Adiponectin as a therapeutic target for diabetic foot ulcer

Table 1 Adiponectin levels in patients with diabetic foot ulcers: A summary of published studies

No.	Ref.	Country	Study objective	Study design and sample size	Results	Adiponectin levels (ng/ mL)				Conclusion
						Non-Diabetic	Diabetic without FUs	DFU	P value
1	Tuttolomondo et al[203], 2010	Italy	To investigate the plasma levels of adiponectin, resistin and IL-6 in subjects with diabetic foot in comparison with subjects without foot complication	Case-control; sample size: 34 patients with type 2 DM with FU and 37 patients with type 2 DM without FUs	The patients with DFUs exhibited higher CRP, HbA1c, lipid profile, IL-6, resistin and lower levels of adiponectin; DFU patients have lower median; plasma levels of adiponectin; patients with foot ulcers had a longer duration of DM, higher percentage was associated with nephropathy, peripheral artery diseases, ischemic heart diseases, transient ischemic attacks or stroke	NA	8.48 × 103 (5.15 × 103-12.87 × 103)1	7.145 × 103 (4.470 × 103-12.170 × 103)1	0.022	Adiponectin levels are negatively correlated with the duration of diabetes and the development of DFUs
2	Zubair et al[81], 2012	India	To investigate the association between inflammation and acute foot syndrome	Case-control; sample size: 162 diabetics with FUs & 162 diabetics without FUs	Adiponectin levels were lower in DFU patients than in subjects without DFU; multiple linear regression analysis showed a significant negative correlation between adiponectin levels and DFU (R2 = -0.0189)	NA	13.4 (12.1-14.2)1	8.4 (7.1-9.2)1	< 0.0001	Diabetic subjects with various grades of diabetic foot ulcer showed a higher IL-6, hsCRP, TNF-α, and lower adiponectin plasma levels in comparison with diabetes without foot ulcer, independent of the concomitant infections
3	Ahmad et al[82], 2012	India	To evaluate plasma levels of Cathepsin D, adiponectin, TNF-α, IL-6, and hsCRP in subjects with diabetic foot in comparison with subjects without foot complications	Prospective cohort multicentric hospital-based study; sample size: 211 diabetics with FUs, 208 diabetics without FUs	The median levels of adiponectin were lower in patients with DFUs; adiponectin plasma levels were found to be negatively correlated with various cardiovascular risk factors, including hypertension, dyslipidemia, and microvascular complications such as neuropathy, retinopathy, nephropathy, and PAD; this was found through both multiple linear regression analysis and forward stepwise regression analysis	NA	13.3 (12.1-14.2)1	8.5 (7.1-9.5)1	< 0.0001	Low plasma adiponectin is a predictor for DFUs; the study suggests that low levels of adiponectin in diabetic patients with foot ulcers could be linked to the development of foot ulcers through microvascular and inflammatory mechanisms. The findings also indicate that adiponectin may play a role in inhibiting the expression of adhesion molecules on endothelial cells, which are involved in the inflammatory vascular response
4	Dhamodharan et al[204], 2015	India	To investigate the genetic association of IL-6, TNF-α, and SDF-1 polymorphisms with serum cytokine, adiponectin, leptin and hsCRP levels in diabetic foot ulcers	Case-control; sample size: A total of 515 subjects were divided into four study groups: Group-I (NGT)/control; n = 106), group-II known T2DM without DFU (T2DM; n = 139); group-III T2DM with neuropathic DFU (DFU-DN; n = 191); group-IV T2DM with PVD (DFU-PVD; n = 79)	The levels of adiponectin were significantly lower in the diabetic groups (T2DM, DFU-DN, and DFU-PVD) compared to the NGT group	536.0 (0.1-1787.0)2	528.6 (6.2-1255.0)2	524.0 (63.3-1641.0)2 in DFU+ DN; 453.5 (164.9-1078.0)2 in DFU + PVD	< 0.05	Low adiponectin levels can be a biomarker of DFUs; SNPs in cytokine/chemokine genes are useful biomarkers for DFU and can help predict the risk of developing DFU
5	Viswanathan et al[205], 2018	India	To examine the involvement of IL-6, TNF-α, and SDF-1) polymorphisms in determining the susceptibility to foot microbial infection, grade of the ulcer) and treatment-outcome; (Debridement vs amputation) in DFU subjects and further, the effect of these SNPs on serum cytokine levels and biomarkers such as leptin, adiponectin, CRP and HOMA-IR	Cross-sectional; sample size: 270 DFU subjects	Data on adiponectin levels are not reported	NA	NA	NA	NA	Screening for SNPs in TNF-α, SDF-1, and IL-6; among DFU subjects would help in identifying high risk individuals and might aid in better patient care
6	Anguiano-Hernandez et al[206], 2019	México	To assess the modification in adiponectin, HIF-1α, NF-κB, IGFBP-3, VEGF and adiponectin in diabetic foot ulcers treated with hyperbaric oxygen	Study design: Not specified; sample size: 17 ambulatory patients and one hospitalized; patient with DFUs; 15 were males & 3 females; 17 T2DM and 1 T1DM; grade 3 and 4 on Wagner scale	Adiponectin levels increase after therapy	NA	NA	-14943 ± 79152 (before therapy); -17281 ± 79622 (after therapy)	0.035	The study found that while treatment increased adiponectin levels, the increase was not significant; however, all patients showed an increase in angiogenesis and fibrosis and a decrease in ulcer size and infection signs after undergoing HBO2 therapy. The results suggest that HBO2 stimulates the expression of IGFBP-3, NF-κB, and HIF-1α and modulates the inflammatory response related to hypoxia
7	Vangaveti et al[207], 2022	Australia	To determine vildagliptin’s effect on inflammatory markers and wound healing in patients with type 2 diabetic foot ulcer	Prospective, randomized, double-blind, placebo controlled, single-centre study; sample size: 50 participants; 25 were assigned to the placebo and 25 to the treatment group	Vildagliptin treatment led to significant improvements in key health markers, including reduced HbA1c, hematocrit, total cholesterol, LDL cholesterol, and total/HDL cholesterol ratio compared to the placebo group. Additionally, vildagliptin demonstrated a protective effect on DFU wound healing	NA	NA	11822 ± 2584.03; Placebo; following; treatment 13138 ± 26712	1.0	The vildagliptin treatment in DFU patients improve wound healing with an associated reduction in some inflammatory biomarkers and a non-significant increase in adiponectin

¹Data presented as median and interquartile (lower and upper quartile).

²Data presented as mean ± SD.

³Data presented as mean ± SEM.

NA: Not available; DFU: Diabetic foot ulcer; NGT: Normal glucose tolerance; DN: Diabetic neuropathy; PAD: Peripheral artery disease; PVD: Peripheral vascular disease; CRP: C-Reactive protein; hsCRP: High-sensitivity C-reactive protein; HIF-1α: Hypoxia-inducible factor-1α; NF-κB: Nuclear factor-kappa B; IGFBP-3: Insulin-like growth factor-binding protein-3; VEGF: Vascular endothelial growth factor; HBO₂: Hyperbaric oxygen; IL-6: Interleukin-6; TNF-α: Tumour necrosis factor-alpha; SNPs: Single nucleotide polymorphisms; SDF-1: Stromal cell-derived factor; VEGF: Vascular endothelial growth factor; LDL: Low-density lipoprotein; HDL: High-density lipoprotein.