Advances in the study of OSA and diabetic foot

The two pathophysiological mechanisms of diabetic foot are diabetic peripheral neuropathy (DPN) and lower extremity arterial diseases (LEAD). Diabetic polyneuropathy (DPN) is a common chronic complication of diabetes. It is characterized by loss of sensation in the distal lower extremities, while severe neuropathic pain may also be present. DPN is the cardinal risk factor of diabetic foot ulceration mediated by unrecognized acute or chronic trauma-mediated diabetic foot ulcers [24]. OSA and nocturnal hypoxia were significantly associated with peripheral neuropathy in nondiabetic patients, independent of age and obesity. A study examining the relationship between OSA and DPN found that type 2 diabetes patients with OSA were four times more likely to develop DPN than patients without OSA. The severity of DPN was independently correlated with the degree of nocturnal hypoxia in OSA, and the lower the minimum oxygen saturation, the higher the prevalence of DPN [25]. The recurrent hypoxic process resembles ischemia-reperfusion injury. It can produce large amounts of reactive oxygen species (ROS) in a variety of ways. The ROS produced by intimal oxidative stress can directly damage the protein, nucleic acid and lipid of nerve tissue and interfere with the respiratory chain of mitochondria, resulting in the damage of nerve structure and function [26]. A small study also found that OSA was associated with axonal degeneration. Continuous positive airway pressure (CPAP) is one of the most effective non-surgical treatments for OSA. CPAP can reduce sleep apnea, alleviate daytime sleepiness, and improve the patient’s prognosis. Six months of continuous positive airway pressure (CPAP) can improved neural action potential amplitude [27]. In type 2 diabetes, Patients with severe OSA were 3 times more likely than those without or with mild OSA to develop a chronic complication associated with diabetes [28]. Results of a meta-analysis showed that compared with diabetic patients without DPN, The OR value of OSA in diabetic patients with DPN was 1.95 [29]. Later, Gu and others [30] found that OSA was significantly correlated with DPN. Further studies have shown that diabetic patients with OSA may increase oxidative stress and damage microcirculation [25] to promote the activation of PARP and reduce the density of nerve fibers in the epidermis [31], thus leading to the occurrence of neuropathy.

Intermittent hypoxemia will not only increase reactive oxygen species and oxygen free radicals, activate different cascades, positively regulate inflammatory reactions, cause endothelial cell secretion dysfunction, promote cell apoptosis, destroy vascular endothelial integrity, lead to endothelial dysfunction, and then lead to extensive vascular damage [32], but also promote the excessive proliferation of vascular smooth muscle cells, This leads to the occurrence and development of atherosclerosis [33]. OSA promotes the occurrence and severity of diabetic LEAD. A study shows that the prevalence of LEAD in OSA patients diagnosed by polysomnography (polysomnography is currently the gold standard for diagnosing OSA) is about 98%, and LEAD grading increases with the severity of OSA. Age and apnea hypopnea index (AHI) are important risk factors for arterial plaque [34]. In addition, in patients with moderate and severe OSA, the atherosclerotic plaque was larger than that in the control group [35]. In OSA patients treated with continuous positive airway pressure (CPAP), arterial stiffness can be improved [36, 37].

In patients with poor sleep quality, the number of immune cells in the skin is lower than those with good sleep quality [38], and the wound healing is also delayed [39]. In patients with diabetes mellitus complicated with OSA, because of intermittent hypoxemia and sleep disorder, is it possible that the number of skin immune cells is low, resulting in the occurrence of wound and refractory wounds? Studies have shown that in patients with diabetes mellitus complicated with OSA, due to prolonged inflammation, oxidative stress, sympathetic activation, physiological adaptation to hypoxia, reactive oxygen species in reactive oxygen species, reactive oxygen species act as the second messenger in the cell, play a role in regulating the biochemical functions of vascular smooth muscle cells and the chemical pathway of fibroblast proliferation, and so on. Reactive oxygen species can cause different degrees of endothelial cell damage, and then affect its normal physiological function [32]. And decreased mobilization of endothelial progenitor cells (ERC) and EPC apoptosis, resulting in the reduction of circulating EPCs, resulting in the reduction of endothelial cell repair ability, which leads to the delay of wound healing [36].

OSA is closely related to the onset of diabetic foot [31]. OSA may lead to the occurrence of diabetic foot through the following mechanisms:

In diabetic patients, the prevalence of diabetic foot was much lower in patients without OSA than in patients with varying degrees of OSA. This suggests that patients with both diabetes and OSA should be aware of the risk of diabetic foot. Although an earlier study by Andrews et al. [40] did not find that OSA could impair the healing of some DF amputation wounds (79.2% of diabetic patients), the study was a retrospective, observational study and the reliability of the findings is debatable. Subsequently in an analysis based on case reports, it was observed that undiagnosed severe OSA may impede the rate of healing of diabetic foot ulcers. Continuous positive airway pressure (CPAP) is one of the treatments for OSA. The effects of CPAP therapy on overall glycemic control remain contradictory, it may be that CPAP is more effective in patients with poorer glycemic control at baseline. However, it is important to entertain other potential benefits of CPAP [41]. In the absence of peripheral arterial disease or infection, severe OSA may delayed healing of the foot ulcers while CPAP treatment may promote healing of the ulcers. Recently, Maltese used S T O P-B A N G score [27] to judge OSA, score ≥ 4 to diagnose OSA. Follow-up 12 months showed that the healing rate of diabetic foot ulcer patients with score ≥ 4 was lower than that of diabetic foot ulcer patients with score < 4. This suggests that in diabetic foot patients, the OSA delayed ulcer healing. In addition, Vas et al. [42] described three patients with type 2 diabetes and obesity who investigated how severe OSA interfered with healing of the diabetic foot. DFU healing was significantly improved in patients treated with OSA under continuous positive airway pressure, while no improvement was observed in patients who refused OSA treatment. Despite the small number of cases, the results are promising and may represent a breakthrough and good prognosis for DF treatment with similar characteristics. Therefore, the presence and severity of OSA should be considered in the treatment and prevention of DF. Physicians should consider OSA as one of the major risk factors for the development of diabetic foot. In addition, DF specialists and sleep disorder specialists can work in a multidisciplinary manner with patients with OSA and DF to address prevention and treatment strategies.

There were some limitations in this study. With the exception of CPAP, this study did not elucidate whether weight loss through lifestyle interventions, pharmacotherapy, or weight loss interventions have been shown to be effective in reducing OSA severity in obese patients with type 2 diabetes. This study focused on the association between OSA and type 2 diabetes. However, the prevalence of OSA is significantly higher in type 1 diabetic patients than in the general population. The epidemiology of OSA in patients with type 1 diabetes, its relationship with the diabetic foot, and the effects of CPAP treatment remain to be studied. Future studies should explore the accurate evaluation of the effects of OSA treatment on glucose metabolism and diabetic complications in prediabetes, type 1 diabetes, and type 2 diabetes.