General Information
In recent decades, the prevalence of diabetes mellitus (DM) has continued to rise. From 1980 to 2014, the number of diabetic patients worldwide increased from 108 million to 422 million, nearly 4-fold, becoming the fourth largest non-communicable disease in the world[20]. Elevated blood glucose is significantly related to reduced male sexual function, and 55%-80% of DM male patients suffer from ED[21, 22], with a pathogenesis involving endocrine, neurological, psychological, vascular, and other lesions[23]. Phosphodiesterase type 5 (PDE5) inhibitors are used as a first-line drug choice for DMED treatment, but the mechanism of its regulatory influence on blood glucose is still unclear, and 40% of patients still have no treatment response[24], which limits its use in treatment. With the increasing prevalence of DMED, higher requirements have been put forward for its diagnosis, treatment, and management. Therefore, the number of studies on DMED has been increasing in recent years, and the annual number of articles published has remained at about 40.
The United States and China are in the leading position in the field of DMED research, and the study of DMED in Asia is becoming more in-depth. The reason for this is related to the epidemiology of DM. The study showed that the countries with the highest number of DM cases worldwide in 2011 were China (90 million), India (61.3 million), and the United States (23.7 million), and the number of DM cases in these three countries is expected to increase to 129.7 million, 101.2 million, and 29.6 million, respectively, by 2030, with 48% of the increase expected to occur in China and India[25]. The increase in the incidence of diabetes and its related complications means an increase in national funding and scientific research investment, and it is expected that all countries and regions will strengthen their cooperation to promote further DMED research.
From the perspective of authors and journals, Ryu JK issued the highest number of documents on DMED and formed a collaborative team with authors such as Ryu JK and Yin GN, whose research on DMED mainly focused on the mining and mechanistic exploration of novel therapeutic targets, such as vasohibin‑1 and injurin 1 expressed by penile endothelial cells, which are expected to be new targets for DMED treatment to improve penile blood supply by mediating angiogenesis[26, 27]. The author who has been co-cited the most frequently in the literature is Bivalacqua TJ, whose research mainly focused on investigating the mechanism of endothelial nitric oxide synthase (eNOS) in DMED[28, 29], which shows that the research hotspots of DMED focus on the mechanism of occurrence and treatment and continue to deepen. The Journal of Sexual Medicine, the International Journal of Impotence Research, and the Journal of Urology are the top three journals in terms of the number of articles published, and they all contain high-quality scientific results, with an average of 36.73 citations per article and an average impact factor of 4.65, indicating that these journals have high influence and authority in the field of DMED.
Hotspots and Frontiers
Combined with the frequency of occurrence of keywords, timeline mapping, and burst word mapping, the research hotspots and development directions in the field of DMED are summarized.
1. Mechanism of DMED: Since the mechanism of DMED is complex and involves vascular, neurological, and endocrine factors, more new proteins or pathways related to its development are being discovered as research continues to progress.
Oxidative stress and endothelial damage: Decreased synthesis or bioavailability of eNOS and in the penile vascular endothelium of DM patients due to oxidative stress damage is essential to the development of ED[30]. Studies have shown that hyperglycemia-induced advanced glycation end products lead to the production of large amounts of reactive oxygen species and reactive nitrogen species[31], increased oxidative stress, decreased eNOS synthesis, cavernous endothelial dysfunction, and abnormal smooth muscle diastole, leading to the development of ED[32, 33]. Moreover, protein oxidation changes in the corpus cavernosum of DM rats were significantly increased, mainly manifested as nitration of tyrosine residues to form 3-nitrotyrosine, which directly inactivated NO and induced apoptosis in endothelial cells[32].
Neurovascular injury and repair: As a secreted glycoprotein, Dickkopf3 regulates the Wnt signaling pathway and upregulates angiopoietin-1, vascular endothelial growth factor (VEGF), and basic fibroblast growth factor, exerting angiogenic and protective functions. However, its expression was significantly reduced in the penile corpus cavernosum of DMED mice, impeding cavernous endothelial cell repair and angiogenesis[34]. The nerve growth factor precursor protein (proNGF) has a high affinity for the p75 neurotrophin receptor (p75NTR). Hyperglycemia-induced overexpression of p75NTR and disrupted homeostasis of NGF and proNGF levels resulted in a significant upregulation of the proNGF/p75NTR pathway in mouse cavernous epithelial cells, accelerating neuronal cell apoptosis and inducing nerve injury[35].
Endocrine disorders: DM was shown to promote apoptosis in testicular cells by affecting Bcl-2 and caspase protease expression, leading to decreased testosterone levels, structural changes in smooth muscle cell, which also contributed to the development of ED[36, 37].Improving the understanding of the molecular mechanisms underlying the development of DMED could contribute to the development of more effective treatments.
2. Continuously innovative treatment: PDE5 inhibitors are used as the first-line treatment for DMED. Clinical studies have shown that the efficiency of sildenafil in the treatment of DMED is 46.3% with good safety, and patient satisfaction with their sexual life is improved after taking the drug orally[38]. Animal experiments have also confirmed that sildenafil improved erectile function by increasing the expression of VEGF and eNOS in the penis of diabetic rats[41]. For hypogonadal patients with testosterone deficiency, testosterone replacement therapy may be used[42]. On the basis of the above-mentioned traditional treatment, drugs more commonly used in other fields have been introduced in the treatment of DMED. This has realized a new use of older drugs, such as valsartan[43], acetylcysteine[44], and melatonin[45], to improve erectile function by inhibiting the activation of the local renin-angiotensin system (RAS) in the cavernous body and reducing oxidative stress and the inflammatory response, all of which have shown good efficacy. In terms of second-line treatment, intracavernosal injection of angiogenic factors and neurotrophic factors is currently the focus of research[46, 47].
However, although PDE5 inhibitors are the first-line therapeutic agents for DMED, their effects depend on the production of endogenous NO. Severe vascular and neurological dysfunction in diabetic patients leads to decreased endogenous NOS activity; so, some patients have an extremely poor response to PDE5 inhibitor therapy[48]. The mining of new treatments has become the main direction of future research, including stem cell therapy and gene therapy. Studies have shown that stem cell transplantation upregulated the autophagic activity of cavernous cells, which differentiated to endothelial cells and smooth muscle cells to repair cell damage and then restored erectile function in DM patients[49]. Adipose-derived stem cells are more frequently used in DMED treatment due to their more convenient acquisition, and their effects were not affected by blood glucose levels[50]. Gene therapy is also a new direction. Target genes such as vascular nerve regeneration factor[51] and insulin-like growth factor 1 (IGF-1)[52] are significantly downregulated in patients with advanced DMED, and repair therapy with these genes also improved erectile function. In addition, low-intensity extra corporeal shock wave therapy (Li-ESWT) for DMED is also a topic of interest in current research, which is a non-invasive therapy with few side effects that can be used as a treatment option for patients with a poor response to oral drugs[53]. Li-ESWT improved the local blood supply of the penis and promoted nerve regeneration with an efficiency of 71% in the treatment of DMED[54]. The methods summarized here provide more options for the treatment of DMED.
3. Comprehensive management of DMED: The incidence of ED in DM patients is three times higher than that in non-DM patients, and age and duration of diabetes are independent risk factors for the occurrence of DMED[55]. Elderly diabetic patients also often suffer from obesity, hypertension, hyperlipidemia, and other manifestations of metabolic syndrome, which are considered to be independent risk factors for endothelial dysfunction, ED, and cardiovascular disease[56]. Therefore, in clinical practice, the assessment and management of ED should be an important part of the follow-up process of DM patients, and early diagnosis and treatment of DMED are important for controlling risk factors and improving patient quality of life[57]. Furthermore, clinicians should take psychological aspects into consideration when treating DMED and should actively attend to the patient’s psychological health and help regulate the patient’s negative emotions[58].