Risk Factor Analysis for Charcot Foot in Patients With Diabetes Mellitus: The Interplay of Inflammatory Cytokines and Metabolic Factors

Hyperglycaemia is a hallmark of diabetes mellitus resulting from defects in insulin secretion, insulin action, or both. Diabetes-related chronic hyperglycaemia is linked to long-term harm complications and failure of several organs, particularly the heart, blood vessels, kidneys, eyes, and nerves and even the musculoskeletal system Charcot neuroarthropathy, is a condition that develops in people with diabetes and neuropathy, causing damage to the bones and joints in the foot There are several risk factors for developing Charcot foot in patients with DM, such as age, gender, duration of diabetes mellitus, blood pressure, blood lipid levels, smoking, and levels of HbA1c. However, little is known about the most significant risk factor to develop such debilitating Charcot foot disease.

Acute Charcot arthritis is also characterized by a marked inflammatory response. Several chronic pro-inflammatory markers are elevated in affected individuals including interleukin-1β, interleukin 6, and tumour necrosis factor-α, and increased receptor activation of nuclear factor-K β ligand, which is imbalanced with its receptor and osteoprotegerin.

Interleukin-10 (IL-10) is a multifunctional cytokine that plays a key role in controlling inflammation and preserving cellular balance. Its primary function is anti-inflammatory, helping to prevent excessive immune reactions by acting mainly through the Jak1/Tyk2 and STAT3 signaling pathway. However, IL-10 can also act as an immune activator under certain conditions, showing stimulatory effects that support immune responses in specific conditions. Given the pivotal role of IL-10 in immune modulation, this cytokine could have relevant implications in pathologies characterized by hyperinflammatory state such as Charcot foot disease.

TNF-α is a member of the vast cytokine family being considered a proinflammatory substance produced many by macrophages and other cells belonging to the innate immunity, many of them classified as indeed Antigen Presenting Cells (APCs) involved in the complex chemotactic process of activation of the adaptive immunity. Elevated levels of TNF-α have been implicated in the development and progression of various neuropathies, including those associated with diabetes.

Although Charcot foot disease is a frequent complication of diabetic neuropathy, less is known about the possibility of its early prevention. This research aims to highlight potentially important early identifiable biomarkers that can lead to Charcot foot disease in patients with DM.