduction and Targeted Therapy (2023)8:152

Signal Transduction and Targeted Therapy (2023)8:152

Signal Transduction and Targeted Therapy (2023)8:152

Signal Transduction and Targeted Therapy (2023)8:152

Signal Transduction and Targeted Therapy (2023)8:152

Signal Transduction and Targeted Therapy (2023)8:152

Signal Transduction and Targeted Therapy (2023)8:152

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