Gremlin-1 and Wagner Classification: Potential Biomarker for Amputation in Diabetic Foot Patients

Diabetic foot (DA), a microvascular complication of diabetes mellitus (DM), is a significant cause of morbidity and mortality. While the prevalence of diabetic foot is reported to be between 4 and 10%, the lifetime risk of developing DA in a person diagnosed with diabetes is as high as 25%. Diabetic foot wounds lead to deterioration of the patient's quality of life, loss of work power, psychosocial trauma, and increased health care costs. These are the most common causes of hospitalization and longest hospital stay in diabetic patients. 50-70% of non-traumatic foot amputations are performed in diabetic patients. It is known that different mechanisms such as neuropathic degeneration (autonomic, motor, sensory), vasculopathy (micro and macroangiopathy), poorly controlled infection, and poor wound healing due to impaired collagen production are together in the etiopathogenesis of DA. In addition, opsonization and phagocytosis processes are reduced in diabetic patients. The decrease in chemotaxis and proliferation of cells responsible for inflammation and especially macrophages that stimulate wound healing by secreting various growth factors is one of the most important factors that delay wound healing. The characteristic feature in a diabetic foot case is a prolonged acute phase reaction. The first step in managing diabetic foot wounds is the evaluation, grading, and classification of the ulcer. There is no commonly agreed classification to be used in diabetic feet. Wagner-Meggit classification, San Antonio classification, University of Texas classification, PEDIS staging are a few of them. Each diabetic foot council uses its own appropriate classification. DA classification is an important guide in deciding on the treatment method and proceeding to amputation. Acute phase reactants such as C-reactive protein (CRP), white blood cell (WBC), neutrophil count, and sedimentation rate (ESR) are widely used as laboratory markers of progressing to amputation in DA, but these are insufficient to reflect the severity of DA disease. In addition, since no systemic effects can be seen in non-infected DA ulcers, an increase in acute-phase reactants may not be detected. For these reasons, new marker studies are needed to predict the prognosis of diabetic feet and determine the severity of the disease. Based on this need, investigators planned to examine the gremlin-1 level in DA foot cases in this study. Gremlin-1 is an extracellular antagonist of bone morphogenetic proteins (BMP) and works by directly neutralizing its ligands and inhibiting BMP signaling. BMP, a subgroup of TGF-B (transforming growth factor), an important pro-fibrinogenic cytokine, is known to have an anti-fibrinogenic role in various organs. BMP and its antagonist gremlin are developmental genes that regulate morphogenesis, and their role in embryogenesis has been clearly demonstrated in limb development, neural crest differentiation, and metanephric kidney organogenesis. Gremlin is silenced in adult tissues, but its induction in injured tissues has been described. Gremlin-1 expression has been shown to increase in pulmonary fibrosis, diabetic nephropathy, fibrotic liver diseases, and various malignancies. These findings indicate that Gremlin-1 plays a role in organ fibrosis. In addition, gremlin-1 plays a role in angiogenesis by binding to vascular endothelial factor receptor-2 (VEGFR-2) in endothelial cells. It is obvious that there is increased inflammation and accompanying fibrosis and angiogenesis during the healing process of DA wounds. Therefore, investigators aimed to examine the relationship between gremlin-1 levels and Wagner classification in DA cases and to test its usability as a biomarker in the progression to amputation.