What is the basic science behind Diabetic Foot in adults or elderly individuals with a history of diabetes mellitus (DM) and comorbidities such as hypertension (HTN) and hyperlipidemia (HLD)?

Basic Science of Diabetic Foot

Core Pathophysiological Triad

Diabetic foot disease results from three interconnected pathological mechanisms: peripheral neuropathy (the dominant factor), peripheral arterial disease, and immune dysfunction, which together create a cascade leading to tissue breakdown and ulceration when the protective skin barrier is breached. 1

Peripheral Neuropathy: The Primary Driver

Peripheral neuropathy is present in approximately 78% of diabetic patients with foot ulcers and manifests through three distinct pathways 1, 2:

• Sensory neuropathy causes loss of protective sensation (LOPS), allowing repetitive minor trauma to go unnoticed and progress to ulceration without the patient's awareness 1
• Motor neuropathy leads to intrinsic foot muscle atrophy, creating characteristic deformities including claw toes, hammer toes, and prominent metatarsal heads that generate abnormally high pressure points 1
• Autonomic neuropathy reduces sweating capacity, resulting in dry, cracked skin that fissures easily and serves as a portal for bacterial entry 1

The underlying mechanisms driving neuropathy include hyperglycemia-induced axon injury, toxic adiposity, oxidative stress, mitochondrial dysfunction, activation of the polyol pathway, and accumulation of advanced glycation end products (AGEs) 3

Biomechanical Cascade

The neuropathic foot undergoes a destructive biomechanical sequence 1:

• Loss of sensation combined with foot deformities and limited joint mobility creates abnormal biomechanical loading patterns 1
• High-pressure areas develop at bony prominences, triggering compensatory callus formation as a protective response 1
• The callus itself paradoxically increases abnormal loading, often leading to subcutaneous hemorrhage and eventual ulceration beneath the thickened skin 1
• This process occurs without pain signals to alert the patient, allowing progression from minor trauma to full-thickness ulceration 4

Peripheral Arterial Disease Component

PAD is present in up to 50% of patients with diabetic foot ulcers due to accelerated atherosclerosis in diabetes 1:

• PAD serves as a major independent risk factor for impaired wound healing and dramatically increases lower extremity amputation risk 1
• Most diabetic foot ulcers are neuro-ischemic (combined neuropathy and vascular disease) rather than purely neuropathic or purely ischemic 1
• The combination of infection with PAD creates a particularly lethal scenario, with non-revascularized patients achieving only approximately 50% limb salvage rates at one year 1

Immunological Dysfunction

Diabetes causes specific immune perturbations that amplify infection risk once the skin barrier is breached 1, 5:

• Polymorphonuclear leukocyte dysfunction increases both infection risk and severity 1
• Macrophage polarization imbalance sustains a pro-inflammatory environment dominated by cytokines such as TNF-α, IL-1β, and IL-6, which impair angiogenesis and delay repair 5
• Regulatory T cell dysfunction and neutrophil impairment contribute to wound chronicity 5
• Poor glycemic control directly predisposes to infection and impairs wound healing capacity 1

Infectious Cascade

Once the protective cutaneous barrier is breached, a predictable infectious sequence unfolds 1:

• Initial colonization occurs with aerobic gram-positive cocci, predominantly Staphylococcus aureus and β-hemolytic streptococci 1
• Chronic wounds develop polymicrobial flora, including enterococci, Enterobacteriaceae, obligate anaerobes, and Pseudomonas aeruginosa 1
• The infection can spread vertically into underlying bone, causing osteomyelitis, which is associated with high amputation risk, prolonged hospitalization, and increased mortality 6

Impact of Comorbidities in Adults and Elderly

Hypertension and Hyperlipidemia

These comorbidities accelerate the pathophysiological cascade 3:

• Elevated triglycerides are an independent risk factor for lower extremity amputation in diabetic patients 3
• Hypertension contributes to both microvascular (neuropathy) and macrovascular (PAD) complications 3
• The metabolic syndrome constellation (insulin resistance, central obesity, dyslipidemia, hypertension) is associated with elevated risk of major cardiovascular events and amplifies diabetic foot risk 3

Renal Disease

Diabetic nephropathy, especially in patients on dialysis, represents an extremely high-risk group 6, 1:

• Renal disease increases infection susceptibility and impairs wound healing capacity 1
• Patients on dialysis are at extremely high risk of developing foot ulceration 4

Cardiovascular Disease

Cardiovascular disease frequently coexists with PAD, creating competing management priorities 1:

• Diabetic patients with foot complications have mortality rates greater than twofold compared to non-ulcerated diabetics 3
• The 5-year mortality rate following amputation is estimated at 39-68%, comparable to aggressive cancers or advanced congestive heart failure 3

Clinical Implications

Common pitfall: Assuming that neuropathy alone causes ulceration—it does not ulcerate spontaneously but requires the combination of insensitivity plus external trauma (most commonly from inappropriate footwear in Western countries) 4

Key takeaway: The diabetic foot represents a convergence of multiple pathological processes where neuropathy removes the protective pain response, biomechanical abnormalities create repetitive stress, vascular disease impairs healing, and immune dysfunction allows infection to flourish—all amplified by poor glycemic control and metabolic comorbidities 1, 7