Regulation Of Signaling Pathways Related To Diabetes Mellitus-induced Erectile Dysfunction By Traditional Chinese Medicine： A Review

Abstract: Erectile dysfunction (ED) is one of the most common manifestations of male reproductive system damage, and it is also a common complication of diabetes mellitus (DM). ED is closely related to the patient's quality of life, sexual partner relationship, and family stability. In addition, it is an early warning signal for many physical diseases. As the incidence of DM keeps growing, the incidence of diabetes mellitus-induced erectile dysfunction (DMED) increases accordingly. Currently, drug treatment for ED presents limited effects, and the treatment of DMED is more difficult. Therefore, developing effective and safe drugs is a clinical problem that needs to be solved urgently. Recent studies have proved that traditional Chinese medicine (TCM) can alleviate oxidative stress, reduce inflammation, and modulate autophagy by regulating multiple signaling pathways, thus ameliorating DMED, showing definite therapeutic effects via multiple pathways, targets, and links. Multiple signaling pathways such as phosphatidylinositol-3-kinase/protein kinase B (PI3K/Akt), nitric oxide (NO)-cyclic guanosine monophosphate (cGMP), Ras homolog family member A (RhoA)/Rho, nuclear factor erythroid 2-related factor 2 (NRF2), mitogen-activated protein kinase (MAPK), adenosine monophosphate-activated protein kinase (AMPK), and protein kinase C (PKC) mediate the occurrence and development of DMED, while there is still a lack of conclusive records. By reviewing relevant articles published in recent years, this paper summarizes the role of the above-mentioned signaling pathways in the occurrence and development of DMED and the research progress in TCM treatment of DMED via regulation of related signaling pathways. This review is expected to provide new ideas and references for further clinical diagnosis and treatment, basic research, and drug development.

 

Keywords: diabetes mellitus; erectile dysfunction; traditional Chinese medicine; signaling pathway; research progress

 

 

 

New Herbal Supplements For Erectile Dysfunction

 

Diabetes Mellitus Erectile Dysfunction (DMED) and the PI3K/Akt Signaling Pathway

Diabetes mellitus (DM) is a common chronic metabolic disorder characterized by elevated blood glucose levels. It can affect one or more organ systems throughout the body, potentially leading to both acute and chronic complications. Erectile dysfunction (ED) is a common complication of diabetes, manifesting as impaired erectile and ejaculatory function, including symptoms such as impotence and retrograde ejaculation[^1].

An umbrella review conducted abroad found that the global prevalence of ED among diabetic patients is as high as 65.8%, highlighting the significant burden of erectile dysfunction in men with diabetes[^2]. Some studies have reported that diabetes-related ED (DMED) is more difficult to treat than general ED[^3]. Although not life-threatening, DMED is closely associated with quality of life, spousal relationships, and family stability, and also serves as an early warning sign for other somatic diseases.

Currently, there are an estimated 529 million people with diabetes worldwide, and this number is projected to exceed 1.31 billion by 2050[^4]. As the number of diabetic patients rises, the incidence of DMED is also expected to increase accordingly.

Pathogenesis of DMED

The development of DMED involves multiple mechanisms, primarily related to:

Endothelial dysfunction in penile vasculature

Neuropathy

Hormonal imbalances

Vascular lesions

Downregulation of nitric oxide synthase (NOS) expression in penile tissue

Increased advanced glycation end-products (AGEs)

Oxidative stress

Inflammatory responses

Cellular autophagy dysregulation[^5][^6]

Among these, chronic hyperglycemia, hyperinsulinemia, and insulin resistance are considered key contributors to AGEs accumulation and elevated oxidative stress, which interfere with the activation of essential signaling pathways, ultimately leading to ED[^7]. The pathophysiology of DMED involves:

Abnormal hemodynamics

Vascular endothelial dysfunction

Neuropathy

Endocrine disorders

Cavernosal smooth muscle damage, etc.[^8]

Treatment Challenges and Potential of Traditional Chinese Medicine (TCM)

Even with strict glycemic control and lifestyle interventions, current strategies are often insufficient to reverse diabetes-induced sexual dysfunction[^9]. The first-line pharmacological treatment remains phosphodiesterase type 5 inhibitors (PDE5Is). However, these drugs are associated with various adverse effects, and 24.3% of patients report no benefit[^10]. Therefore, the search for effective and safer treatments is an urgent clinical need.

Recent studies have demonstrated that Traditional Chinese Medicine (TCM) can alleviate DMED by modulating key signaling pathways, reducing oxidative stress, suppressing inflammation, and regulating autophagy. TCM has the advantages of multi-target, multi-pathway, and holistic therapeutic effects[^11].

Several signaling pathways involved in DMED include:

PI3K/Akt

NO/cGMP

RhoA/Rho kinase

Nrf2

MAPK

AMPK

PKC, etc.[^12]

However, there is still a lack of consolidated reviews summarizing these mechanisms. Therefore, this paper aims to review recent domestic and international literature to explore the roles of these signaling pathways in DMED and summarize the research progress of TCM interventions, providing new insights for clinical practice, basic research, and drug development.

1. PI3K/Akt Signaling Pathway

1.1 PI3K/Akt Pathway and Its Role in DMED

Phosphoinositide 3-kinase (PI3K) is the upstream activator of the PI3K/Akt signaling pathway. Upon cellular stress, PI3K on the plasma membrane is phosphorylated, generating phosphatidylinositol-3,4,5-trisphosphate (PIP3). PIP3 then recruits Akt from the cytoplasm to the plasma membrane and facilitates its phosphorylation at the Ser1177 site, leading to full Akt activation.

Activated Akt initiates a cascade of downstream signaling events, phosphorylating targets such as:

B-cell lymphoma 2 (Bcl-2) family anti-apoptotic protein Bad

Mammalian target of rapamycin (mTOR)

Caspase-3

Glycogen synthase kinase-3 (GSK-3)

Endothelial nitric oxide synthase (eNOS)

These mediators regulate cell differentiation, survival, and anti-apoptotic responses[^13].

The PI3K/Akt pathway is widely expressed in vascular endothelial cells and plays a crucial role in regulating vasodilation and vasoconstriction. Chronic hyperglycemia impairs the normal activation of the PI3K/Akt/eNOS axis, leading to reduced nitric oxide (NO) synthesis-a key molecule in penile erection. NO is currently one of the most well-studied vasodilators, with protective roles such as:

Vasodilation

Anti-inflammation

Antioxidant effects

Inhibition of platelet aggregation

A reduction in NO production leads to impaired relaxation of cavernosal smooth muscle, ultimately resulting in erectile dysfunction[^14].

1.2 Intervention of DMED via the PI3K/Akt Pathway by Traditional Chinese Medicine

Shaofu Zhuyu Decoction is a classical Chinese herbal formula composed of multiple herbs, with effects including promoting blood circulation, removing blood stasis, tonifying the kidney, and boosting Qi. MAO et al.[11] found that this formula could inhibit inflammation and tissue fibrosis in diabetic rats, thereby restoring erectile function. Pharmacological analysis suggested that the mechanism by which Shaofu Zhuyu Decoction improves DMED may involve multi-target regulation, including:

Cytochrome P4501B1 (CYP1B1)

Dipeptidyl peptidase 4 (DPP4)

Nitric oxide synthase 2 (NOS2)

Lipocalin 2 (LCN2)

PI3K/Akt signaling pathway

The study identified isorhamnetin as the primary active compound in the formula and conducted experimental validation. In animal experiments, isorhamnetin increased levels of:

Superoxide dismutase (SOD)

Glutathione peroxidase (GPx)

Catalase (CAT)

Nitric oxide (NO)

It also reduced malondialdehyde (MDA) levels, improved the intracavernosal pressure to mean arterial pressure (ICP/MAP) ratio, and increased smooth muscle content in the corpus cavernosum of diabetic mice[^15].

In cellular experiments, isorhamnetin was shown to upregulate the expression of PI3K, Akt, and eNOS proteins, suggesting that it may activate the PI3K/Akt/eNOS signaling pathway to exert anti-inflammatory, antioxidant, and anti-apoptotic effects, thereby protecting vascular endothelial cells in the corpus cavernosum[^15].

Jia Xiaoyue et al.[16] used Shaofu Zhuyu Decoction combined with sildenafil to treat DMED patients. Among 41 patients in the treatment group, the total effective rate reached 90.2%, which was significantly better than sildenafil alone.

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Xiaoyao Powder is another TCM formulation containing quercetin, kaempferol, β-sitosterol, Angelica sinensis, Poria, Paeonia alba, Atractylodes macrocephala, Bupleurum, ginger, honey-fried licorice, and mint. It is known to harmonize the liver and spleen, relieve liver Qi stagnation, and strengthen the spleen and nourish the blood. In DMED rat models, Xiaoyao Powder was shown to downregulate the expression of the receptor for advanced glycation end-products (RAGE) at both the mRNA and protein levels, while upregulating PI3K and Akt protein expression, indicating that its therapeutic effect may be mediated via the RAGE/PI3K/Akt pathway[^17].

The PI3K/Akt/mTOR pathway is a classic signaling cascade for autophagy regulation. PI3K/Akt modulates autophagy primarily by controlling the activity of mTOR:

Activated mTOR inhibits autophagy

Inhibited mTOR promotes autophagy

Both excessive activation or inhibition of mTOR can disrupt autophagy homeostasis, resulting in structural and functional impairments.

Feng Junlong et al.[18] found that Leech-Centipede Granules can increase testosterone (T) levels, erection frequency, ICP/MAP ratio, and phosphorylation and mRNA expression of PI3K, Akt, and mTOR in DMED rats. The efficacy was superior to tadalafil, a first-line ED medication. The proposed mechanism is activation of the PI3K/Akt/mTOR pathway, which prevents apoptosis of penile smooth muscle cells and improves erectile function.

 

Icariin II, a flavonoid compound isolated from Epimedium, was studied by Zhang et al.[19] via in vivo and in vitro experiments. They found that icariin II combined with metformin might activate the PI3K/Akt/mTOR signaling pathway to reduce excessive proliferation of corpus cavernosum smooth muscle cells (CCSMCs).