Topical Application of Glucagon-like Peptide-1 Receptor Agonists and Dipeptidyl Peptidase-4 Inhibitors in a Human Ex Vivo Wound Healing Model

Background: The unpredictability of scarring following surgery poses a challenge for plastic surgeons and raises concern for the psychological well-being of patients. Glucagon-like Peptide-1 receptor agonists (GLP-1RAs) and Dipeptidyl Peptidase-4 inhibitors (DPP4i) are both anti-diabetic medications that reduce glucagon and increase insulin production in patients with Type II Diabetes Mellitus (TIIDM). DPP4 inhibition leads to an upregulation of endogenous GLP-1, which reduces glucagon and increases endogenous insulin production. These medications have recently been associated with improved wound healing and cutaneous fibrosis in humans, animals, and in vitro settings. GLP-1 also has a significant impact on adipocyte metabolism. Specifically, GLP-1 receptor activation promotes pre-adipocyte differentiation and inhibits apoptosis. Adipose-derived stem cells (ADSCs) and pre-adipocytes, which are both found in dermal white adipose tissue (dWAT), are pivotal in promoting wound healing. The role of dWAT mainly depends on the nature of environmental stress signaling and can promote cellular differentiation into either a myofibroblast- or adipocyte-like cell. However, the influence of GLP-1 on dWAT, wound healing, and fibrotic signaling is poorly defined. We hypothesize that GLP-1 regulates fibrotic and adipogenic pathways in skin tissue to promote a pro-regenerative environment. Thus, this study aims to investigate the molecular and cellular effects of GLP-1 signaling on dermal fibrosis and tissue regeneration.

Specific Aim 1: Determine the influence of GLP-1 upregulation on fibrotic signaling (dermal tissue), which is critical for understanding the potential extensions of its therapeutic applications outside of glycemic control in type II diabetes. Namely, patients suffering from fibrotic skin disorders due to autoimmune diseases or hypertrophic scarring may particularly benefit from the outcomes of this investigation.

Specific Aim 2: Determine the effect of GLP-1 upregulation on myofibroblast transformation and adipocyte metabolism. The study will assess topical DPP4i and GLP-1RA administration to fibrotic skin and examine pro-adipogenic signaling. By targeting diseased fibrotic tissue to promote adipogenesis, we hope to alter the extracellular matrix environment to restore normal tissue architecture. This study presents a novel approach to improving subcutaneous fibrosis and wound healing.