The global prevalence of diabetes mellitus has risen by 16% in the last 2 years (DM) and is expected to continue this trajectory. Indeed, it is estimated to affect 537 million people in 2021, with this gure expected to rise to 643 million by 2030 and 783 million by 2045 [1]. Diabetes is primarily caused by the body’s inability to produce or respond to insulin, resulting in car­bohydrate metabolic dysfunction [1]. Chronic insulin resistance can raise blood and urine glu­cose levels [1]. Diabetes patients are more likely to develop other systemic pathologies that can affect the feet, eyes, skin, kidneys, and cardio­vascular systems. Because of the harmful nature of this disease process, it is a major risk factor for atherosclerotic disease. Peripheral artery disease (PAD) is a type of occlusive disease that typically affects the lower extremities. PAD is now thought to affect approximately 12 million

people in the United States. Patients with PAD are more likely to have lower extremity amputa­tions, and it can be an early warning sign of other harmful cardiovascular pathologies. Most of these amputations begin with diabetic foot ulcers [2]. A patient with a diabetic foot ulcer has a 2.5 times higher risk of death at 5 years than a patient with diabetes who does not have a foot ulcer. Infection occurs in more than half of diabetic ulcers. Approximately 20% of moder­ate or severe diabetic foot infections result in amputation. Peripheral artery disease raises the risk of nonhealing ulcers, infection, and ampu­tation on its own [3].

Hyperglycemia is derived from the Greek word hyper (high [4]) + glykys (sweet/sugar) + haima (blood). Hyperglycemia is the physiologic state of blood glucose greater than 125 mg/dL while fasting and greater than 180 mg/dL 2 h postprandial [4]. A patient has impaired glucose tolerance, or considered “prediabetes,” with a fasting plasma glucose of 100–125 mg/ dL. Hyperglycemia has the potential to cause several systemic life-threatening complications that include damage to the eye, kidneys, nerves, heart, and peripheral vascular system [4]. Hence, it is vital for patients with diabetes to manage hyperglycemia effectively and efciently to pre­vent complications of the disease and improve patient outcomes.

Between 30% and 70% of patients with diabetes mellitus, both type 1 and type 2, will present with a cutaneous complication of diabetes mel­litus at some point during their lifetime. Hyperglycemia is an inammatory condition that causes sensory and motor nerve defects, which blunt the perception of adverse stimuli and produce an altered gait. Peripheral neuropa­thy, vascular disease, and metabolic dysfunction all play a key role in diabetic tissue necrosis (Fig.53.1). Altered lower extremity biomechan­ics can increase the likelihood of developing foot ulcers and other osseous malformations. DM causes a pathogenic environment, which induces abnormal cellular responses to infection, immu­nological and microvascular dysfunction, and peripheral neuropathy. These dynamic processes are implicated in the pathogenesis of the wound healing impairment and the diabetic foot ulcer. The skin houses a dense network of sensory

Hyperglycemia causes tissue damage and oxi­dative stress through four major mechanisms (Fig.53.2):

or another involved in the development of diabetic microangiopathy [8]. Previous studies have revealed that the cytokines and proteins associated with inammation (interleukins IL-6 and IL-8; tumor necrosis factor alpha, TNF-α [7]; C-reactive protein; brinogen) were signicantly elevated in the diabetic patients at baseline [7]. Hyaluronan (HA) plays an important role in the integumentary physiology. HA is a key glycosaminoglycan that facilitates the reepithelialization process [9]. HA is an integral part of the extracellular matrix of basal keratinocytes, which are major constituents of the epidermis which foster keratinocyte proliferation and migration. Hyperglycemia primes the degrada­tion of HA in the glycocalyx of endothelial cells, consequently increasing leukocyte recruitment and creating a proinammatory microenvironment [10]. Therefore, the thickness of the glycocalyx on blood vessel endothelia is signicantly reduced, leading to the loss of protective functions and other deleterious changes [10]. This leads to an imbal­ance of free radicals and antioxidants in the body, which results in the overproduction of reactive oxygen species (ROS) [6, 11]. Excess ROS can lead to cell and tissue damage and delayed wound healing. Therefore, decreasing ROS levels through antioxidative systems may reduce oxidative stress­induced damage to improve healing [6, 11].

Endothelial cell damage secondary to hyperglyce­mia induces vascular impairment, consequently decreasing the delivery of oxygen and vital nutri­ents to organ systems. Additionally, the alteration of the capillary or arteriolar vessel structure also hinders activated white blood cells to specic tis­sues, increasing the susceptibility, and accelerates the occurrence and progression of diabetic ulcers and infectious/gangrenous processes [6, 11]. A hyperglycemic state causes a decrease in the oxy­gen, nutrient supply, and vascular impairment resulting in hair alterations like hair thinning, hair fragility, sparseness of hair, or decreased hair growth speed. Some studies have found that lower leg hair loss could be an early predictor of diabetic foot through vascular impairment [12].

The Society of Vascular Surgery (SVS) opined that the current classication systems of diabetic foot ulcers/infection have two major problems: “(1) the validity and natural history of the con­cept of CLTI and (2) the failure of most existing systems to assess and grade the major factors that inuence both risk of limb loss and clinical man­agement” [13]. The proposed SVS Lower Extremity Threatened Limb Classication System is based simply on grading each of the three major factors (wound, ischemia, and foot infection [WIfI]) [13]. Uncontrolled diabetes typically presents with several deleterious factors of which ischemia is just one component of a much larger problem. They devised a dynamic classication system that integrates a global methodology in the stratication of these disease pathologies: wound extent, ischemia, and foot infection [13] (Fig.53.3). This resulted in a para­digm shift in evaluating the risks of amputation and the potential benets of vascular intervention [13]. The target population of the WIfI system incorporates patients across a broad spectrum of lower extremity vascular disease etiologies [13]. The main idea behind this new classication sys­tem was to help patients categorize their condi­tion in a similar fashion to the TNM (tumor, nodes, metastasis) system commonly utilized in malignancies [9, 13]. Clinicians should then doc­ument and classify the severity of the infection based on its extent and depth and the presence of any systemic ndings of infection. Grades are

calculated separately by measuring the wound depth; ischemia based on TBI, ABI, and TcPO2; and systemic to local infection from the IDSA guideline [13]. Once the grades are combined and calculated, a risk of amputation is generated [13]. For infected wounds, we recommend that clinicians send appropriately obtained specimens for culture prior to starting empiric antibiotic therapy, if possible [13].

Study parameters [14]:

– Each patient was assigned a score from 0 to 5:

• 1 point given for calcication in each of the following arterial segments:

• >2 cm in the dorsalis pedis, plantar, and metatarsal arteries

• >1 cm in the hallux and lesser digital arteries

tion programs consist of interdisciplinary teams that work synergistically to exchange informa­tion, discuss assessment, and create joint plans to achieve the goal of limb salvage in an inte­grated model. This model often incorporates podiatric and vascular surgeons (“toe and ow” model) as the core of an interdisciplinary team but which may include other medical specialties as well.