Exendin-4, a glucagon-like peptide-1 analogue, accelerates diabetic wound healing

Jun-Neng Roan; Han-Ni Cheng; Chao-Chung Young; Chi-Ju Lee; Ming-Long Yeh; Chwan-Yau Luo; Yau-Sheng Tsai; Chen-Fuh Lam

doi:10.1016/j.jss.2016.09.024

Exendin-4, a glucagon-like peptide-1 analogue, accelerates diabetic wound healing

J Surg Res. 2017 Feb:208:93-103. doi: 10.1016/j.jss.2016.09.024. Epub 2016 Sep 17.

Authors

Jun-Neng Roan¹, Han-Ni Cheng², Chao-Chung Young³, Chi-Ju Lee⁴, Ming-Long Yeh⁵, Chwan-Yau Luo⁶, Yau-Sheng Tsai⁷, Chen-Fuh Lam⁸

Affiliations

¹ Institute of Clinical Medicine, National Cheng Kung University Hospital, College of Medicine, National Cheng Kung University, Tainan, Taiwan; Division of Cardiovascular Surgery, Department of Surgery, National Cheng Kung University Hospital, College of Medicine, National Cheng Kung University, Tainan, Taiwan.
² Department of Anesthesiology, National Cheng Kung University Hospital, College of Medicine, National Cheng Kung University, Tainan, Taiwan.
³ Department of Dermatology, National Cheng Kung University Hospital, College of Medicine, National Cheng Kung University, Tainan, Taiwan.
⁴ Department of Biomedical Engineering, National Cheng Kung University, Tainan, Taiwan.
⁵ Department of Biomedical Engineering, National Cheng Kung University, Tainan, Taiwan; Medical Device Innovation Center, National Cheng Kung University, Tainan, Taiwan.
⁶ Division of Cardiovascular Surgery, Department of Surgery, National Cheng Kung University Hospital, College of Medicine, National Cheng Kung University, Tainan, Taiwan.
⁷ Institute of Clinical Medicine, National Cheng Kung University Hospital, College of Medicine, National Cheng Kung University, Tainan, Taiwan.
⁸ Department of Anesthesiology, Buddhist Tzu-Chi General Hospital and Tzu-Chi University School of Medicine, Hualien, Taiwan; Department of Anesthesiology, Taipei Medical University Hospital and School of Medicine, College of Medicine, Taipei Medical University, Taipei, Taiwan. Electronic address: lamcf@mail.ncku.edu.tw.

PMID: 27993221
DOI: 10.1016/j.jss.2016.09.024

Abstract

Background: Diabetes disregulates inflammatory responses and impairs vascular function in wounds. Glucagon-like peptide-1 receptor (Glp-1R) agonists are hypoglycemic agents with pleiotropic vascular protective and anti-inflammatory effects. The therapeutic potential of a Glp-1 analogue in a diabetic rat model of excisional wound injury was investigated.

Materials and methods: Excisional wounds were created on the dorsum of streptozotocin-induced diabetic rats, which received placebo or Glp-1 analogue exendin-4 (Ex4; 0.5 μg/kg/d, i.p.) for 2 wk. The final-to-initial wound area ratio was measured for 14 d. Levels of superoxide anions and proinflammatory cytokines in the wound were determined. Angiogenesis was assessed using the Matrigel assay. Expression levels of proangiogenic factors and extracellular matrix proteins were measured.

Results: Ex4 restored wound closure in diabetic rats and significantly suppressed the generation of superoxide anions and interleukin-6 in wounds. The number of circulating endothelial progenitor (CD34⁺/KDR⁺) cells increased significantly in Ex4-treated diabetic rats, which also showed increased capillary tube formation. Protein levels of vascular endothelial growth factor receptor-2, phosphorylated endothelial nitric oxide synthase, matrix metalloproteinase-2, and transforming growth factor-β were increased in diabetic rats receiving Ex4 therapy. Ex4-enhanced vascularity, dermal regeneration, and epidermal regeneration, while it decreased hemorrhaging and increased the number of proliferative cells in the dermis.

Conclusions: Ex4 accelerated excisional wound healing in subjects with diabetes. Glp-1R activation attenuates inflammatory response and enhances angiogenesis during the early proliferation phase of wound healing in diabetic subjects, while it enhances transforming growth factor-β/matrix metalloproteinase-mediated regeneration during the maturation phase. These results suggest that Ex4 could be used as a standard hypoglycemic agent in diabetic patients with wound injury.

Keywords: Diabetes; Endothelial progenitor cells; Exendin-4; Glucagon-like peptide; Wound healing.

MeSH terms

Animals
Diabetes Mellitus, Experimental / drug therapy*
Drug Evaluation, Preclinical
Exenatide
Glucagon-Like Peptide 1 / analogs & derivatives
Hypoglycemic Agents / pharmacology
Hypoglycemic Agents / therapeutic use*
Male
Neovascularization, Physiologic / drug effects
Peptides / pharmacology
Peptides / therapeutic use*
Rats, Sprague-Dawley
Venoms / pharmacology
Venoms / therapeutic use*
Wound Healing / drug effects*

Substances

Hypoglycemic Agents
Peptides
Venoms
Glucagon-Like Peptide 1
Exenatide