Research progress of dipeptidyl peptidase 4 inhibitors on healing of chronic diabetic foot ulcers_Chinese Journal of Reparative and Reconstructive Surgery

Authors：

GAO Yunyi , LIANG Yujie ,  RAN Xingwu

Diabetic Foot Care Center, Department of Endocrinology and Metabolism, West China Hospital, Sichuan University, Chengdu Sichuan, 610041, P.R.China;

Corresponding author：

RAN Xingwu, Email: ranxingwu@163.com

Keywords：

Dipeptidyl peptidase 4 inhibitor; diabetic foot; ulcer; wound healing

DOI：

10.7507/1002-1892.201802034

Video：

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Objective To review the effect of dipeptidyl peptidase 4 (DPP-4) inhibitors on the wound healing and its mechanisms in chronic diabetic foot ulcers. Methods The latest literature concerning DPP-4 inhibitors for chronic diabetic foot ulcers was extensively reviewed, as well as the potential benefit and mechanism of DPP-4 inhibitors on wound healing of diabetic foot ulcers was analyzed thoroughly. Results DPP-4 inhibitors can accelerated the ulcer healing. The mechanisms probably include inhibiting the expression of the matrix metalloproteinase (MMP) and restoring the balance of the wound MMP and the tissue inhibitors of MMP; promoting recruitment of endothelial progenitor cells and augmenting angiogenesis; optimizing extracellular matrix construction and the immune response to persistent hypoxia in chronic diabetes wounds, and so on. At present, clinical researches show that DPP-4 inhibitors may be considered as an adjuvant treatment for chronic diabetic foot ulcers. Conclusion DPP-4 inhibitors show promise in the local wound healing of chronic diabetic foot ulcers. However, more strictly designed, adequately powered, long-term follow-up, and high-quality randomized control trials are needed to further verify their efficacy and safety for chronic diabetic foot ulcers.

Citation： GAO Yunyi, LIANG Yujie, RAN Xingwu. Research progress of dipeptidyl peptidase 4 inhibitors on healing of chronic diabetic foot ulcers. Chinese Journal of Reparative and Reconstructive Surgery, 2018, 32(5): 630-633. doi: 10.7507/1002-1892.201802034 Copy

1.	Jiang Y, Wang X, Xia L, et al. A cohort study of diabetic patients and diabetic foot ulceration patients in China. Wound Repair Regen, 2015, 23(2): 222-230.
2.	冉兴无, 郑月宏. 加强多学科协作, 提高糖尿病缺血性足溃疡的治愈率. 中华糖尿病杂志, 2016, 8(7): 385-387.
3.	Saboo A, Rathnayake A, Vangaveti VN, et al. Wound healing effects of dipeptidyl peptidase-4 inhibitors: An emerging concept in management of diabetic foot ulcer-A review. Diabetes Metab Syndr, 2016, 10(2): 113-119.
4.	Salazar JJ, Ennis WJ, Koh TJ. Diabetes medications: Impact on inflammation and wound healing. J Diabetes Complications, 2016, 30(4): 746-752.
5.	Scheen AJ. A review of gliptins for 2014. Expert Opin Pharmacother, 2015, 16(1): 43-62.
6.	Baticic Pucar L, Pernjak Pugel E, Detel D, et al. Involvement of DPP Ⅳ/CD26 in cutaneous wound healing process in mice. Wound Repair Regen, 2017, 25(1): 25-40.
7.	Marfella R, Sasso FC, Rizzo MR, et al. Dipeptidyl peptidase 4 inhibition may facilitate healing of chronic foot ulcers in patients with type 2 diabetes. Exp Diabetes Res, 2012, 2012: 892706.
8.	Long M, Cai L, Li W, et al. DPP-4 inhibitors improve diabetic wound healing via direct and indirect promotion of epithelial-mesenchymal transition and reduction of scarring. Diabetes, 2017, 67(3): 518-531.
9.	Hu MS, Longaker MT. Dipeptidyl peptidase-4, wound healing, scarring, and fibrosis. Plast Reconstr Surg, 2016, 138(5): 1026-1031.
10.	Schürmann C, Linke A, Engelmann-Pilger K, et al. The dipeptidyl peptidase-4 inhibitor linagliptin attenuates inflammation and accelerates epithelialization in wounds of diabetic ob/ob mice. J Pharmacol Exp Ther, 2012, 342(1): 71-80.
11.	Berlanga-Acosta J, Schultz GS, López-Mola E, et al. Glucose toxic effects on granulation tissue productive cells: the diabetics’ impaired healing. Biomed Res Int, 2013, 2013: 256043.
12.	Liu Y, Min D, Bolton T, et al. Increased matrix metalloproteinase-9 predicts poor wound healing in diabetic foot ulcers. Diabetes Care, 2009, 32(1): 117-119.
13.	Li Z, Guo S, Yao F, et al. Increased ratio of serum matrix metalloproteinase-9 against TIMP-1 predicts poor wound healing in diabetic foot ulcers. J Diabetes Complications, 2013, 27(4): 380-382.
14.	Ta NN, Li Y, Schuyler CA, et al. DPP-4 (CD26) inhibitor alogliptin inhibits TLR4-mediated ERK activation and ERK-dependent MMP-1 expression by U937 histiocytes. Atherosclerosis, 2010, 213(2): 429-435.
15.	Proost P, Struyf S, Schols D, et al. Processing by CD26/dipeptidyl-peptidase Ⅳreduces the chemotactic and anti-HIV-1 activity of stromal-cell-derived factor-1alpha. FEBS Lett, 1998, 432(1-2): 73-76.
16.	Fadini GP, Boscaro E, Albiero M, et al. The oral dipeptidyl peptidase-4 inhibitor sitagliptin increases circulating endothelial progenitor cells in patients with type 2 diabetes: possible role of stromal-derived factor-1alpha. Diabetes Care, 2010, 33(7): 1607-1609.
17.	Negro R, Greco EL, Greco G. Active stromal cell-derived factor 1α and endothelial progenitor cells are equally increased by alogliptin in good and poor diabetes control. Clin Med Insights Endocrinol Diabetes, 2017, 10: 1179551417743980.
18.	Dei Cas A, Spigoni V, Cito M, et al. Vildagliptin, but not glibenclamide, increases circulating endothelial progenitor cell number: a 12-month randomized controlled trial in patients with type 2 diabetes. Cardiovasc Diabetol, 2017, 16(1): 27.
19.	Fadini GP, Bonora BM, Cappellari R, et al. Acute effects of linagliptin on progenitor cells, monocyte phenotypes, and soluble mediators in type 2 diabetes. J Clin Endocrinol Metab, 2016, 101(2): 748-756.
20.	Li F, Chen J, Leng F, et al. Effect of saxagliptin on circulating endothelial progenitor cells and endothelial function in newly diagnosed type 2 diabetic patients. Exp Clin Endocrinol Diabetes, 2017, 125(6): 400-407.
21.	Huang CY, Shih CM, Tsao NW, et al. Dipeptidyl peptidase-4 inhibitor improves neovascularization by increasing circulating endothelial progenitor cells. Br J Pharmacol, 2012, 167(7): 1506-1519.
22.	Marchetti C, Di Carlo A, Facchiano F, et al. High mobility group box 1 is a novel substrate of dipeptidyl peptidase-Ⅳ. Diabetologia, 2012, 55(1): 236-244.
23.	Chavakis E, Hain A, Vinci M, et al. High-mobility group box 1 activates integrin-dependent homing of endothelial progenitor cells. Circ Res, 2007, 100(2): 204-212.
24.	De Mori R, Straino S, Di Carlo A, et al. Multiple effects of high mobility group box protein 1 in skeletal muscle regeneration. Arterioscler Thromb Vasc Biol, 2007, 27(11): 2377-2383.
25.	Mitola S, Belleri M, Urbinati C, et al. Cutting edge: extracellular high mobility group box-1 protein is a proangiogenic cytokine. J Immunol, 2006, 176(1): 12-15.
26.	Schlueter C, Weber H, Meyer B, et al. Angiogenetic signaling through hypoxia: HMGB1: an angiogenetic switch molecule. Am J Pathol, 2005, 166(4): 1259-1263.
27.	Straino S, Di Carlo A, Mangoni A, et al. High-mobility group box 1 protein in human and murine skin: involvement in wound healing. J Invest Dermatol, 2008, 128(6): 1545-1553.
28.	Stone RC, Pastar I, Ojeh N, et al. Epithelial-mesenchymal transition in tissue repair and fibrosis. Cell Tissue Res, 2016, 365(3): 495-506.

1. Jiang Y, Wang X, Xia L, et al. A cohort study of diabetic patients and diabetic foot ulceration patients in China. Wound Repair Regen, 2015, 23(2): 222-230.
2. 冉兴无, 郑月宏. 加强多学科协作, 提高糖尿病缺血性足溃疡的治愈率. 中华糖尿病杂志, 2016, 8(7): 385-387.
3. Saboo A, Rathnayake A, Vangaveti VN, et al. Wound healing effects of dipeptidyl peptidase-4 inhibitors: An emerging concept in management of diabetic foot ulcer-A review. Diabetes Metab Syndr, 2016, 10(2): 113-119.
4. Salazar JJ, Ennis WJ, Koh TJ. Diabetes medications: Impact on inflammation and wound healing. J Diabetes Complications, 2016, 30(4): 746-752.
5. Scheen AJ. A review of gliptins for 2014. Expert Opin Pharmacother, 2015, 16(1): 43-62.
6. Baticic Pucar L, Pernjak Pugel E, Detel D, et al. Involvement of DPP Ⅳ/CD26 in cutaneous wound healing process in mice. Wound Repair Regen, 2017, 25(1): 25-40.
7. Marfella R, Sasso FC, Rizzo MR, et al. Dipeptidyl peptidase 4 inhibition may facilitate healing of chronic foot ulcers in patients with type 2 diabetes. Exp Diabetes Res, 2012, 2012: 892706.
8. Long M, Cai L, Li W, et al. DPP-4 inhibitors improve diabetic wound healing via direct and indirect promotion of epithelial-mesenchymal transition and reduction of scarring. Diabetes, 2017, 67(3): 518-531.
9. Hu MS, Longaker MT. Dipeptidyl peptidase-4, wound healing, scarring, and fibrosis. Plast Reconstr Surg, 2016, 138(5): 1026-1031.
10. Schürmann C, Linke A, Engelmann-Pilger K, et al. The dipeptidyl peptidase-4 inhibitor linagliptin attenuates inflammation and accelerates epithelialization in wounds of diabetic ob/ob mice. J Pharmacol Exp Ther, 2012, 342(1): 71-80.
11. Berlanga-Acosta J, Schultz GS, López-Mola E, et al. Glucose toxic effects on granulation tissue productive cells: the diabetics’ impaired healing. Biomed Res Int, 2013, 2013: 256043.
12. Liu Y, Min D, Bolton T, et al. Increased matrix metalloproteinase-9 predicts poor wound healing in diabetic foot ulcers. Diabetes Care, 2009, 32(1): 117-119.
13. Li Z, Guo S, Yao F, et al. Increased ratio of serum matrix metalloproteinase-9 against TIMP-1 predicts poor wound healing in diabetic foot ulcers. J Diabetes Complications, 2013, 27(4): 380-382.
14. Ta NN, Li Y, Schuyler CA, et al. DPP-4 (CD26) inhibitor alogliptin inhibits TLR4-mediated ERK activation and ERK-dependent MMP-1 expression by U937 histiocytes. Atherosclerosis, 2010, 213(2): 429-435.
15. Proost P, Struyf S, Schols D, et al. Processing by CD26/dipeptidyl-peptidase Ⅳreduces the chemotactic and anti-HIV-1 activity of stromal-cell-derived factor-1alpha. FEBS Lett, 1998, 432(1-2): 73-76.
16. Fadini GP, Boscaro E, Albiero M, et al. The oral dipeptidyl peptidase-4 inhibitor sitagliptin increases circulating endothelial progenitor cells in patients with type 2 diabetes: possible role of stromal-derived factor-1alpha. Diabetes Care, 2010, 33(7): 1607-1609.
17. Negro R, Greco EL, Greco G. Active stromal cell-derived factor 1α and endothelial progenitor cells are equally increased by alogliptin in good and poor diabetes control. Clin Med Insights Endocrinol Diabetes, 2017, 10: 1179551417743980.
18. Dei Cas A, Spigoni V, Cito M, et al. Vildagliptin, but not glibenclamide, increases circulating endothelial progenitor cell number: a 12-month randomized controlled trial in patients with type 2 diabetes. Cardiovasc Diabetol, 2017, 16(1): 27.
19. Fadini GP, Bonora BM, Cappellari R, et al. Acute effects of linagliptin on progenitor cells, monocyte phenotypes, and soluble mediators in type 2 diabetes. J Clin Endocrinol Metab, 2016, 101(2): 748-756.
20. Li F, Chen J, Leng F, et al. Effect of saxagliptin on circulating endothelial progenitor cells and endothelial function in newly diagnosed type 2 diabetic patients. Exp Clin Endocrinol Diabetes, 2017, 125(6): 400-407.
21. Huang CY, Shih CM, Tsao NW, et al. Dipeptidyl peptidase-4 inhibitor improves neovascularization by increasing circulating endothelial progenitor cells. Br J Pharmacol, 2012, 167(7): 1506-1519.
22. Marchetti C, Di Carlo A, Facchiano F, et al. High mobility group box 1 is a novel substrate of dipeptidyl peptidase-Ⅳ. Diabetologia, 2012, 55(1): 236-244.
23. Chavakis E, Hain A, Vinci M, et al. High-mobility group box 1 activates integrin-dependent homing of endothelial progenitor cells. Circ Res, 2007, 100(2): 204-212.
24. De Mori R, Straino S, Di Carlo A, et al. Multiple effects of high mobility group box protein 1 in skeletal muscle regeneration. Arterioscler Thromb Vasc Biol, 2007, 27(11): 2377-2383.
25. Mitola S, Belleri M, Urbinati C, et al. Cutting edge: extracellular high mobility group box-1 protein is a proangiogenic cytokine. J Immunol, 2006, 176(1): 12-15.
26. Schlueter C, Weber H, Meyer B, et al. Angiogenetic signaling through hypoxia: HMGB1: an angiogenetic switch molecule. Am J Pathol, 2005, 166(4): 1259-1263.
27. Straino S, Di Carlo A, Mangoni A, et al. High-mobility group box 1 protein in human and murine skin: involvement in wound healing. J Invest Dermatol, 2008, 128(6): 1545-1553.
28. Stone RC, Pastar I, Ojeh N, et al. Epithelial-mesenchymal transition in tissue repair and fibrosis. Cell Tissue Res, 2016, 365(3): 495-506.

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