Association of host antimicrobial peptides with type II diabetes mellitus complications: a systematic review

Background This systematic review aims to review and assess the importance and relationship between host defence antimicrobial peptides with type 2 diabetes mellitus (T2DM) complications and the correlation of their expression with hyperglycaemic status. Main body The systematic search included three electronic databases (PMC, PubMed, and Google Scholar) that were searched from July to November 2023. After identifying and screening the research articles, eleven studies fulfilled the selection criteria and were included (six case–control and five cross-sectional studies). The Newcastle Ottawa Scale assessed the selected studies’ quality. Most studies indicated a correlation between certain types of AMPs and diabetic complications. Conclusion Hyperglycaemia in type 2 diabetes mellitus (T2DM) affects the expression of certain types of antimicrobial peptides (AMPs) which have a dual function (antibacterial and modulation of immune response) that may enhance inflammation which may correlate with the development of long-term complications


Introduction
Diabetes is a worldwide medical problem, and according to certain organizations, such as the World Health Organization, at least 366 million individuals worldwide are expected to have diabetes mellitus (DM) by the year 2030 [1].The incidence of type 2 diabetes mellitus (T2DM) is increasing rapidly and representing > 90% of all cases of diabetics worldwide [2].The greater prevalence of T2DM will increase the risk of infectious illnesses and associated comorbidities [3].Although the T2DM progression is heterogeneous, it is recommended that low-grade inflammation attend to the development of T2DM [4] causing the progress of T2DM-related complications, including neuropathy, nephropathy, retinopathy, and cardiovascular diseases (CVDs) [5].
Antimicrobial peptides (AMPs) are small polypeptides or oligopeptides, highly conserved effector molecules that are essential to innate immunity [6].They are mainly synthesized by epithelial and acute inflammatory cells as the initial line of defence against pathogens for instance; neutrophils [7].It has been widely described that these peptides contribute to the progress of inflammation [8], also can modulate the host immune system by different mechanisms like endotoxin neutralization, activation of immature dendritic cells, chemotaxis, induction of cytokine [9], promote re-epithelization and wound closure, and support angiogenesis [10] through activation a wide diversity of receptors.Additionally, AMPs show antimicrobial effects through the disruption of cell membranes and protein synthesis of pathogenic microorganisms [11].The expression of AMPs in healthy tissues may assist in preventing both the onset and progression of inflammatory diseases such as T2DM [12].
The human antimicrobial peptides (AMPs) can be divided into 15 classes, but the most important endogenous AMPs can be classified into two main groups: defensins and cathelicidin.Defensins are AMPs produced from several types of epithelial cells and several immune cells, including leukocytes and neutrophils.According to the difference in their structure, they can be divided into three classes: alpha-defensins, beta-defensins, and thetadefensins.Alpha-defensins (human neutrophil peptides, HNP) are produced by Paneth cells (which are found at the base of crypts of the small intestine) and stored in azurophilic granules of human neutrophils, while betadefensins (HBD) are produced by epithelial cells such as keratinocytes, activated monocytes/macrophages, dendritic cells, and Paneth cells [13].
Alpha-defensins (HNP), in addition to exerting broad antimicrobial activity, may cause chemotaxis and enhance the elevation of pro-inflammatory cytokines [14,15].Also, HNP promotes the adherence of low-density lipoprotein cholesterol to endothelial cells found in blood vessels, confirming its role in atherosclerosis [16].
Cathelicidin (LL-37) possesses biological properties such as neutralization, endotoxin, chemokine mimicking activities, modulation of immune response, cytokine production, and histamine release.Also, because of its antimicrobial activity, LL-37 plays an important role in the development of diabetic foot ulcers by inducing angiogenesis, keratinocyte migration, and proliferation.
Several studies have demonstrated the increased or decreased concentrations of AMPs in patients with T2DM [17][18][19].However, the overall association of these peptides with T2DM complications still needs to be clarified.Understanding the critical role of AMPs in T2DM complications will be critical to reveal their potential as diagnostic and therapeutic agents.This systematic review was aimed at giving a comprehensive view of the recently available published articles that investigated the AMPs importance in patients with T2DM complications.
The purpose of the current systematic review is to define the association of AMP (defensins and cathelicidins) with T2DM complications.

Literature search strategy
Three electronic databases (PubMed, PMC, and Google Scholar) were used to search literature studies from the period between July and November 2023.The following keywords were used to find related literature: "Type 2 Diabetes mellitus" AND "Antimicrobial peptides" OR "T2DM with complications" AND "Host defence peptides" OR "diabetic foot ulcer" AND "Human beta-defensin" OR "LL-37" AND "Diabetes mellitus Type 2" OR "HBD" AND "Type 2 Diabetes mellitus" OR "antimicrobial peptides human defensin" AND "DFU" OR "Human β-defensin" AND "Type II Diabetes mellitus" OR "Human beta-defensin" AND "diabetic foot infection" OR "Human defensins" AND "Type 2 Diabetes mellitus" OR "LL-37" AND "Type 2 Diabetic foot ulcer" OR "host antimicrobial peptides" AND "Diabetes mellitus Type 2".

Screening of the retrieved articles and selecting strategy
The screening strategy was done by the two reporters, and the studies were screened first by titles, second by abstracts, and finally through reading the full texts.

Inclusion criteria of the searched articles
Original articles that were published in the English language between 2010 and 2023 have been searched.Articles that study the expression of APM in patients with T2DM were included.

Exclusion criteria of the searched articles
Meta-analysis and systemic review, review articles, nonpublished articles, and studies that deal with T1DM or T2DM that do not deal with AMPs were excluded.

Extraction criteria for the studies
The search strategy had been restricted to English papers.Studies with humans (not animals) of various ages and sexes were considered.Review articles, unpublished articles, articles published before 2010, studies reported as abstracts at scientific conferences, and others were excluded (Fig. 1) [20].

Quality appraisal of the included studies
Newcastle Ottawa Scale was used to implement the quality assessment of the included studies for case-control and cross-sectional studies.Four were cross-sectional, while six of the included studies were case-control, and one of them the study design was not written but it is considered a cross-sectional study.NOS for case-control comprises three categories (Selection, Comparability, and Exposure) with eight numbered items.Each item in the selection and exposure categories can be given one star as maximum, and for comparability, two stars can be awarded.Thus, the maximum score of nine is shown in Table 1.NOS adapted for cross-sectional studies was also used with three categories (Selection, Comparability, and Outcome) with a nine score as a maximum, as shown in Table 2.
A score of seven or above was regarded as a highquality study since a standard assessment of what constitutes a high-quality study has not yet been widely acknowledged.

Characteristics of the studies
All of the involved studies were observational studies classified: six of which were case-control [11,12,17,[21][22][23], four were cross-sectional [24,[25][26][27], and one study  design was not written [28].Also, all of the included studies were performed in vivo involving humans only (not animals).Various fluids and\or tissue samples were taken for the AMP assessment, including blood samples in six studies [17,21,24,23,29], gingival crevicular fluid samples in two studies [12,22], saliva in one [25], biopsies and tissue samples from DFU in one study [27], one study collected both blood and biopsy from gastrointestinal tract [11], one study collected both nasal swab and blood samples [26], and one study collected both blood and saliva [28] for the analysis, as shown in Table 3.
The total number of patients and healthy subjects was 1471.All studies investigated AMP by using ELISA.Six of them used another technique with ELISA like culture technique (two studies), qPCR (two studies), and qRT-PCR (two studies), as shown in Table 3.

The relationship between AMPs and advanced glycation end products (AGE)/hyperglycaemia
Six studies had investigated the effect of AMP and its relationship with hyperglycaemia.El-Mowafy et al. 2022 found that in comparison with healthy control, there is a significantly higher serum level of α-defensins in T2DM (P < 0.001) and also that α-defensin significantly correlates with fasting blood glucose (r = 0.441, P < 0.01), AGEs (r = 0.703, P < 0.001).Meguro et al. 2014 documented that the levels of plasma LL-37 do not have a significant correlation with glycated haemoglobin (HbA1c), as shown in Table 4. Sharma et al. 2022 observed elevated levels of HßD-3 and HßD-1 in T2DM subjects with poor glycaemic status and with chronic periodontitis.Xiao et al. 2022 observed a higher expression level of HβD-2 and LL-37 in the saliva of diabetic individuals with poor glycaemic control and moderate-to-severe chronic periodontitis (CP).Also, individual impact analysis results revealed a positive synergistic effect of periodontal state and blood glucose level with the salivary concentration of LL-37 and HBD-2.This suggested that the worse the glycaemic control, the more severe CP and the greater the level of HBD-2 and LL-37 in saliva, as shown in Table 4.
Yilmaz et al. 2020 demonstrated that HbA1c values, AGE, salivary cathelicidin level, and periodontal parameters all showed a significant positive correlation (p < 0.001).Additionally, a significant positive connection (p < 0.001) was seen between the salivary human betadefensin (HBD)-3 and AGE level.FPG levels and salivary hBD-2 levels had a negative correlation (p < 0.001).The regression analysis shows a negative correlation between HbA1c levels and the concentrations of hBD-2 and hBD-3.Kumar et al. 2017 found that in PTB, circulating HBD-2 and LL-37 have a positive correlation, whereas granulysin has a negative relationship with HbA1c or fasting blood glucose (FBG) levels, indicating a crucial relationship between these variables and inadequate control of glucose levels, as shown in Table 4.
All the previous studies in Table 5 had not investigated the impact of age on AMP expression and T2DM complications except El-Mowafy et al. 2022 reported that serum levels of α-defensin showed a significant correlation with age (r = 0.566, P < 0.01).

AMPs and oral health complications
The current study included four studies investigating the AMP level in T2DM with periodontitis.Yilmaz et al. 2018 documented that the gingival crevicular fluid (GCF) of T2DM patients with GP (generalized periodontitis) showed significantly lower levels of hBD-1 compared to the healthy group (median 0.05 pg/μL, min-max (0.0-0.49)), as shown in Table 5.
Inversely, Sharma et al. 2022 have documented that HßD-3 and HßD-1 have been shown higher levels in chronic periodontitis with worsening glycaemia, while in gingivitis patients the HßD-1 and HßD-3 levels are elevated in comparison periodontitis patients.Also, Xiao et al. 2022 found that T2DM with poor glycaemic control and moderate-to-severe CP have higher salivary expression levels of LL-37 and HBD-2 in comparison with those with good glycaemic control and mild CP, as shown in Table 5.

AMPs and other complications
Five studies investigated the correlation of AMPs with T2DM complications like diabetic nephropathy, retinopathy, cardiovascular disease, diabetic foot ulcer, and GIT complications.
El-Mowafy et al. 2022 found significantly increased serum levels of human α-defensins (3.4-fold change) in patients with diabetes (P < 0.001) or diabetic neuropathy (DR) (P < 0.001) in comparison with control subjects.On the other hand, patients with diabetic neuropathy (DPN) and those with diabetes did not significantly differ in their levels of human α-defensin, as shown in Table 5.
Meguro et al. 2014 stated that the plasma LL-37 levels did not correlate significantly with the clinical stage of diabetic nephropathy and diabetic retinopathy.Also, there is no difference in the plasma level of LL-37 rendering to history of cardiovascular disease.Furthermore, plasma LL-37 level was positively correlated with inflammatory markers and inversely with high-density lipoprotein cholesterol (HDL-C), as shown in Table 5.
Meng et al. 2019 stated that in diabetic wounds of patients with diabetic foot ulcers, the centre was shown higher gene expression of alpha-defensins than the edge when different portions of the wound were taken, as shown in Table 5.
Linn et al. 2023 documented that in the gastric corpus of T2DM patients, the expression of HBD-1 was significantly reduced in comparison with the control group, as shown in Table 5.

AMP and bacterial carriage and/or susceptibility to infection
The current meta-analysis included two studies that deal with AMPs in T2DM patients and their correlation with bacterial carriage and/or susceptibility to infection.Plataki et al. 2021 found that in comparison with non-S aureus carriers, in carrier groups (persistent and intermittent), serum cathelicidin levels were meaningfully greater and also there was no significant variance in LL-37 levels between each of the carriage groups.Serum LL-37 levels were significantly elevated in methicillin-resistant significantly elevated levels of circulating human beta-defensin-2 (in pulmonary TB-DM, geometric men = 72.6 pg/mL vs 5.2 pg/mL in diabetes) and LL-37 (in PTB-DM, Gm = 3.9 ng/mL vs 1.2 ng/mL in diabetes) were compared to diabetic patients.The concentration of circulating HBD-2 and LL-37 has shown a significant increase in PTB-diabetic subjects with bilateral disease (LL-37 GM = 4.1 ng/mL) (HBD-2 GM = 114.2pg/mL) in comparison with those with unilateral disease (LL-37 GM = 1.6 ng/ mL) (HBD-2 GM = 39.8 pg/mL).Likewise, there are significantly elevated levels of circulating LL-37 in cavitary disease (GM 4.7 ng/ml) than those without (GM of 2.7 ng/ mL).Additionally, in PTB-DM individuals, HBD-2 and LL-37 showed a positive correlation with smear grades.

Vit D contribution to AMP production in T2DM
25-hydroxy vitamin D (25(OH) D) might promote the epithelial host defence against bacterial infection by producing of AMP like LL-37.
Linn et al. 2023 documented that the expression of HBD-3 in the corpus (r s = −0.74;p = 0.004) and HD-6 in the antrum (r s =−0.397; p = 0.045) was shown to be inversely correlated with serum vitamin D concentrations, while the absolute levels of HBD-3 and HD-6 expression were extremely low.The other AMPs investigated did not correlate with serum vitamin D levels.
Plataki et al. 2021 documented that fifty-two T2DM individuals (35.6%) were colonization by S. aureus and that a moderate inverse correlation is between LL-37 and 25(OH)D in S aureus nasal carriage (p = 0.011, coefficient = −0.392).However, in non-carriers T2DM, there is

Discussion
Diabetes mellitus is one of the main chronic non-communicable illnesses threatening people's health and life [30].Diabetic patients are characterized by impaired both innate and acquired immunity.AMPs are a connection between innate and acquired immune responses.In the host immune system, the phagocytic cells are considered the main sites for AMP expression where they exert antimicrobial activity against ingested pathogens [31].Several AMPs kill pathogens by disturbing the electrochemical balance across the lipid microbial membrane or by translocation across the membrane into the cytoplasm of bacteria to act on intracellular targets [32].In addition to direct antimicrobial activity, AMP can regulate the host immune response through various mechanisms involving stimulation of cytokine production and antigen (Ag) presentation 34].However, the association between these AMPs and T2DM complications needs to be cleared.T2DM is characterized by the presence of a low-grade inflammatory component.Metabolic inflammation is characterized by a moderate increase in cytokine production, particularly (IL)-6, IL-1, or TNF-α, which injures cellular insulin signalling, contributing to insulin resistance and diabetes [35].The primary physiological role of the resident microbiota is to act as a microbial barrier against microbial infections.Furthermore, the microbiota governs the synthesis of interleukins such as IL-12, determines Th1 and Th2 responses, and modulates the creation of antibacterial compounds such AMP.The presence of a healthy microbiome appears to be necessary for AMP synthesis.Bacteroides thetaiotaomicron appears to be one of the primary individual species driving this production [36].In addition, the gut microbiota affects the synthesis of defensins, LL-37, C-type lectins, ribonucleases, and S100 proteins in intestinal epithelial and Paneth cells, all of which kill or inactivate germs.This study centred on the significance of AMPs in T2DM and associated consequences.

The association of AMPs and advanced glycation end products (AGE)/hyperglycaemia
In T2DM patients, insulin resistance and the degree of glycaemic control are a vital variable.Four studies investigated the effect of LL-37 on AGE\glucose in patients with T2DM.One of them documented no significant correlation with HbA1c, whereas the other three documented a positive significant correlation with blood glucose\AGE and HbA1c [24][25]28].The differences in the results might be due to the type of the sample taken (either plasma or saliva) and/or the type of T2DM selected patients.Both α-defensins and HBD-1 were investigated in two different studies.Significant correlations were documented between the increased level of these AMPs and AGE, FBG, and glycaemic control [12,17].Also, HBD-2 was investigated in three studies, two of them documented a positive correlation with blood glucose and/or HbA1c [23,28], HBD-3 was studied in two studies and both of them documented a significant correlation with poor glycaemic control and AGE [12,25].Therefore, these AMPs may considered as immunodiagnostic markers used in DM diagnosis.
The relation between HbA1c and inflammation was previously described [37][38][39][40], and the immune activity is driven by poorly controlled hyperglycaemia [23].In diabetes, the levels of AGE are elevated [41].AGEs attach to specialized receptors called RAGE receptors.The activation of RAGE will activate NF-kB, which worsens inflammation in diabetes [42].It has been documented that the expression of defensins and LL-37 is induced by several various classes of nutrients [43].This expression may elucidate the association between LL-37/defensins and AGEs.The mRNA expression of LL-37 and HBD is immediately enhanced in several types of human cells by glucose.However, the expression of HBD-3 and proteins in epidermal keratinocytes will inhibit when treated with high glucose [44].This was confirmed by a study in which the expression of HBD-3 in diabetic rats did not enhance following the wounds [45].According to [46], in cultivating human keratinocytes in hyperglycaemic conditions, the constitutive expression of HBD-3 reduced both at mRNA and protein levels.The suppression of P38 mitogen-activated protein kinases (p38MAPK) signalling may be illustrated by this reduction, which resulted from increased advanced glycation end product (AGE) formation.In another in vitro study, it was documented that the levels of AMPs were reduced in the presence of high advanced glycation end products (AGEs) level even though AGE can induce a transient increase of P38 mitogen-activated protein kinases (p38MAPK) signalling [47].Furthermore, Pereira et al., 2013 have been found that both intrinsic glucose and insulin transcriptional activities are required for achieving optimal HBD-1 expression [48].These processes may illuminate the cause of decreased HBD level in DM patients.On the other hand, host defence peptides coordinate various immune functions which are crucial to maintain homeostasis.However, if AMP production exceeds the normal physiological range, it could contribute to undesired inflammation in response to local and systemic infections [49].
Age is considered an independent predictor of poor glycaemic control and T2DM complications [50].

AMPs and oral health complications
Periodontitis is considered as inflammatory disease, it occurs as result of bacteria that weaken the supportive tissues of teeth [22], and it involves both innate and acquired immune response.It was documented that the prevalence of periodontal disease was greater in T2DM patients compared to healthy adults.The state of glycaemic control in diabetes subjects is an essential determinant since the severity of gingival inflammation and periodontal destruction is shown in those with poor control [12].
AMPs (as a vital constituent of the innate immune response) are expressed in GCF and saliva.Studies have revealed that all human beta-defensins (HBD) are expressed more in non-inflamed oral tissues than in inflamed tissues; therefore, their expression in healthy tissues may help prevent the initial and/or progression of the disease [53].In periodontitis patients, AMP like HBD-4 is differentially regulated by bacterial pathogens, commensal organisms, and infection.They promote wound healing, angiogenesis, and boosting phagocytosis in addition to their antibacterial activity.In diabetics, tissue alterations caused by metabolic instabilities inhibit the ability of the host to deal with plaque pathogens, resulting in severe inflammation of the gingival tissue [54].Tissue protective actions decline as necrosis increases, worsening periodontal damage in diabetes individuals [55].
The results of the included studies in the current metaanalysis showed both increased level or decreased levels of certain types of AMPs expression which seems to be affected by glycaemic control and the stage or severity of the disease.It has been documented that in the early stages of inflammation (gingivitis), production of gingival HBD increases significantly but declines as the disease progresses (periodontitis) [55].Also, diabetes and periodontal disease have an impact on GCF's hBD-1 levels.The alterations in the levels of hBD-1 GCF may be attributed to the susceptibility of diabetics to periodontitis [22].Additionally, it has been documented that the gingival tissue of diabetic patients with periodontitis exerted overexpression of hCAP18/LL-37, hBD-2, and hBD-3, but did not appear to protect them from acquiring periodontitis [55].Therefore, these AMPs may be considered as immunodiagnostic markers used in periodontitis diagnosis.
Furthermore, a study has found that α-defensins and LL-37 are expressed in the junctional epithelium, and HBDs are expressed in oral and sulcular epithelia indicating that defensins have distinct functions in various locations of the periodontium [56,57].

AMPs and other complications
T2DM may cause serious health problems that influence both smaller and larger vessels, i.e. microvascular and macrovascular complications, respectively.The microvascular risks affect the renal system with persistent kidney failure (nephropathy) and nerve injury (neuropathy) increasing the possibility of diabetic foot ulcer and/or amputations.Additionally, retinopathy can be due to blindness, whereas macrovascular disorders (coronary heart failure, peripheral artery disease, and stroke) can cause blindness [58].The disruption of the body's vascular system, associated with a hyperglycaemic condition, is caused by impaired digestion of carbohydrates, protein, and electrolytes.Under this state, due to disproportionate glucose build-up in specific cells, lipid metabolism malfunction, and better reactive growth, the retina, glomerulus, middle, and peripheral nerves are all pretentious endothelial cells [59].
Diabetes is associated with a low-grade and chronic inflammatory condition characterized by unusual production of pro-inflammatory cytokines, but it has been previously shown that pro-inflammatory conditions through hyperglycaemia promote the production of neutrophil extracellular traps (NETs) [60], and HNP 1-3 are also implicated in the generation of NET [61].As a result of frequent degranulation of enrolled neutrophils from the skin after infections, the level of HNP1-3 might be elevated.The highest human α-defensins concentrations were revealed in subjects with neuropathic or nephropathic and cardiovascular diseases.This may be due to decreased renal functions in degraded the peptides in nephropathic patients [62].Human alpha-defensin 1-3 enhances the deposition of LDL in the vessels, inhibits fibrinolytic activity on the surfaces of vascular cell, and deposits in the intima of atherosclerotic plaques.HNP 1-3 may have clinical consequences in diabetic individuals with hypercholesterolemia or vascular dysfunction [16,63].As a result, these AMPs may be regarded immunodiagnostic indicators, playing an essential role in the prediction of T2DM complications.
In T2DM patients with foot ulcers, HbA1c and FPG levels were significantly higher than the reference values.AGE disposal is important in both microvascular and macrovascular lesions.Furthermore, AGEs can cause the basement membrane to shrink, increasing oxidative stress and stimulating inflammation [64].As a result, the skin becomes more sensitive and weak, preventing wound healing.
AMPs may have a therapeutic function in DM complications.In the instance of DFU, AMPs have been shown to have a good effect on eliminating bacteria that cause diabetic foot infection.In addition, certain AMPs have immunomodulatory and angiogenic characteristics, neutralize bacterial toxins, increase cell proliferation and migration, block pro-inflammatory responses, and biofilm formation processes, and promote wound healing.In a study by Miranda et al. (2023), LL-37 cream was found to improve wound healing and reduce IL-1α, TNF-α, and aerobic bacteria colonization in DFU with mild infection.However, it did not decrease IL-1α, TNF-α, or the number of aerobic bacteria colonization [65].

AMP and bacterial carriage and/or susceptibility to infection
It has been shown that AMPs are essential for controlling infection owing to their various immunomodulatory actions that stimulate and/or enhance immune responses [66].The two studies included in the current meta-analysis demonstrated greater levels of LL-37 in S aureus carrier patients and PTB patients in comparison with healthy individuals, highlighting the relevance of these AMPs during bacterial infection and carriage, especially in T2DM patients.Because their immunological responses were dysregulated, it has been established that mice with LL-37 deficiency display greater susceptibility to bacterial infections of the skin [67], the intestinal tract [68], the urinary tract [69], the cornea [70], and lung [71], revealing the crucial role of AMPs in host defence.Also, the role of AMPs in host immune defences has been shown against tuberculosis (TB) [72].It has been suggested that AMPs are attractive therapeutic candidates for anti-mycobacterial treatment [73].
It has been proven that AMPs have an essential therapeutic function in several illnesses and have the potential to combat numerous infections that arise in a wide range of tissues.In TB, AMPs play an important role in successfully removing tuberculosis-causing bacteria.In the early stages of infection, AMPs are directly responsible for bacterial death.In later phases, it modulates the release of anti-inflammatory and pro-inflammatory cytokines [19].

Vit D contribution to AMP production in T2DM
It was discovered that 25-hydroxy vitamin D may help epithelial hosts defend against bacterial infection by producing AMP.However, Plataki et al. 2021 discovered a modest negative link between LL-37 and Vitamin D in T2DM patients with S aureus nasal carriage, but a large positive relationship between blood vitamin D and LL-37 in non-carriers.Linn et al. 2023 found that HBD-3 expression was inversely linked with blood vitamin D concentrations.These findings may emphasize the complications of diabetes.Vitamin D deficiency has been linked to insulin resistance, reduced insulin release, and type 2 diabetes in both epidemiological and experimental studies.Furthermore, vitamin D deficiency is associated with elevated inflammatory markers, and polymorphisms in vitamin D-related genes may lead to poor glycaemic control and T2DM.Vitamin D has been shown to reduce inflammation by reducing the generation of pro-inflammatory cytokines through the NF-kB pathway [26].

Conclusion
According to the involved studies, hyperglycaemia in T2DM changes the expression of specific types of AMPs and increases inflammation, which may be associated with the development of long-term complications, increased susceptibility to bacterial infection, and impaired wound healing.A dysregulated immune response in T2DM patients may result in increased or reduced expression of AMPs.Nonetheless, additional studies are needed to determine the specific function of AMPs in the onset and progression of diabetes complications.Increased AMP expression may indicate an excessive inflammatory response, whereas lower expression may indicate an inadequate immune response or AMP degradation by cysteine proteases generated by bacterial pathogens to penetrate the immune response.

FPG Fasting plasma glucose NF-kB
Nuclear factor kappa GP Gingival periodontitis LTB Latent tuberculosis

Fig. 1
Fig. 1 PRISMA 2020 flow chart of literature selection process for new systematic reviews infection Significantly higher levels of Circulating HNP1-3, HBD-2, and LL-37 in DM-PTB LL-37, HBD-2, and HNP 1-3 had a positive association with HbA1c and FBG levels had a higher gene expression of HNP a significant relationship between serum levels of LL-37 and vitamin D (p < 0.001, coefficient = 0.48).

Table 1
Newcastle Ottawa scale (for case-control studies).One star (*) is awarded for each item in the selection and exposure, and two stars (**) can be given for

Table 2
Quality Evaluation of The Cross-Sectional Studies via Modified Newcastle Ottawa scale.A maximum of one star (*) can be given to research for each numbered item in the Comparability categories.For the Selection category, up to five stars (** stars for the Ascertainment of the Exposure) may be awarded, and for the Outcome category, up to *** stars (two stars for the Assessment of Outcome) may be provided

Table 5
Types of AMPs in the included studies and their association with T2DM complications Susceptibility to bacterial infection T2DM had Low serum vit D and LL-37 levels Circulatory LL-37 levels were greater in S. aureus nasal carriers than in non-carriers LL-37 and 25(OH)D had a positive correlation in the non-carrier group but an inverse association in the carrier group