1 s2.0 S0753332222005236 Main

Biomedicine & Pharmacotherapy 151 (2022) 113134
Contents lists available at ScienceDirect
Biomedicine & Pharmacotherapy

journal homepage: www.elsevier.com/locate/biopha
Review
Diabetes mellitus and diabetic foot ulcer: Etiology, biochemical and

molecular based treatment strategies via gene and nanotherapy
Arokia Vijaya Anand Mariadoss a, Allur Subramaniyan Sivakumar a, Chang-Hun Lee b, Sung
Jae Kim a, *
a
Department of Orthopaedic Surgery, Dongtan Sacred Heart Hospital, Hallym University, College of Medicine, Hwaseong, Republic of Korea
b
Department of New Biology, Daegu Gyeongbuk Institute of Science and Technology, Daegu, Republic of Korea
A R T I C L E I N F O A B S T R A C T
Keywords: Diabetes mellitus (DM) is a collection of metabolic and pathophysiological disorders manifested with high
Diabetes mellitus glucose levels in the blood due to the inability of β-pancreatic cells to secrete an adequate amount of insulin or
Diabetic foot ulcer insensitivity of insulin towards receptor to oxidize blood glucose. Nevertheless, the preceding definition is only
Metabolic disorders
applicable to people who do not have inherited or metabolic disorders. Suppose a person who has been diagnosed
Insulin receptors
Glucose transporters
with Type 1 or Type 2DM sustains an injury and the treatment of the damage is complicated and prolonged. In
Nanomedicine that case, the injury is referred to as a diabetic foot ulcer (DFU). In the presence of many proliferating macro
phages in the injury site for an extended period causes the damage to worsen and become a diabetic wound. In
this review, the scientific information and therapeutic management of DM/DFU with nanomedicine, and other
related data were collected (Web of Science and PubMed) from January 2000 to January 2022. Most of the
articles revealed that standard drugs are usually prescribed along with hypoglycaemic medications. Conversely,
such drugs stabilize the glucose transporters and homeostasis for a limited period, resulting in side effects such as
kidney damage/failure, absorption/gastrointestinal problems, and hypoglycemic issues. In this paper, we review
the current basic and clinical evidence about the potential of medicinal plants, gene therapy, chemical/green
synthesized nanoparticles to improving the metabolic profile, and facilitating the DM and DFU associated
complications. Preclinical studies also reported lower plasma glucose with molecular targets in DM and DFU.
Research is underway to explore chemical/green synthesized nanoparticle-based medications to avoid such side
effects. Hence, the present review is intended to address the current challenges, recently recognized factors
responsible for DM and DFU, their pathophysiology, insulin receptors associated with DM, medications in trend,
and related complications.
1. Introduction pathological conditions, and insulin deficiency/resistance. Studies

reveal that T2DM is more prevalent than T1DM. A survey in 2018 among
Diabetes Mellitus (DM) is one of the earliest identified diseases different epidemiology regions suggests that by 2030, 439 million
whose complications are well understood by humankind. Though it was people might get affected by T2DM due to modern food habits [3].
initially described 3000 years back from Egyptian documentation, in the A literature survey from CDC (Center for Disease Control and Pre
early 19th century, two major classes of DM were differentiated as Type vention, USA) states that only 10% of people are affected by this T1DM
1 Diabetes Mellitus (T1DM) and Type 2 Diabetes Mellitus (T2DM) based than T2DM. Further, the survey states that over 370 million are affected
on the absence of insulin or its reduced secretion [1]. Also, DM is a by T2DM. Other studies reveal that 80% of T2DM affected people live in
collection of metabolic disorders, which are complicated by defects/ developing regions of Asian and African countries. This is due to a
complete absence in insulin (a peptide hormone) secretion (T1DM) or sedentary lifestyle and food habits. Also, CDC projected that 10% of
receptor damage resulting in low secretion (T2DM) of insulin [2]. When cases would rise from low-to-middle income and developing countries
a patient fails to maintain the insulin level, it triggers other metabolic from the current stage. In the developed states of the US, T2DM will
impairments (hypertension, cardiovascular disease, obesity), increase to 25.8 million, which is about 7.8% of the total population due
* Corresponding author.
E-mail address: [email protected] (S.J. Kim).
https://doi.org/10.1016/j.biopha.2022.113134
Received 8 March 2022; Received in revised form 5 May 2022; Accepted 15 May 2022
Available online 24 May 2022
0753-3322/© 2022 The Authors. Published by Elsevier Masson SAS. This is an open access article under the CC BY-NC-ND license
(http://creativecommons.org/licenses/by-nc-nd/4.0/).
A.V.A. Mariadoss et al. Biomedicine & Pharmacotherapy 151 (2022) 113134
to poor lifestyle and habits [4]. affected with T2DM. Several studies reported that about 30–60% of
subjects with T2DM are identified with the associated disorder of
2. Types of diabetes mellitus obstructive sleep apnea [8]. Diet is another critical risk factor, but at the
same time, the subject can overcome this risk factor and its associated
Two major types of DM are characterized based on the secretion or T2DM. Obesity is reflected in the incidence of diseases in both devel
absence of insulin. However, few other DM subtypes are also identified oping and developed countries. The increase in T2DM among children
and were not focused on them. T1DM (i.e due to autoimmune β-cell and adults is associated with the widespread etiology of obesity [9]. The
destruction) was identified as an autoimmune disease due to the com results obtained from the alcoholic subjects-directed clinical trials show
plete absence of insulin or receptor damage since birth. Researchers that possible risk is directly correlated with insulin resistance in T2DM
identified this T1DM as a T-cell mediated acquired autoimmunity dis cases [10]. Some of the important risk factors, signs, symptoms and
order. The other kind, T2DM, is described by insulin resistance, affecting treatment for DM are presented in Fig. 1.
insulin secretion. Compared to T2DM, T1DM patients were found with a
low life span, and they were highly prone to cardio-vascular diseases 4. Pathogenesis of DM
(CVD) and severe metabolic conditions in their medical history [5]. The
technological vs. scientific issue plays a significant role in discovering In general, after a meal, there will be a rise in blood sugar level,
new technology or medicine to extend the life span of DM patients. This which motivates insulin secretion, and subsequent generation of energy
review is aimed to address DM and its complications and the techniques (ATP), which is transported, biotransformed or stored in muscles in the
used to manage DM. Also, the types of drug delivery against DM are form of fat substances. The major portion of the triose-phosphate is
critically analyzed. converted into glucose and glycogen through gluconeogenesis. In the fed
time, glucose arrives in liver via GLUT2, when blood glucose levels are
3. Major lifestyle factors and their effects on DM high the excess glucose converts into glycogen through glucose-6-
phosphate called glycogenesis. When glucose is needed as a source of
Diabetes mellitus is observed globally in every country with a high energy in starvation time, glucagon is hydrolyzed by glycogen phos
prevalence, and its mortality rate is changing. The estimated data sug phorylase to generate glucose (glycogenolysis), which balances hypo
gest that by the year of 2049, over 690 million people might get affected glycemic conditions to immediate energy supplement to all parts of the
by DM due to the significant changes in their lifestyles. There is a notable body; which balances hypoglycemic conditions to immediate energy
increase in the % of the incidence of T1DM in 2020 than in 2019. supplement to all parts of the body [11]. The pathophysiology of insulin
Another survey says that children from 0 to 14 years of age have been and its associated biochemical conditions is depicted in Fig. 2. Fig. 2.a
affected, especially male children than female children [6]. In the disclosed that GLUT2 is present in pancreatic β-cell. Blood glucose ar
modern world, people give importance to lifestyle habits such as rives pancreatic plasma membrane via GLUT2 transporter allows
smoking, alcohol, eating fat-rich junk foods (pizza, burger, white glucose to β-cells. The high concentration of glucose inside the cell, al
sugar-rich cakes, and fried foods), and thus ignore physical activity due lows the beta cells to produce more ATP by glycolysis and cellular
to which they encounter T2DM around the age of 30–40 [7]. Extensive respiration, thus increasing the intracellular ratio of ATP to ADP inside
epidemiological study reports show that individuals following these β-cells. β-cells have potassium channels that are sensitive to this ratio.
lifestyle habits will become obese, and they are prone to the risk of being The increase of ATP causes these channels to close, causing a buildup of
Fig. 1. Some of the important risk factor, signs & symptoms and treatment for diabetes mellitus.
2
Fig. 2. The pathophysiology of insulin and its associated biochemical conditions in Type 2 Diabetes Mellitus. Abbreviations: KATP: adenosine triphosphate sensitive
potassium; K: potassium; Ca2+: Calcium2+ ions; PI3Ks: Phosphoinositide 3-kinases; GLUT4: Glucose transporter type 4.
potassium ions inside the cell and depolarizing the cell. This change in
Table 1
membrane potential causes voltage-gated calcium channels to open,
Metabolic and systemic complications of Diabetes Mellitus.
allowing calcium to flow into the cell. Calcium triggers insulin granules
to fuse with the plasma membrane, releasing insulin into the blood Metabolic complications Long-lasting/Systemic complications
stream [12]. Fig. 2b sketches that insulin binds to insulin receptors, has Diabetic ketoacidosis, Lactic acidosis Neuropathy
activates IRS-1 in normal conditions. Then IRS-1 can activate PI3Kinase, Contagions Amputation, cerebrovascular damage,
dementia.
which leads to phosphorylation and the activation of AKT thereby it
Hyper blood sugar, imbalanced osmotic Atherosclerosis, cardiovascular
stimulates GLUT2 pancreatic as well as GLUT4 translocation from pressure, non-ketonic coma, ketone damage, heart blockage, long term fat
cytosol to the plasma membrane and the glucose uptake from blood and bodies as a fatty streak deposition in heart muscle
maintaining normal glucose [13]. Fig. 2c highlighted that, DM is char Fatigue, hazy vision, polyuria and Kidney damage leads to permanent
acterized by high blood glucose is the response to deficiency in insulin polydipsia renal dialysis, retinopathy, foot
problems
production by beta-cell/insulin resistance. The finding ways to increase
Macrovascular diseases including stroke, Cataract, osteoporosis and blindness
PI3K/Akt activation due to dysfunctional insulin signaling in tissues altered blood pressure, vascular damage
[14]. Hyperlipoproteinemia Women may have irregular periods
There will be a complete absence or deficiency of insulin secretion by and infertility
Diabetic foot ulcers Gum diseases
autoimmune damage on pancreatic β-cells in T1DM. Hence, it is iden
Rhinocerebral mucormycosis malignant Depression associated with a high risk
tified as a metabolic conflict accompanied by T1DM. Finally, the dam otitis externa, emphysematous of micro-macro vascular events
age in the β-cells symbolizes the onset of T1DM, thereby infiltrating pyelonephritis
white blood cells, specifically monocytes, lymphocytes along with
pseudomorphic mixtures of somatostatin secreting glands and pancre
atic glycogen polypeptide induced immunogens causing the impaired evaluation, like Siddha and Naturopathy. To regulate/control diabetes,
condition [15]. Autoimmune-altered genetic makeup by environmental insulin administration’s modest and trouble-free passage is required,
toxicity is the reason for the destruction of islets of the β-cells. Another and still, it is a demand in the pharmacological drug delivery market
important type of T2DM occurs due to β-cell imbalance to take up [19]. Conventional drug delivery methodologies still have some limi
glucose uptake and its regulation via insulin receptors. Multiple genetic tations as well as side effects. The following regulations are still chal
and environmental factors are shown to be responsible for T2DM. lenging: dosage fixation, the severity of glycemic index, low potency,
Especially, obesity and high-fat diet cause defects in β-cells and pe and achieving the specific target. The same limitations are applicable for
ripheral tissue causing insulin resistance and glucose uptake/oxidize natural herbs or neutraceutical treatments given for DM [20].
ability [16]. The pathogenic complications of DM are listed in Table 1.
As soon as multiple complications with DM are observed, the im 5. Diabetic foot ulcer
mediate step is to avoid the defined strategy. It is crucial to understand
and overcome the fundamental stage of broad glycemic status and the Type 2 diabetics is a common metabolic disorder in those above 40
associated disorder. The healthcare services will sort them out. In the or middle-aged people. Diabetic foot ulcer (DFU) is an associated
21st century, the new group of drugs such as sulphonylureas induce problem in those admitted in hospital for severe diabetics. While in
hypoglycemia and higher BMI, while metformin affects GIT and causes treatment for DM, DFU is a common long-term complication, and its
diarrhea, nausea, and lactic acidosis as side effects [17]. Some impact leads to noticeable morbidity and mortality. The ulceration/
new-generation drugs (incretin, thiazolidinedione) also have similar destruction causes infection in deep tissues accompanied by neurolog
side effects. In this regard, the scientific community is making contin ical aberrations in various conditions of peripheral arterial disease
uous efforts to formulate a single or combined oral drugs/therapeutic (PAD) of the lower limb of DM patients [21]. Under this condition, the
agents to achieve glycemic control with limited side effects [18]. protective layer of the skin gets infected by bacterial contamination
The current developments in therapeutics for DM and its combined while the epidermis layer starts to damage. Also, amputation is needed
management emphasize the immediate need for substantial in in diabetic subjects with DFU conditions to reduce infection in lower
vestigations to identify potential drug delivery by natural products. limbs. Recently, Diabetic Federation Control reported that 20–30% of
Apart from allopathy, some other medications are also available as a the diabetic population were hospitalized for DF. In each year, 5% of the
natural supplement without formulation and pharmacological new diabetic case were increased, and out of 5%, 1% is reported for
amputation for DFU. It has been noticed that every 20 s, a diabetic
3
patient is admitted for lower limb amputation [22,23]. In DFU, sensa in diabetic subjects. Infection in foot nerve/bones with ischemia was
tional loss in foot nerves is called diabetic peripheral neuropathy (DPN), mainly seen in diabetic patients as per the University of Texas system
and trauma is a substantially high-risk factor. Also, the above said were [33].
solely responsible for DFU, and it contributed to 90% of the cases Reviews state that supervision of DFU is quite critical, and a golden
admitted for foot ulceration related neuropathic problems. standard protocol is needed. Patients should be educated on DFU, foot
However, the following factors of foot deformities, arthropathy, and lesion, glycemic control, proper care of injuries, diet control, and sur
previous foot ulceration were also listed for significant risk factors along gery. There are advanced products for wound care and few cost-effective
with PAD and DPN [24]. In addition, the effect might be extended as a therapies such as, negative pressure/Acupuncture wound therapy
long-term defect due to diabetic retinopathy, nephropathy, poor dia (NPWT), and hyperbaric oxygen therapy for DFU. However, since, low
betic management with uncontrolled glycaemic control, and high-risk and middle-income country people fail to spend for these therapies [34],
factors associated with DFU. Recent statistical reports stated that the proper care for diabetic lesions is questionable in diabetic patients from
major cause of DFU is failure of managing their diabetic behavior by low-income countries. Almost 50–80% of diabetic foot infections are
low-income people. Therefore, diabetic patients with poor hygiene, inevitable. But proper footcare (washing, using anti-microbial cream
smoking and alcohol behaviors have above 20% chances of developing when injured, use of TT, foot massage), diabetic control from hyper
DFU [25,26]. Few studies state DM-associated DFU is relatively high in glycemic condition, and monthly or quarterly check-up for diabetic
Europe and USA than in Asia. This is because of the traditional food patients are useful in preventing DFU [35]. In addition, diabetic patients
habits for diabetic management, DPN and PAD by the Asians that reduce may increase DFU when their working environment involves/supports
the chances of DFU and its associated amputation [27,28]. infection. So, the occupation of diabetic patients also plays a significant
T2DM may give ways to develop various other complications like role in emerging DFU.
chronic glycemia, obesity, peripheral vascular disease and foot de DFU patients should be cautious and keep an eye on their feet often,
formities. Hence, DM is not only the reason for DFU, whereas 90% of the or on behalf of the patient, one family member must inspect the diabetic
DFU is developed by neuropathic-ischemic abnormalities associated foot and take care of infected patients if the patient is aged. Regular foot
with DM. Then the remaining 10% is affected by ischemic ulcers asso examination is a special care in DFU. During the infection, irrespective
ciated with DFU. Generally, DFU and its development in diabetic pa of minor or major injury, it should be treated with care and monitored
tients is explained by the following two metabolic pathways, 1. daily. Cleaning, dressing and applying creams or gentle treatment will
Autonomic neuropathy and 2. Peripheral sensor meter. Briefly, when the help regrowth of tissue. The selection of footwear is also significant such
diabetic patients develop an infection in foot followed by hyper pressure that they trigger nerve impulses and blood circulation. Physician-
in foot nerves, nerve deformities and inability to move foot, the chances prescribed footwear products (soft shoes, sandals, acupressure shoes)
of severe foot ulcers increase [29]. Alavi et al. (2014) did a simple case support treating callus or foot deformities. Apart from the care
experiment. They found that increased plantar pressures during gait mentioned earlier, the physician’s role in routine check-ups and
subsequently leads to foot ulceration in diabetic patients [30]. Literature following up the patient’s condition, testing blood glucose level and
reveals that the following factors such as high threat factors for foot frequent counseling about DFU care are essential [36,37].
ulcer patients with diabetic condition are as, Apoptosis/necrosis is a mutual process and inevitable in the cell
cycle. In tissue injuries, necrotic debridement is essential in the injured
✓ Long-term type 2 diabetics (duration of disease). tissue portion to treat inner tissues and bacterial infection. Debridement
✓ Prolonged kidney infection. aids elimination of unwanted or affected tissue in infected places, callus
✓ Aging. formation, release from high pressure and growth of new tissues. Me
✓ Uncontrolled body mass index (BMI). chanical, biological, enzymatic, and surgical procedures are used for
✓ Lesion in vision. debridement. Mechanical debridement is a rare selective process. It is a
✓ Uncontrolled hypercholesterolemia & Hyperglycemia. manual method of eliminating necrotic tissue by hard wet–to–dry
✓ Peripheral neuropathy. infection dressings that need a highly pressurized hydrotherapy process.
✓ Trauma. Biological debridement is a type of sterilization process. It has also been
✓ Disturbances in joint movement due to uric acid deposition. reported that biological debridement is an apt and successful procedure
✓ Callus. in removing pathogens while it kills healthy tissues during sterilization.
✓ Peripheral neuropathy. Enzymatic debridement uses enzymes as an agent to kill necrotic tissue.
When compared to all the open debridement, enzymatic debridement is
With the above risk factors for DFU, diabetic foot lesion is a signif a successful method in killing necrotic tissue without affecting healthy
icant infectious factor in developing DFU. However, the foot lesion is cells-however, a little expensive method for treating ulcers. After
classified depending on the minor to severe primary infection in the foot. debridement, stem cell therapy is an emerging and advanced strategic
In addition, diabetic foot lesion is graded and/or classified by the therapy to cure DFU. Preliminary results show stem cells therapy in
Wagner system, University of Texas system, and PEDIS system. Also, the dicates a promising effect against DFU. Overall, DFU is a controllable
above-said systems describe a few features of diabetic foot ulcer and infection when injured diabetic patients are given proper hygiene care
classify them based on mild to severe site of infection, depth of ulcera [38,39].
tion, nerve infection and neuropathic infection leads to ischemia. The
diabetic foot lesion is usually graded using the above systems from 6. Current therapeutic approaches for DM
0 (start of the lesion) to 5 (entire foot damage) by the medical practi
tioners [31]. Wagner-Meggitt system is one of the predominant systems, Diabetes mellitus is a disorder with no known/effective treatment
followed by almost all the practitioners with 0 (no risk) to 5 (high risk) and is highly prevalent worldwide. According to World Health Organi
grade classification. Briefly, grade 0 is no lesion in the foot; grade 1 is a zation (WHO) data, 387 million people aged between 40 and 59 years
lesion in the superficial layer, grade 2 is an ulcer in joint or in deep from low- and middle-income underdeveloped/developing countries
tissue, grade 3 is infection causes sepsis, grade 4 is gangrene and grade 5 face this DM as a significant severe killer disease and a threat to humans
is severe foot lesion in diabetic patients. Many classifications are avail [40]. In general, selection of medicine to treat diabetes, based on
able, but all are slightly modified from the Wagner system [32]. Uni reducing or monitoring lowering glucose level and its associated types of
versity of Texas system classifies the foot lesion into four stages A to D. therapy is dependent on a list of factors, such as the severity of the
Each stage has been further classified into four different grades glycemic condition, BMI, the capability of monitoring blood glucose
depending on the presence of ischemia and/or infection or both of them level and selection of cost of the prescription [16].
4
So far, over six decades, the majority of the research works reported T2DM. Clinical trials reveal that these drugs are widely used to manage/
that the therapeutics/treatment for T1DM would involve the stimulation control the uncontrolled blood glucose levels and associated T2DM with
of insulin secretion by Glucagon-Like Peptide (GLP) equivalents such as certain limitations and significant side effects. On the other hand, some
exenatide and liraglutide by compensating β-cell imbalances as well as medications have some strategies for insulin secretion stimulation when
most extended survival of islet cells through direct insulin injection prescribed with combinational oral therapy (sulfonylureas) [44].
while inhibiting dipeptidyl peptidases-4(DPP-4) [41]. Also, these GLP Another vital drug is metformin, approved by Food and Drug Adminis
analogs aim to regenerate islet cells by islet neogenesis associated pro tration (FDA) and it also prescribed as a combinational drug to manage
tein (INGAP) peptide therapy [42]. This will aim at islet cell regenera DM, insulin level and BMI. Like metformin, troglitazone is also used for
tion, which is surrounded by other cells. As that of Type 1, the combined insulin therapy, actively controlling hyperglycemia and its
therapeutic approach for T2DM also contains predictable therapeutics, management [45].
such as sulfonylureas (enhance insulin discharge), troglitazone (raises
the insulin function against excess fat stored in the muscle), metformin
(acts on insulin mechanism by oxidizing liver tissue glucose, and some of 6.1. Role of Medicinal plants for the treatment of DM
the acarbose) and miglitol (lowers the absorption of the carbohydrates
from meals) [43]. Diabetes mellitus can cause many neuro- and nephrological imbal
We have discussed the allopathic medications and their actions on ances. There are numerous types of glucose/insulin balancing/moni
insulin management and their secretion by β-cells in both T1DM and toring drugs identified as anti-diabetics with diverse mechanisms. Also,
those different mechanisms must stimulate insulin secretion to increase
Fig. 3. Multiple therapeutic targets of plant

secondary metabolites in diabetes management.
Multiple therapeutic targets of plant secondary
metabolites in diabetes management [50]. Ab
breviations: IRS-1: insulin receptor substrate 1;
P3K: PI3K: phosphatidylinositol 3-kinase; AKT:
ak strain transforming; PGC-1α:
peroxisome-proliferator-activated receptor-γ
coactivator-1 alpha; FoxO: forkhead box O;
AMPK: adenosine monophosphate-activated
protein kinase; PI3Ks: phosphoinositide 3-ki
nases; TNF-α: tumor necrosis factor alpha;
IL-6: interleukin 6; glucose 6Pase: glucose
6-phosphatase; PEPCK: phosphoenolpyruvate
carboxykinase.
5
peripheral absorption of glucose from the intestine. After over three One of the significant advantages of this nanoparticle-mediated drug
decades of research, a substantial development was made by numerous delivery is that it will not allow the patient to enter the severe condition
anti-diabetic drugs to maintain insulin levels, although with some dis and associated serious infections. It has enormous benefits, including
advantages [46]. Advanced research was also tried with medicinal enhanced bioavailability of drugs at specific organs, tissues, and tumors
plants as the best sources as they are cheap, readily available, toxic-free with high mass dosage to act on the target site directly. Every technology
with zero side effects. The medicinal plants are rich in flavonoids, ter has some drawbacks, and here the stability is the biggest challenge in the
penoids, alkaloids, glycosides, and carotenoids, which can facilitate the three-dimensional nanostructures to two-dimensional layered nano
management of DM. These antioxidant and anti-diabetic activity-rich surfaces. Also, the protocol is yet to be standardized for easy manufac
medicinal plants can improve pancreatic hormone secretion, absorption ture. With additional concern, this nanoparticle drug delivery and
of intestinal glucose, and energy utilization [47,48]. Nowadays, people exposure can become toxic or hazardous when the nanomaterials such
with diabetes choose natural medicinal plants with the as carbon buckyballs and nanotubes are inhaled, ingested, or absorbed
above-mentioned antioxidant properties to reduce side effects and through the skin. But compared to traditional drug delivery treatment
associated risks. Since medicinal plants have less-toxic ingredients for T1DM and T2DM the insulin delivery is painless. Conversely, recent
(tannins, phenolic compounds and catechins) with almost zero side ef micro and nano-drug deliveries have facilitated the regulated insulin
fects, there is a continued interest in using them as a possible treatment administration and its delivery [54].
for DM. These hypo-glycemic herbs enhance insulin secretion, increase
glucose absorption, aid the oxidization of excess muscle fat, and prevent
glucose synthesis in liver cells [49]. The detailed graphical representa 6.3. Green synthesized nano-drug delivery for DM
tion of multiple therapeutic targets of plant secondary metabolites in
diabetes management is presented in Fig. 3 . Plants are cheap and easily obtained sources with enough medicinal
properties. Medicinal plants are rich in antioxidants and exhibit anti-
cancer and anti-diabetic activities [55]. Although plants can easily
6.2. Nanoparticle-based therapeutic approach in DM fuse with other compounds, plant-derived nano drug-mediated delivery
systems are considered superior. Phytocompounds isolated from plants
Nanotechnology aspects have been applied in some of the recent are given immense importance as alternative medicine [56,57]. At
advanced research. Nanoparticle-based drug delivery for diabetes has present, the FDA has approved nearly 50% of the anti-diabetic drugs,
been proved efficient with fewer side effects. Novel probes can be which were plant-derived phytocompounds or their derivatives. Several
introduced through nanoparticles to monitor blood glucose via insulin research groups are working on medicinal plant-mediated or green
delivery [51]. Nanoparticle-mediated drug delivery is a promising tool synthesized nano-drug discovery, and some of them have entered the
that can approach the target. The pores in the delivery systems are market [58,59].
noticeably large, giving passage to small molecules like oxygen, glucose, Additionally, 1200 medicinal plants have been approved to have
and endocrine molecules [52]. Meanwhile, it will allow enough small anti-diabetic activity by the FDA. Without documentation, more than
molecules along larger immunoglobulins of immune cells to maintain 15,000 medicinal plants are used as anti-diabetic drugs in rural areas
the immune system against pathogenic microbes. In nanoparticle-based worldwide. Those undocumented medicinal plants are taken as oral
drug delivery, microcapsules have replaced Langerhans islets, which are drugs with zero side effects. Drug delivery research has improved
commonly imitated from pigs, which may have a chance for less skin considerably with anti-diabetic phytocompounds [60]. Also, improved
allergy to diabetes patients. This treatment will help avoid high immu enzymatic digestion from GIT with improved pharmacokinetics and
nosuppressants with harmful side effects [53]. Some of the important pharmacodynamics profile was obtained even with a lower drug dose
nanotechnology-based treatment methods of DM are presented in Fig. 4. [61]. Drugs are encapsulated in a nano polymeric membrane called
Fig. 4. A different aspect of nanotechnology-based screening and treatment strategies of DM. Abbreviations: TDD: target drug delivery; T1DM: Type 1 Diabetes
Mellitus; NPs: nanoparticles.
6
nanocapsules or nanospheres. Polymers are deemed most important in T2DM. The most critical point is that the materials used for nano-drug
nano-delivery systems because of their flexibility, functionalization, and deliveries are from inorganic or synthetic chemical , and their prepa
various molecular synthesis [62]. In the recent past, different kinds of ration is tough or mostly chemical processed. Some materials are ob
nano formulations were prepared from medicinal plants for the treat tained from natural sources but processed with an organic chemical. So,
ment of DM against both T1DM and T2DM (Fig. 5). it might be half-synthetic. The experiments conducted with clinical and
In anti-diabetic drugs, phytocompounds have potential function with animal models have some limitations when taken into molecular studies
low/zero side effects [63,64]. The British Medical Journal declares that [68].
phytocompounds are linked to four hypoglycemic mechanisms in dia
betes treatment. This includes phytocompounds that help reduce car
bohydrate breakdown and its absorption and digestion while allowing 6.4. Chemical mediated nano-drug delivery for DM
energy metabolism. Hence, this will improve endocrine and liver
metabolic rates, antioxidant, and anti-inflammatory functions [65]. Oral Chemical-mediated or synthetic nanocarriers are extensively used
route drugs have some critical defects if the medicines are anti-diabetic nowadays in the management of DM. Various types of therapeutics are
phytocompounds. Phytocompound-mediated oral nano-drug delivery is followed to treat diabetes. But the side effects/infection associated
used to treat T2DM. The following advantages were observed when metabolic disorders are extensive. Also, patients feel pain due to infec
phytocompounds were used in anti-diabetic therapy in animal trials tion caused by daily insulin injection when diabetes is uncontrolled. So,
[66]. to avoid those complications [69], a carrier with nanosized material can
carry insulin without painful injections. The next-generation diabetic
• Phytocompound-mediated nano delivery mechanisms helps to therapeutical management of different forms of insulin-based nano-
improve the strength of the drugs and scavenge them from enzymatic formulation is depicted in Fig. 6. These nanoparticles are synthesized
free radicals from GIT secretion. from polysaccharides, synthetic polymers, and lipids. This
• Nano drug delivery improves the pharmacodynamics and pharma nano-mediated drug delivery aims to improve homeostasis and drug
cokinetics of molecular-level systems, which help increase the stability and achieve 100% bioavailability. A type of synthetic polymer
cellular drug influx. E.g. P-glycoprotein. called PLGA is branded for its quick biodegradability and biocompati
• The intestinal lymphatic system avoids the first-pass effect. Hence, bility and is recognized as a popular polymer used in the management of
this nano-drug delivery can enter lymph through the lymphatic DM [70]. Once an insulin-phospholipid complex is made, it is trans
system with the help of Mast cells, increasing the systemic ported with PLGA by reverse micelle-solvent evaporation. When the
circulation. nanoparticles reach the stomach, they are digested by acidic digestive
• Above all, nanocarriers achieve targeted drug release by controlling enzymes. There would be no injury or rupture of the insulin molecule
and avoiding the opsonization of drug release [67]. during this procedure, as evidenced by numerous in vivo studies [71].
Generally, PLGA nanoparticles are negatively charged. Hence, they have
With these advantages, phytocompounds indicate better anti- a low permeability with a mucus layer, and can cross the cell membrane
diabetic ability with improved bioavailability, less toxicity, and spe easily. Polylactic acid, polyallylamine (PAA), penetratin, niosomes, poly
cific target site even with low dosage. A recent study reveals that (amidoamine) dendrimers, polymeric micelles, PEG-PE, Eudragit-based
naturally formulated hyaluronic acid can be used as a beneficial drug for nanoparticles, and some of the inorganic nanoparticles are extensively
used in nano-drug carriers [72]. Besides these synthetic nanoparticles,
Fig. 5. Different type of plant-based nanoformulation against the treatment of DM. Abbreviations: PLGA: poly D,L-lactic-co-glycolic acid; PEG: polyethylene glycol;
NPs: Nanoparticles; SNEDDS: self-nanoemulsifying drug delivery system; ARF: alkaloid rich fraction; NLCs: nanostructured lipid carriers; SLNs: solid lipid nano
particles, NEs: Neosomes.
7
complications. However, the insulin injection systemic pathway is

somewhat changed from the endocrine pancreatic islet of β-cells. Gene
therapy states that exogenous gene transfer into suitable beneficiary
cells of patients can provide a complete remedy to specific diseases
[113]. Gene therapy is an optimistic approach to treating diabetes. It
targets the main causative substances that were arrested or sent back to
their original condition. In this therapy, DNA, small interfering RNA
(siRNA), mRNA, microRNA, and some antisense oligonucleotides are
used as the primary genetic drugs [114]. Also, this is divided into im
mune gene therapy, replacement gene therapy and regulatory gene
therapy.
7.1. Immune gene therapy
This type of gene therapy might be started in patients with T1DM.

The current approach regarding this therapy attempts to stop or reverse
an autoimmune response to target genes. These target genes protect the
islet cells. IL-10, an anti-inflammatory cytokine with various biological
signaling and functions with immune response, is highly expressed with
Type 2 MHC antigens [115]. Th1 and Th2 cells are chronic immune cells
that overcome the autoimmune antigens that produce autoimmune
disease. In a study, rAAVIL-10 (intramuscular recombinant
adeno-associated viral vector endocrine murine IL-10) was adminis
Fig. 6. The next generation diabetic therapeutical management of different trated into non-obese diabetic mice and found 60% of non-obese dia
form of insulin-based nanoformulation. PLGA: poly(lactic-co-glycolic acid); betic mice injected with higher-dose rAAVIL-10 maintained euglycemic
SLNP: solid-liquid nanoparticles, NPs: nanoparticle; CPP: cell- condition until 117 days. On the contrary, the mice administered with
penetrating peptides.
low dose rAAVIL-10 could not hold diabetes for at least 17 days. Cole
man et al. (2016) documented that immune precursor-mediated gene
metal-coated synthetic and green synthesized nanoparticles also play a therapy diminishes the destruction of pancreatic cells while restoring
significant role in drug delivery against T2DM. Silver, gold, and super the long-term tolerance of islet cells against its antigen by memory T
paramagnetic material-coated nanoparticles are used in insulin man cells [116]. It concludes that IL-10 gene expression positively affected
agement [73]. Anti-diabetic activity of different NP formulations with reducing autoimmunity [117]. So, immune precursor-mediated immune
their mode of action and possible involvement of carbohydrate meta gene therapy could be an interventive immunotherapy against T1DM.
bolic pathway are presented in Table 2.
For example, some in vivo studies have reported alginate-bead coated 7.2. Replacement gene therapy
(anionic polysaccharide) nanoparticles in glucose-lowering. Colloidal
gel-coated gold, silver, and superparamagnetic particles play a signifi As per various reports, various damage factors are responsible for the
cant role in targeted drug delivery. Nanoparticles are also used exten damage β-cells of islets of pancreatic cells in patients with T1DM and
sively in glucose monitoring management. Precise and regular blood T2DM. Also, non-β-cells can secrete insulin that can replace the damaged
glucose monitoring is essential in the control and management of DM. pancreatic β-cells. Hence, successful replacement gene therapy must
But it is acknowledged that frequent blood collection with painful nee fulfill the following conditions.
dles or sticks is considered dangerous or a nuisance to check clinical
glucose with the presently available testing. Hence, glucose sensors • It should be an active/actual insulin gene transfer system.
capable of quantifying glucose accurately without pain were developed • It must be managed with the regulatory mechanism by controlling
[110]. Also, this procedure can be done in-home without diagnostic blood glucose levels and insulin elevation by islet cells.
specialists. Patients widely use nano chip-based glucose-sensing • Those replacement-involved cells can secrete immature proinsulin
Accu-check glucometers at home. Even though certain limitations and until it reaches β-cells to be active and mature insulin to meet the
negative feedback are raised in nanoparticles-mediated drug delivery, target.
extensive research is needed to sort these issues [111]. • The replacement gene on target cells should have with same
biochemical function as β-cells, and significantly, it should not be
7. Gene therapy attacked by the autoimmune system [118].
According to researchers, several gene mutations have been related RNA viral vectors such as adeno associated-virus, lentivirus, and
to an increased risk of DM. In general, mutations in any gene involved in non-liposomal vectors of liposomes and plasmids have been used as
glucose regulation may raise the risk of developing T2DM. These include replacement genes in the tissues/liver, pancreas, GIT, and endocrine K
genes that control the production of glucose, the production and regu cells. Many studies have been carried out with transgenic mice induced
lation of insulin, and sensing of glucose levels in the body. Mitochondrial STZ. After, STZ GIP promoter transfers the insulin as replacement gene
genome mutations are denoted as mitochondrial diabetes. This is also therapy to K cells to GIT, euglycemia will be achieved. It shows that K
known as MELAS syndrome (Mitochondrial encephalomyopathy, lactic cells can be a better replacement and have the potential to secrete
acidosis and stroke-like episodes). enough insulin while maintaining blood glucose homeostasis and energy
Recent anti-diabetic clinical trials and their involved models have supplementation [119]. In 2015, Romer and Sussel treated STZ-induced
exposed that hypoglycemic insulin drugs or insulin injections or analogs non-obese diabetic mice and dogs with adeno-associated viral vectors
can give just a temporary effect to minimize hyperglycemic impact, and that carried insulin replacement gene therapy from glucokinase genes
there is no improvement on the islets of β-cells of insulin maintenance of into skeletal muscle cells. These two genes enhanced the insulin level by
blood glucose homeostasis and avoiding various illnesses [112]. It is translocating GLUT4 and glucokinase by transport glucose to muscle
challenging to admit exogenous drug administration and to mimic the cells. Generally, glucokinase will play as a ’glucose sensor.’ It is essential
8
Table 2
Antidiabetic activity of different NP formulations with their mode of action and possible involvement of carbohydrate metabolic pathway.
Nanoformulation Experimental model Mode of action Possible involvement of metabolic Refs.
pathway
Vildagliptin -gold and silver In vitro DPP-IV inhibitory Augment the stability, extend the drug release, increase the DPP-IV inhibitory pathway [74]
NPs activity glycaemic level in the postprandial conditions
Wedelolactone-AuNPs RIN-5F Reduce lipid peroxidation, improve the antioxidants status and GLUT2 signaling pathway [75]
insulin secretion
L. japonica-AgNPs In vitro assay Inhibit the α-amylase and α-glucosidase Inhibition Polysaccharide digestive [76]
enzymes
W. somnifera-PtNPs STZ induced diabetic in Reduction in plasma glucose Improve insulin signaling cascade [77]
Sprague-Dawley rats mechanism
H. sabdariffa-SeNPs STZ induced diabetic rats Improve the serum testosterone, reduce the oxidative stress Conceivable involvement of Nrf2- [78]
keap1 signaling pathway
CuNPs STZ induced diabetic rats Prevent the cardio-vascular structural and functional defects, May be the participation of [79]
Increased bioavailability of NO in the endothelium and reduced PI3K–Akt–eNOS signaling pathway
the oxidative stress
AuNPS Human foreskin fibroblasts Decreased RAGE expression, normalize the antioxidant and AGE-mediated RAGE vascular [80]
& STZ induced BALB/c angiogenesis system complications Mechanism
mice
ZnONPs STZ induced diabetic rats Enhance glycaemic condition, improve the inflammatory Nrf2-keap1 signaling pathway [81]
changes, renewal of islets of Langerhans and increased insulin-
secreting granules.
ZnONPs STZ induced type 1 diabetic Improvement of renal function, inhibition of renal fibrosis, JAK/STAT signaling mechanism [82]
rats oxidative stress, inflammation, regulation the abnormal
angiogenesis, amendment of podocyte injury.
Amino acid-functionalized Db/db diabetic mice Regulate the pancreas dysfunctions, reduced oxidative stress and IRS2/PI3K/AKT signal pathway [83]
gadofullerene NPs inflammation, retaining glucose and lipid metabolism
SLNs from HFD-STZ induced diabetic Reduce blood glucose, insulin resistance, decreased lipid Nrf2-keap1 signaling pathway [84]
P. acacia and rats peroxidation (malondialdehyde), boost up the endogenous
P. curviflorus antioxidant system
SLNs-F. religiosa STZ & fructose induced Noticeable hypoglycaemic and insulin-sensitizing effects IRS/PI3K/AKT/GLUT4 signaling [85]
diabetic rats pathway
Ferulic acid-chitosan NPs STZ induced diabetic rats Enhancement body weight, decrease in blood glucose level along AMPK/SREBP-1c Signaling Pathway [86]
with a regulatory effect on blood lipid profile
Quercetin-PLGA-NPs STZ induced diabetic rats Enhance the oral therapy by minimizing the dose and dosage Possible involvement of insulin [87]
frequency signaling cascade mechanism
Chitosan/alginate/ STZ induced diabetic rats Reduce the elevated blood glucose level and lipid profile (total AMPK/SREBP-1c Signaling mechanism [88]
maltodextrin/pluronic- cholesterol, triglycerides, HDL cholesterol). Maintain the body-
microparticles weigh and speed up the wound healing mechanism
Ursolic acid- STZ induced diabetic rats Remedial action on pancreatic toxicity decreases hyperglycemia Nrf2-keap1 signaling mechanism [89]
Nanosuspension and reducing elevated oxidative stress.
Berberine-Nanosuspension STZ induced diabetic in Decreases blood glucose and improves lipid metabolism AMPK/FoxO1/mTORC1/SREBP-1c [90]
C57BL/6 mice Signaling Pathway
Sesamol-PLGA- HFD-STZ induced type-II Diminished the TNF-α levels in wound tissue and enhanced Inhibition of PI3K/Akt/mTOR signaling [91]
Nanosuspension diabetic rats collagen deposition. Regulate the HSP-27, VEGF ERK, and PDGF- pathways
B expression. Speed up the re-epithelization, fibroblast
migration, collagen deposition and reduced inflammatory cell
infiltration
Psidium guajava HFD-STZ induced type-II Retrieve the blood glucose level, recover the hepatic and renal AMPK/FoxO1/mTORC1/SREBP-1c [92]
diabetic rats damage Signaling Pathway
Lycopene-Nanosuspension NIDDM in diabetic rats Alleviate the cholesterol, triglycerides, LDL, HDL, VLDL, and AMPK/SREBP-1c Signaling mechanism [93]
antioxidant corresponds
Eudragit-Nanosuspension Nicotinamide-STZ induced Rapidly reduced the blood glucose with Superior Possible involvement of insulin [94]
diabetic rats pharmacokinetic effects signaling cascade pathway
Silymarin-nanostructured Caco-2 cellline, HFD-STZ Considerable down-regulation of blood glucose and lipid profile, AMPK/SREBP-1c Signaling pathway [95]
lipid carriers induced diabetic mouse especially in triglyceride level
Nanostructured Lipid 3T3-L1 cellline and Wound Neutralize the inflammation process and decrease MMP-9 Possible inhibition of Proliferation, [96]
Carriers of Pioglitazone healing model in Wistar expression Angiogenesis and Remodeling of
albino rats diabetic wound
Nanostructured Lipid NIH 3T3 and HaCaT cellline Speed Up the wound closure mechanism and boost up the Nrf2-keap1 signaling pathway [97]
Carriers of EGF and antioxidant enzyme
curcumin
Phenytoin Loaded Diabetic Foot Ulceration in Strengthen the skin penetration mechanism Keratinocyte Protein Signaling [98]
Nanostructured Lipid human pathway
Carriers
Baicalin-loaded HFD-STZ induced diabetic Regulate the fasting Blood Glucose, Glycosylated Hemoglobin AMPK/SREBP-1c Signaling pathway [99]
nanostructured lipid rats in Sprague-Dawley level, regulate the lipid metabolism
carriers
Thymoquinone-Loaded In Vitro Wound Healing Stimulate the fibroblast proliferation and migration, diminish Nrf2-keap1 signaling pathway [100]
Nanostructured Lipid Models in (NIH/3T3 and the nitrosative stress, decreasing the apoptotic process,
Carrier 3T3-L1 increasing cell proliferation and lowering the ROS levels
Lycopene-Niosomes Alloxan induced diabetic Decrease the blood glucose, diminished the T cell-dependent Nrf2-keap1 signaling pathway [101]
rats adaptive immune response, expanding the total antioxidant
function
Berberine-Niosomes Caco-2 cells, HFD-STZ Reduced the blood glucose level, reduces the P-glycoprotein MAPK/ERK signaling pathway [102]
induced diabetic mice efflux of BBR and improves its permeability
(continued on next page)
9
Table 2 (continued )
Nanoformulation Experimental model Mode of action Possible involvement of metabolic Refs.
pathway
Embelin-niosomes STZ induced diabetic rats Increases in SOD, CAT, and GSH, decline the lipid peroxidation Nrf2-keap1 signaling pathway [103]
level
Pioglitazone-niosomes STZ induced T2DM in Reduction in glucose levels Possible involvement of insulin [104]
diabetic rats signaling cascade mechanism
Gymnema sylvestre- Alloxan induced diabetic Reduced the blood glucose level, improved the anti- IRS/PI3K/AKT/GLUT4 signal pathway [105]
niosomes rats hyperglycemic activity
Fumaria officinalis- Alloxan induced diabetic Boost up the anti-inflammatory gene (IL-10), improve the pro- Immunomodulation/reverse [106]
Niosomes rats inflammatory gene expression (TNF-alpha, IL-6) ameliorate the relationship between inflammation and
oxidative-stress insulin stimulation
Amentoflavone-Micelle KKAy Mice Lowering blood lipids, reducing inflammatory responses PPAR γ, PI3K/Akt signaling pathway [107]
Silymarin-pluronic STZ induced T2DM in Improve the status of anti-hyperglycemic, anti-hyperlipidemic Nrf2-keap1 and AMPK/SREBP-1c [108]
nanomicelles diabetic rats and antioxidant status pathway
Betanin-liposomes STZ induced diabetes Decreased the blood glucose and body weight, enhanced the Nrf2-keap1 and IRS/PI3K/AKT/ [109]
nephropathy serum insulin level, regularize the hyperglycemia, oxidative GLUT4 pathway
stress, hyperlipidemia, and lower the tissue damage
STZ: Streptozotocin; T2DM: Type 2 diabetes mellitus; HFD: High fat diet; NIDDM: Non-insulin-dependent diabetes mellitus.
to key regulatory enzymes that regulate the insulin hormone as per dressing without side effects. Only a few reports claim to treat diabetic
blood glucose concentration requirement [120]. wounds with diabetic foot ulcers effectively, but those have failed.
9. Nanotechnology vs. diabetic wound

7.3. Regulatory gene therapy
Drug delivery through nanoparticle/nanomaterials-based diabetic
Initially, all biosynthesis processes are regulated by a set of pro
wound healing treatments shows some benefits in reducing side effects
grammed procedures with programmed genes [118]. From the start of
or quick wound healing. Nanoparticles act as drug delivery systems with
the synthesis through the maturation of pancreatic β-cells to the desti
controlled drug release. They have also been reported to have anti-
nation of insulin secretion, many cytokines are involved in the regula
cancer, anti-diabetic, anti-microbial properties [136]. It has already
tion. Hence, researchers attempt to transfer the genes that encode
been well demonstrated that nanoparticles treat damaged tissues by
interrelated cytokines to the organism. This process will normalize in
stimulating cell proliferation, migration, microbe inhibition, thereby
sulin secretion, and the blood glucose level will be regulated. IGF1
controlling wound healing [137].
(insulin-like growth factor-1) is a β-cell mitogen that will stimulate
Recently, 3D polymer hydrogels have been used in tissue engineering
amino acids and glucose absorption from GIT. Further, it will control the
and drug delivery. Hydrogels with high water content, expanded elas
excess of glucose into glycogen and balance the insulin burden to life
ticity and biocompatibility have reaped success in this regard. It has
style. IFN-beta, AAV8, and AAV-IGF-1 genes are the best suited for
been discovered that nanoparticles collaged with hydrogels exhibit
regulatory gene therapy, which have an excellent therapeutic prospec
controlled drug release and localization in wound burst and structural
tive for type 1 diabetes [121]. Apart from gene therapy, chemical- and
remodeling and localization [138]. Meanwhile, according to another
green synthesis-mediated nano-drug delivery, nutrition therapy, and
report, characteristic nanofibers tuned mechanical properties and
stem cell phage therapy are also involved in the treatment/control of
increased pore size and surface area through chronic wound control
diabetes [122]. Some of the important gene therapy methods employed
[139]. AgNPs have been used as an anti-inflammatory agent against
in the clinical management of DM is tabulated in Table 3.
burns, chronic ulcers, tissue regeneration, targeted drug delivery, and
collagen installation for chronic diabetic wounds in detail.
8. Diabetic wound therapeutics in trends Non-polymeric nanoparticles, including AgNPs and AuNPs, are also used
as anti-infective and anti-inflammatory agents in primary therapeutic
In general, the ability to tolerate a long-term wound is a critical issue. mediators. Numerous reports have shown that healthcare professionals
Wound healing is also slowed down in alcoholics, the elderly, and people use AgNPs and AuNPs to deliver unconditional and controlled drug
with metabolic disorders, blood clotting problems, and diabetes. Among delivery. Furthermore, those NPs act as anti-infective and antibiotics
all, diabetic patients and their injuries and wounds significantly impact against bacterial infections. Thus, hospitals require these NPs for dia
healing, which may take extended period. According to an IDF report, betic wound healing [140]. As a result, AgNPs have a much greater ef
more than 500 million new diabetic patients will be added in the coming fect on wound healing than APS. It has also been noted that Au alone
decade. As a result, the world requires rapid recovery from diabetic cannot perform any biological activity such as anti-microbial activity. It
wounds to avoid other diabetic complications or keep people with dia must be bound or combined with some biomolecules to show activity
betes alive. Various treatments with various approaches have been against damaged tissue/regeneration activity [141]. AuNPs coated with
developed to treat diabetic wounds. The systemic delivery method is peptides and enzymes lead to faster healing of diabetic wounds in an
commonly used, for example, when prescribing drugs to diabetic pa animal model [142]. In another study, wound healing was nearly 80%,
tients, the drugs enter the bloodstream. However, there will be severe/ and the injury site was closed within six days with KGF coated AuNPs in
causative side effects if wound treatment is not provided [134]. diabetic rat model [143].
On the other hand, indigenous people use natural/topical treatments In general, overexpression of GM3S causes slow wound healing due
such as herbal, plant, and massage to reduce side effects. Nonetheless, to the high insulin levels and resistance. This was demonstrated in a
these approaches are insufficient for treating diabetic wounds. mice mode. The treatment with Au-NPs combined with peptide LL37
Furthermore, both treatments are time-consuming and have a delayed and plasmid DNA showed better histopathological effects on the injury
response to injuries. According to the literature, bioengineered grafts, site and reduced pathogenesis. As a result, Ag exhibits greater activity
growth factor therapy, synthetic hydrophobic polymer dressings, natu and functions when compared to Au. However, an in vivo study found
ral polymer therapy for unwanted allergic conditions, and foam dressing that AgNPs with nanopolymers appear late in wound healing and may be
are all used to treat diabetic wounds [135]. However, no effective reduced by a saline wash in the wound site. Furthermore, a delayed
treatment/therapy is currently available for effective diabetic wound
10
Table 3 metabolism is maximum, it will be a better candidate than other NPs.

Some of the important Gene therapy method employed in the clinical manage Also, the ZnO has been studied against melanoma, inflammation, bac
ment of DM. terial infection and diabetes. They have also been effective in healing
Gene therapy Model Mode of action Ref. chronic diabetic wounds and injuries [145]. ZnO NPs with polymeric gel
AAT NOD mouse Modifies the T cell [123]
combined biomolecules have been experimented against diabetic
receptor repertoire, induced Sprague-Dawley rats. Ceramic nanoparticles are used as a
Reduces cell-mediated transporter to deliver the drug to the target site of injury or inflamma
autoimmunity tory site. Hence, these ceramic NPs act as shuttle to deliver the drugs
NeuroD/BETA2 NOD mouse Reverse the [124]
[146].
hyperglycemia, induce
islet neogenesis
rAAA-insulin analog Sprague–Dawley Cure the autoimmune- [125] 10. Conclusion
rats mediated diabetes,
Reduction of type 1 Diabetes mellitus is a metabolic disorder caused by the absence or
diabetes
OGT2115 C57BL/6J mice Aggravates [126]
low secretion of insulin with uncontrolled glucose elevation in the
hyperglycemia, blood. Genetic inheritance, uncontrolled diet, sleep apnea, obesity,
Stimulates the lifestyle, and occupational factors play a significant role in developing
infiltration of diabetes. Also, it is not a gender or age-based one. Hormonal therapy,
immunocytes
allopathy, natural plant-mediated or green/chemical-mediated nano
ADi-100 diabetic mice Reversing the [127]
hyperglycemia improved particle drug delivery, and various gene therapy methods are followed
the apoptosis stimulating to control or manage blood glucose levels well. There are numerous
Bax content management options for diabetic wound therapy now available. Tradi
GAD65206-220 Nude mice Induce the IL-10 and [128] tional approaches have several drawbacks. One of the key constraints of
GAD65536-550, TGF-β expression in
traditional diabetic wound management therapy is the rate and pro
Insulin B9-23 and pTregs, silencing the
Insulin C17-A1 autoreactive T cells, gression of healing of a diabetic wound. Several nanotechnologies and
Modulates DCs by nanoproducts have recently entered the market, showing promising
upregulating Il-10hi and results for diabetic wounds.
downregulating CD40lo
Klotho db/db mouse Decrease the blood [129]
glucose, Improve the CRediT authorship contribution statement
hormonal effect in
autocrine and paracrine Arokia Vijaya Anand Mariadoss: Conceptualization, Methodology,
effects Validation, Data curation, Writing – original draft. Allur Sub
DsAAV8–MIP–GLP-1 Male-balb/c mice Reduce autoimmune [130]
ramaniyan Sivakumar: Validation, Data curation, Writing – review &
destruction including
beta-cell expression of editing. Chang-Hun Lee: Visualization, Writing – review & editing.
interleukin-4, mitigate Sung Jae Kim: Funding acquisition, Project administration, Supervi
the onset of diabetes sion. Writing – review & editing. All authors gave final approval of the
AAV2/8- C57BL/6 male Trigger capsid specific [131]
published article and are accountable for all aspects of the work.
mice CD8+ T cell responses,
Promoted the
environment less Data Availability
immunologically
tolerant The data presented in this study are available on request.
LentiVIP Sprague Dawley Reverses hyperglycemia, [132]
rats prevents weight loss
normally, suppression of Conflict of interest
Th1 cytokines, activation
of regulatory T cells, and All authors have no conflicts of interests to be declared.
increased IL-10 synthesis
FGF21 High fat diet- Favor the weight loss, [133]
induced diabetic Reduced the
Data availability
rat inflammation and fat
accumulation in adipose Data will be made available on request.
tissue; reverse the
steatosis and fibrosis,
Acknowledgements
increase the insulin
sensitivity, decrease the
risk of tumor formation This work was supported by the Basic Science Research Program of
due to HFD the National Research Foundation of Korea (NRF-2019R1F1A1059300),
and by the Korea Medical Device Development Fund grant funded by the
Korea government (the Ministry of Science and ICT, the Ministry of
inhibition of the bacterial cell wall resulted in an irreversible stop. Zinc
Trade, Industry and Energy, the Ministry of Health & Welfare, the
is another trace element used to treat both T1 and T2 DM in the form of
Ministry of Food and Drug Safety (KMDF_PR_20200901_0082)) and also
ZnO and ZnO2 NPPs. Zinc is an essential co-factor that promotes meta
Hallym University Research Fund. The authors would like to thank and
bolic homeostasis by accelerating the activity of over 300 enzymes and
credit to pngtree (https://pngtree.com) for utilizing some of the figures
co-enzymes during metabolism. In general, Zn is used to maintain or
used in this manuscript.
lower hypertension and high blood glucose levels by absorbing glucose
and storing it in skeletal and adipose tissue as glycogen. With this
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Biomedicine & Pharmacotherapy 151 (2022) 113134

Contents lists available at ScienceDirect

Biomedicine & Pharmacotherapy

Diabetes mellitus and diabetic foot ulcer: Etiology, biochemical and

1. Introduction pathological conditions, and insulin deficiency/resistance. Studies

Fig. 3. Multiple therapeutic targets of plant

complications. However, the insulin injection systemic pathway is

7.1. Immune gene therapy

This type of gene therapy might be started in patients with T1DM.

9. Nanotechnology vs. diabetic wound

Table 3 metabolism is maximum, it will be a better candidate than other NPs.

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