Preamble

Chinese General Practice · Reviews and Monographs · From Mechanism to Treatment: Diabetic Autonomic Neuropathy

Diabetic Autonomic Neuropathy (DAN) is a common and serious chronic complication of diabetes mellitus. It can affect various organ systems throughout the body, including the cardiovascular, gastrointestinal, and genitourinary systems, as well as the sweat glands and pupils. DAN significantly impacts the quality of life of patients with diabetes and is associated with increased morbidity and mortality. Despite its clinical importance, DAN is often underdiagnosed and undertreated in its early stages due to its insidious onset and diverse clinical manifestations.

Pathophysiological Mechanisms

The pathogenesis of DAN is multifactorial and complex, involving a combination of metabolic, vascular, and inflammatory pathways. Chronic hyperglycemia is the primary driver, leading to several biochemical abnormalities:

1. Polyol Pathway Activation: Excess glucose is converted to sorbitol by aldose reductase, leading to osmotic stress and depletion of myo-inositol and NADPH, which are essential for maintaining nerve function.
2. Advanced Glycation End-products (AGEs): Non-enzymatic glycation of proteins and lipids results in the formation of AGEs, which induce oxidative stress and pro-inflammatory signaling through their receptors (RAGE).
3. Oxidative Stress: An imbalance between the production of reactive oxygen species (ROS) and antioxidant defenses leads to mitochondrial dysfunction and direct damage to neuronal DNA and lipids.
4. Microvascular Impairment: Ischemia and hypoxia of the nerve fibers occur due to impaired endoneurial blood flow, further exacerbating nerve damage.

Clinical Manifestations and Classification

DAN manifests in various forms depending on the affected autonomic nerves:

• Cardiovascular Autonomic Neuropathy (CAN): Characterized by resting tachycardia, exercise intolerance, orthostatic hypotension, and, in severe cases, silent myocardial ischemia or sudden death.
• Gastrointestinal Neuropathy: Common symptoms include gastroparesis (delayed gastric emptying), constipation, diarrhea, and fecal incontinence.
• Genitourinary Neuropathy: Manifests as bladder dysfunction (cystopathy), erectile dysfunction in men, and sexual dysfunction in women.
• Sudomotor Dysfunction: Leads to anhidrosis in the lower extremities and compensatory gustatory sweating or hyperhidrosis in the upper body.

[FIGURE:1]

Diagnostic Approaches

Early diagnosis of DAN is crucial for preventing irreversible damage.

1.421001 湖南省衡阳市，南华大学附属第一医院内分泌代谢科

Introduction

Diabetic neuropathy (DN) represents the most common and devastating chronic complication of diabetes mellitus. Among its various manifestations, diabetic autonomic neuropathy (DAN) has garnered particular attention due to its involvement in multiple organ systems. Pathological mechanisms including metabolic abnormalities induced by hyperglycemia, oxidative stress, and microvascular lesions can lead to autonomic nervous system dysfunction, manifesting clinically as resting tachycardia, gastroparesis, and bladder dysfunction.

Pathophysiology and Clinical Manifestations

The pathogenesis of DAN involves complex interactions between metabolic derangements and neurovascular damage. Sustained hyperglycemia triggers polyol pathway activation, advanced glycation end-product formation, and protein kinase C activation, collectively contributing to neuronal injury and autonomic dysregulation. These molecular alterations compromise the structural and functional integrity of autonomic fibers innervating cardiovascular, gastrointestinal, genitourinary, and sudomotor systems.

Therapeutic Strategies

Management of DAN requires a multifaceted approach grounded in optimized glycemic control as the foundation of therapy. Pharmacological interventions encompass aldose reductase inhibitors to counteract polyol pathway flux, antioxidant agents to mitigate oxidative damage, and neurotrophic factors to support nerve regeneration. Emerging therapeutic avenues include neuromodulation techniques and individualized intervention protocols that enable targeted regulation of systemic autonomic dysfunction.

Conclusion

This review synthesizes current understanding of DAN pathophysiology, multi-organ clinical presentations, and treatment strategies centered on autonomic nervous system modulation. By integrating mechanistic insights with clinical applications, we aim to provide a theoretical framework for elucidating DN pathogenesis and refining therapeutic interventions in diabetic autonomic neuropathy.

Keywords: diabetes mellitus; autonomic nervous system diseases; regulatory mechanisms; diagnosis; therapeutic strategies

2. Department of Laboratory Med

ne, the F rst Aff ated Hosp tal, Hengyang Med cal School, Un ty of South Ch na, Hengyang 421001, Ch

3. Department of Rehab

on Med ne, the F rst Aff ated Hosp tal, Hengyang Med cal School, Un ty of South Ch Hengyang 421001, Ch Correspond ng author: HU Y n, Assoc ate professor/Master superv

Abstract

c neuropathy (DN) s a common and ser ous long-term compl on of d abetes, w th autonom neuropathy ga ng cons derable attent on due to ts effects on var ous organ systems. The dysfunct on of autonom c nerves caused by patholog cal mechan sms such as metabol mbalances, ox ve stress, and m crovascular damage due to h gh blood sugar levels, lead ng to cl cal symptoms l ke rest ng tachycard a, delayed stomach empty ng, and bladder ssues. The management c autonom c neuropathy (DAN) nvolves a foundat onal approach of str ngent glycem c control, complemented by a on of aldose reductase tors, ant dants, and neurotroph c agents to synerg cally allev ate cl cal symptoms.

Furthermore, the ut on of neuromodulat on techn ques and the mplementat on of personal zed treatments enable targeted modulat on of the system rments. Th s art cle prov des a comprehens ve rev ew of the pathophys cal mechan sms of ts cl cal man festat ons across mult ple t ssues and organs, and treatment strateg es based on autonom c nervous system regulat on, a ng to establ sh a theoret cal foundat on for n-depth analys s of DN patholog cal mechan sms and opt on of ntervent on approaches.

Keywords: Diabetes mellitus; Autonomic nervous system diseases; Regulation mechanism; Diagnosis; Therapeutic strategy

Pan Ziyun, Yin Hao, Lin Zhirou, et al. From Mechanism to Therapy: Diabetic Autonomic Neuropathy [J]. Chinese General Practice, 2026. DOI: 10.12114/j.issn.1007-9572.2025.0335. [Epub ahead of print]. PAN Z Y, YIN H, LIN Z R, et al. From mechanism to therapy: diabetic autonomic neuropathy [J]. Chinese General Practice, 2026. [Epub ahead of print]. Editorial Office of Chinese General Practice. This is an open access article under the CC BY-NC-ND 4.0 license.

Diabetic neuropathy (DN) is one of the most common chronic complications of diabetes, and its clinical significance is self-evident. As the duration of diabetes progresses, approximately half of all patients will eventually develop some form of neuropathy.

Furthermore, recent research progress and continuous updates to international guidelines have provided new insights into the classification, diagnosis, and treatment of DN \cite{1,2,3}. The autonomic nervous system (ANS) is composed of the sympathetic, parasympathetic, and enteric nervous systems, playing a central role in maintaining internal homeostasis \cite{1,2,3}. It regulates various involuntary functions, including heart rate, blood pressure, gastrointestinal motility, perspiration, and body temperature. Diabetic autonomic neuropathy (DAN) is a critical subtype of DN that often leads to resting tachycardia, gastroparesis, dysuria, abnormal sweating, and foot ulcers, significantly impacting patients' quality of life and prognosis. Therefore, exploring the mechanisms and treatments of DAN within the context of diabetes is of great importance: autonomic dysfunction caused by diabetes directly leads to imbalance and damage across multiple physiological systems. This article reviews the mechanisms of DAN in various tissues and organs, its clinical manifestations, and DN treatment strategies based on ANS regulation ([FIGURE:1]). This review aims to provide a reference for an in-depth understanding of the pathogenesis of DN and to offer new perspectives for clinical research on related treatments.

Figure 1: Diagram of diabetic autonomic neuropathy and treatment strategies in multiple organ systems.

1 DAN

The ANS is a tripartite regulatory system composed of the sympathetic, parasympathetic, and enteric nervous systems. It is extensively distributed across effector organs such as the myocardium, smooth muscle, and glands, playing a central role in maintaining internal homeostasis. The "fight or flight" sympathetic nervous system and the "rest and digest" parasympathetic nervous system achieve a dynamic balance of physiological functions through a sophisticated mechanism of antagonism and synergy, controlling processes such as blood pressure, heart rate, digestion, urination, and thermoregulation \cite{5, 6}. Precisely because the ANS is distributed throughout the entire body, various organs are susceptible to autonomic dysfunction in the presence of diabetes.

Diabetic neuropathy (DN) is a heterogeneous syndrome of nervous system damage induced by chronic hyperglycemia and its associated metabolic disturbances, presenting with diverse clinical manifestations. It can be classified into three major types: diffuse neuropathy, mononeuropathy, and radiculopathy or plexopathy. The former category includes distal symmetric polyneuropathy (DSPN) and diabetic autonomic neuropathy (DAN). Among these, DSPN is the most common, accounting for approximately 75% of all DN cases, followed by autonomic neuropathy. Autonomic neuropathy refers generally to autonomic nerve damage involving the cardiovascular, gastrointestinal, and urogenital systems. Mononeuropathy is also relatively common, typically resulting from local microvascular ischemia or traumatic compression. It should be noted that DSPN and autonomic neuropathy frequently coexist; for instance, small-fiber neuropathy often involves both impaired sensory function and damage to autonomic nerve fibers, leading to patients experiencing sensory abnormalities alongside autonomic changes such as reduced sweating. Research has demonstrated that DAN is closely linked to patient prognosis; for example, severe cardiovascular autonomic neuropathy can lead to a 5-year mortality rate as high as 25%–50%, which is significantly higher than that of patients without this complication.

2 DAN

Pathophysiological Mechanisms

In the diabetic state, persistent hyperglycemia mediates damage to neural tissues by activating multiple interconnected metabolic pathways. The primary mechanisms include the overactivation of the polyol pathway, which leads to the accumulation of sorbitol and increased oxidative stress. Simultaneously, hyperglycemia promotes the formation of advanced glycation end-products (AGEs) and activates their downstream receptor signaling. The abnormal activation of the protein kinase C (PKC) pathway directly disrupts the structure and function of nerve cells, while the activation of the hexosamine pathway produces end-products that mediate abnormal protein modifications, thereby interfering with normal cellular signal transduction.

Microvascular complications further exacerbate this damage, manifesting as endothelial dysfunction in the vasa nervorum, thickening of the basement membrane, and an imbalance of vasomotor factors, all of which lead to ischemia and hypoxia in neural tissues \cite{10-11}. The hyperglycemic environment also induces systemic insulin resistance and inflammatory responses, stimulating immune cells to release pro-inflammatory cytokines such as tumor necrosis factor-alpha (TNF-$\alpha$) and interleukin-6 (IL-6), while activating signaling pathways such as NF-$\kappa$B.

Furthermore, a reduction in the synthesis of key neurotrophic factors, including nerve growth factor (NGF) and insulin-like growth factor-1 (IGF-1), leads to neuronal apoptosis and impairs axonal regeneration and myelin repair. Mitochondrial dysfunction also plays a critical role, resulting in insufficient adenosine triphosphate (ATP) production, disrupted calcium homeostasis, and the overproduction of reactive oxygen species (ROS), which further accelerates nerve cell apoptosis. Collectively, these pathological changes cause irreversible structural damage, such as axonal degeneration of autonomic nerve fibers, demyelination, and apoptosis of ganglion cells. These processes ultimately culminate in autonomic dysfunction across multiple systems, including the cardiovascular, gastrointestinal, and urogenital systems [FIGURE:2].

3 AN

Pathogenesis and Clinical Manifestations in Various Organs and Systems

The pathogenesis and clinical manifestations of the disease vary significantly across different organs and systems, reflecting the complex interplay between systemic physiological disruptions and localized tissue responses.

1. Central Nervous System

In the central nervous system, the pathogenesis is primarily driven by neuroinflammation and oxidative stress, leading to neuronal dysfunction. Clinical manifestations often include cognitive impairment, sensory deficits, and motor coordination challenges. Advanced stages may present with progressive neurodegeneration, which can be monitored through specific biomarkers and neuroimaging techniques.

2. Cardiovascular System

The cardiovascular impact is characterized by endothelial dysfunction and vascular remodeling. The underlying mechanism involves the activation of inflammatory pathways that contribute to atherosclerosis and myocardial strain. Patients frequently present with hypertension, arrhythmias, or signs of congestive heart failure. Early detection of these clinical signs is critical for managing long-term cardiovascular risk.

3. Respiratory System

In the lungs, the disease often manifests as interstitial thickening and impaired gas exchange. The pathogenesis involves the recruitment of inflammatory cells to the alveolar spaces, leading to fibrosis in chronic cases. Clinically, this translates to dyspnea, persistent cough, and reduced exercise tolerance. Pulmonary function tests typically reveal restrictive patterns and decreased diffusion capacity.

4. Gastrointestinal and Hepatic Systems

The gastrointestinal tract may exhibit altered mucosal permeability and malabsorption. In the liver, the pathogenesis often involves metabolic dysregulation and hepatocyte injury, which can progress to steatosis or fibrosis. Clinical presentations range from non-specific abdominal pain and dyspepsia to elevated liver enzymes and jaundice in severe systemic involvements.

5. Renal and Endocrine Systems

Renal involvement is marked by glomerular filtration disturbances and tubular injury, often manifesting as proteinuria or electrolyte imbalances. Simultaneously, the endocrine system may face disruptions in hormonal feedback loops, leading to metabolic syndromes or thyroid dysfunction. These systemic imbalances further complicate the clinical picture, requiring a multidisciplinary approach to treatment.

3.1 血管系统

Diabetic cardiovascular autonomic neuropathy (DCAN) refers to damage to the sympathetic and parasympathetic nerves that innervate the heart and blood vessels. A hallmark of its pathogenesis is the imbalance between the sympathetic and parasympathetic nervous systems. Typically, the vagus nerve (parasympathetic) is affected first, leading to relative sympathetic dominance, which manifests as resting tachycardia in the early stages \cite{13-16}. As the disease progresses,

Chinese General Practice

$Ca^{2+}$ = Calcium ion.

the sympathetic nerves also become gradually involved, leading to a decline in heart rate regulation. Patients may then exhibit late-stage manifestations such as a fixed heart rate and orthostatic hypotension. This autonomic imbalance weakens vagal inhibition and causes excessive sympathetic activation, resulting in elevated catecholamine levels and activation of the renin-angiotensin-aldosterone system (RAAS). Sympathetic hyperactivity not only exacerbates insulin resistance, creating a vicious cycle, but also exerts deleterious effects on the myocardium, including increased myocardial oxygen consumption, ventricular remodeling, and an elevated risk of rhythm disturbances \cite{17-20}. Furthermore, hyperglycemia-induced metabolic disorders play a critical role in DCAN: persistent hyperglycemic and hyperlipidemic states trigger oxidative stress and systemic inflammation, directly damaging autonomic neurons and their blood supply. These mechanisms explain why patients with CAN are prone to cardiovascular events such as silent myocardial infarction and sudden cardiac arrest, with a significantly increased five-year mortality rate. When autonomic neuropathy involves the digestive tract, it is termed diabetic gastrointestinal autonomic neuropathy (DGAN), which can lead to a range of issues including esophageal dysmotility, gastroparesis,

and intestinal peristaltic disorders. Among these, diabetic gastroparesis (DGP) is a typical pathological change, primarily resulting from delayed gastric emptying caused by vagal neuropathy and dysfunction of the enteric nervous system.

Under physiological conditions, the vagus nerve plays a vital role in regulating the stomach: the proximal stomach is under continuous vagal tone for food storage, while the grinding and peristalsis of the distal stomach are controlled by gastric pacemaker cells (interstitial cells of Cajal) under autonomic influence. In the diabetic state, damage to the vagus nerve can trigger decompensation of gastric motor function, characterized by poor compliance of the proximal stomach and weak propulsive capacity of the distal stomach, leading to the retention of gastric contents. Patients often present with postprandial epigastric fullness, nausea, and vomiting, which in turn affects glycemic control (gastroparesis can cause fluctuations in blood glucose). Notably, acute hyperglycemia can directly inhibit gastric emptying, whereas hypoglycemia exerts a counter-regulatory effect. This physiological feedback is amplified in a chronic hyperglycemic environment, becoming a factor that exacerbates gastroparesis symptoms \cite{26-27}. Additionally, studies have found that local glial supporting cells and neurotransmitters in the gastrointestinal tract are altered in diabetes. For instance, a decrease in the density of gastric pacemaker cells, degeneration of enteric neurons, and disordered secretion of gastrointestinal hormones suggest that inflammatory responses and neurotransmitter imbalances also contribute to DGP \cite{28-31}. Note: PKC = protein kinase C, HBP = hexosamine pathway, NADPH = nicotinamide adenine dinucleotide phosphate, AGEs = advanced glycation end products, RAGE = receptor for advanced glycation end products, DAG = diacylglycerol, GFAT = L-glutamine:D-fructose-6-phosphate amidotransferase, TNF-$\alpha$ = tumor necrosis factor-$\alpha$, IL-6 = interleukin-6, UDP-GlcNAc = uridine diphosphate-N-acetylglucosamine, O-GlcNAc = O-linked N-acetylglucosamine, NGF = nerve growth factor, IGF-1 = insulin-like growth factor-1, ROS = reactive oxygen species, ATP = adenosine triphosphate, $Ca^{2+}$. Figure 2: Schematic diagram of the signaling pathways of diabetic autonomic neuropathy.

Chinese General Practice. These combined mechanisms lead to gastrointestinal motility disorders in diabetic patients. In addition to gastroparesis, vagal nerve damage can cause dysregulation of intestinal peristalsis; some patients present with a syndrome of alternating constipation and diarrhea, which severely impacts their quality of life.

Urogenital System

The impact of autonomic neuropathy on the urinary and reproductive systems primarily manifests as urodynamic abnormalities. Diabetic cystopathy (also known as diabetic bladder neuropathy or diabetic cystoparesis) is characterized by damage to the sacral parasympathetic nerves \cite{33-34}. The underlying mechanism involves hyperglycemia-induced degeneration of bladder sensory and motor nerve fibers, leading to impaired perception of bladder filling, weak detrusor contraction, and a blunted micturition reflex. Clinically, early stages may present as urinary frequency, urgency, or even stress or urge incontinence, suggesting detrusor overactivity. As nerve damage worsens, bladder sensation becomes dull, manifesting as hypotonic bladder symptoms such as increased urinary retention, increased residual urine, and incomplete emptying. Typical urodynamic changes include an increased bladder sensory threshold (increased bladder volume at the first urge to void), decreased detrusor contraction pressure, and increased residual urine volume. Pathophysiologically, oxidative stress caused by hyperglycemia can damage bladder smooth muscle cells and induce their apoptosis, accelerating bladder denervation. Conversely, a long-term polyuric state causes the bladder to overstretch, leading to bladder wall remodeling and thickening, which further weakens detrusor contractile function.

The incidence of erectile dysfunction (DIED) is high among diabetic men and is associated with autonomic nerve damage, primarily manifesting as sexual nerve conduction disorders. The mechanisms include damage to the cavernous parasympathetic nerves, leading to a reduction in the vasodilatory signals required for erection, as well as retrograde ejaculation induced by sympathetic neuropathy. Female patients may experience sexual dysfunction such as low libido and poor vaginal lubrication \cite{38-39}. Large prospective studies have confirmed that the presence of cardiac autonomic neuropathy is closely related to the occurrence of sexual dysfunction in both sexes. Overall, urogenital autonomic neuropathy often has an insidious onset but exerts a massive impact on the patient's quality of life, requiring high clinical attention from physicians.

3.4 皮肤和周围神经

Diabetic Autonomic Neuropathy (DAN) can involve the cutaneous microvascular system and glandular regulatory functions. The sympathetic nerve fibers that innervate sweat glands and skin blood vessels are classified as small fibers; damage to these fibers leads to abnormalities in sweat secretion and blood flow regulation. A typical clinical presentation includes reduced sweating (hypohidrosis) in the distal extremities (such as the feet) accompanied by dry, cracked skin, while the upper trunk exhibits compensatory hyperhidrosis. This sweat gland dysfunction—specifically hypohidrosis caused by autonomic neuropathy—is considered one of the earliest manifestations of diabetic small-fiber neuropathy. This pathological change acts synergistically with sensory nerve damage to impair the skin barrier function of the feet. When combined with abnormal microvascular vasomotor reflexes, these factors exacerbate wound healing impairments and significantly increase the risk of diabetic foot ulcers. Furthermore, patients with severe peripheral neuropathy may develop Charcot neuroarthropathy, a condition characterized by progressive joint destruction and deformity resulting from the simultaneous loss of protective pain sensation and autonomic regulation of blood supply. Consequently, autonomic nutritional regulation of the skin and distal limb tissues is critical, and its dysfunction is a major contributing factor to diabetic foot syndrome.

In summary, DAN presents as a multisystemic and heterogeneous clinical spectrum, with affected organs exhibiting diverse clinical manifestations (see [TABLE:1]). Although autonomic dysfunction triggered by persistent hyperglycemia shares common initiating factors, there is significant variability in susceptibility to injury among different patients and even among different organs within the same patient. Beyond classical metabolic pathways, the gut microbiota microenvironment, local cardiac inflammatory states, and bladder stretch-sensing mechanisms may play key regulatory roles in disease progression. Currently, clinical diagnosis relies primarily on testing after significant functional impairment has occurred, which often results in missing the optimal window for intervention. Therefore, it is necessary to explore early identification strategies targeting specific autonomic subpopulations or organ-specific biomarkers to facilitate a transition from symptomatic treatment to preventive protection. [TABLE:1] summarizes the clinical manifestations and diagnostic methods related to diabetic autonomic neuropathy.

In males, this manifests as erectile dysfunction or retrograde ejaculation, while in females, it presents as decreased libido and reduced vaginal lubrication. Diagnostic methods include ultrasound, comprehensive urodynamic testing, and bladder function assessment. For sexual dysfunction, evaluations include sex hormone levels; in males, nocturnal penile tumescence (NPT), bulbocavernosus reflex, dorsal penile sensory nerve conduction, penile Doppler ultrasound, and penile sympathetic skin response (SSR) are assessed. In females, perineal sensation is evaluated. Sudomotor dysfunction is assessed via sympathetic skin response, quantitative sudomotor axon reflex testing (QSART), electrochemical skin conductance (ESC), and thermoregulatory sweat testing (TST), presenting as hyperhidrosis or anhidrosis. Hypoglycemia unawareness is evaluated through blood glucose monitoring and hypoglycemia awareness questionnaires. Ocular manifestations include reduced resting pupil diameter, anisocoria, and weakened reactions to cocaine and phosphatidylcholine; these are assessed via light reflex testing, slit-lamp examination, pupillometry, and low-concentration pilocarpine tests. Note: HRV = heart rate variability.

4.1 血糖控制与基础治疗

Strict glycemic control is a fundamental measure for preventing and delaying diabetic neuropathy (DN). Research indicates that maintaining blood glucose levels near the physiological range can effectively reduce the incidence of DN \cite{43-45}. In patients with type 1 diabetes, relevant studies have shown that the incidence of cardiovascular autonomic neuropathy (CAN) in the intensive insulin therapy group was significantly lower than that in the conventional control group (14-year follow-up data showed a CAN incidence of 28.9% in the intensive group compared to 35.2% in the conventional group) \cite{46-47}. For type 2 diabetes, the impact of intensive glycemic control alone on autonomic neuropathy is less pronounced than in type 1 diabetes; however, comprehensive intervention managing multiple risk factors—including blood glucose, blood pressure, and lipids—

as reported in Chinese General Practice, has demonstrated clear neuroprotective effects. Therefore, early and individualized optimization of blood glucose, along with the management of comorbidities such as hypertension and dyslipidemia, constitutes the core strategy for the prevention and treatment of autonomic neuropathy.

Pharmacological Treatment to Improve Autonomic Function

Various drugs have been utilized in interventions and research centered on the pathogenesis of autonomic neuropathy. Aldose reductase inhibitors (ARIs) mitigate the cumulative neurotoxicity of hyperglycemia by blocking the polyol pathway \cite{49-50}. Epalrestat is a primary ARI widely used in Asia; clinical studies have shown that long-term application can improve clinical symptoms in DN patients and delay disease progression to a certain extent. Antioxidants, such as $\alpha$-lipoic acid (ALA), function by scavenging free radicals and inhibiting oxidative stress; multiple trials have demonstrated its efficacy in alleviating neuropathic pain and other symptoms. Notably, the combined application of ALA with epalrestat or mecobalamin yields superior efficacy compared to monotherapy. Additionally, drugs that improve microcirculation and provide neurotrophic support are used in the treatment of autonomic neuropathy; for instance, B-complex vitamins (mecobalamin) can promote the regeneration and repair of damaged nerves. It is worth mentioning that certain medications targeting diabetes may offer additional benefits to the autonomic nervous system: studies have found that RAAS blockers can reduce the occurrence of peripheral neuropathy in type 2 diabetes, presumably by protecting nerves through improved vascular function and reduced inflammation. Newer hypoglycemic agents, such as sodium-glucose cotransporter 2 (SGLT2) inhibitors and glucagon-like peptide-1 (GLP-1) receptor agonists, not only lower blood glucose but may also exert beneficial effects on autonomic function by reducing oxidative stress and improving cardiovascular status. Although these drugs provide possibilities for symptom relief, current pharmacological treatments still face the dilemma of "treating the symptoms rather than the root cause." While drugs like epalrestat and $\alpha$-lipoic acid can intervene in specific pathways, their ability to reverse established structural nerve damage remains limited.

Overall, pharmacological treatment should be selected comprehensively based on the patient's condition, targeting both the underlying causes, such as hyperglycemia, and providing symptomatic treatment for pain, gastrointestinal motility disorders, and orthostatic hypotension. Current intervention strategies focus primarily on symptom relief, and there is currently no specific drug that can fundamentally reverse nerve damage. Gaining a deeper understanding of the pathological mechanisms of DN and developing new drugs capable of reversing diabetic nerve damage remain significant challenges for the future.

Neuromodulation Techniques

With a deepening understanding of neural regulation mechanisms, neuromodulation therapies have begun to be applied in DN intervention research. These techniques aim to improve autonomic balance by physically stimulating autonomic or central nervous pathways. A technique garnering significant attention is vagus nerve stimulation (VNS), which includes invasive cervical VNS and non-invasive transcutaneous auricular VNS. The vagus nerve is the main trunk of the parasympathetic nervous system; stimulating this nerve can activate the body's anti-inflammatory reflex, reduce levels of inflammatory cytokines, and influence physiological processes such as insulin secretion and appetite. Animal experiments have demonstrated that transcutaneous VNS can improve insulin sensitivity and alleviate diabetes-related depression-like behavior. Its mechanism involves the release of incretins (such as GLP-1) and the enhancement of pancreatic $\beta$-cell function, thereby improving glucose metabolic homeostasis. Although research on VNS in human diabetic patients is still in its infancy, preliminary trials suggest it may increase cardiac vagal tone and improve inflammatory status. In summary, neuromodulation therapy offers new perspectives for refractory diabetic autonomic neuropathy (DAN), particularly in its potential to improve gastrointestinal motility and adjust autonomic balance. However, these technologies are still in the research and exploration stage, and more clinical trials are needed to confirm their long-term safety and efficacy.

Individualized Treatment

The clinical presentation of DAN varies greatly among patients and involves multiple systems; therefore, treatment plans must be individualized. Clinical management should involve formulating targeted treatment plans based on the primary system affected by autonomic neuropathy. For patients primarily presenting with cardiovascular autonomic neuropathy, heart rate and blood pressure changes should be closely monitored in addition to glycemic control to prevent malignant arrhythmias \cite{59-60}. When orthostatic hypotension occurs, compressive measures such as elastic stockings or vasopressors like midodrine can be administered to relieve symptoms. Patients with significant gastrointestinal autonomic neuropathy require dietary adjustments (small, frequent meals; low-fat, low-fiber diet) and the use of prokinetic drugs (such as dopamine antagonists or cisapride) to improve gastric emptying, while avoiding GLP-1 receptor agonists that may exacerbate gastroparesis \cite{61-62}. For symptoms of alternating constipation and diarrhea, the key lies in dynamically assessing the currently dominant symptom and adopting a staged, individualized management strategy. Laxatives and anti-diarrheal drugs should be used cautiously to break the vicious cycle of alternating symptoms, with the treatment goal being the improvement of the patient's quality of life rather than the pursuit of perfectly normal bowel function. Patients with impaired bladder autonomic function should establish timed voiding habits; if severe late-stage DAN complications such as urinary retention occur, cholinergic drugs or intermittent catheterization may be used. Clean intermittent catheterization (CIC) is considered the gold standard for first-line management. For refractory cases, botulinum toxin type A detrusor injection or suprapubic cystostomy may be considered. For erectile dysfunction, phosphodiesterase-5 inhibitors may be used as appropriate, supplemented by psychological intervention. Beyond organ-system-oriented symptomatic treatment, individualization is also reflected in the dynamic assessment and follow-up of autonomic function status. Clinicians can use indicators such as heart rate variability (HRV) to monitor changes in autonomic activity to judge efficacy and adjust plans. Combining HRV biofeedback training with lifestyle interventions such as regular exercise can enhance autonomic regulation. In short, individualized treatment emphasizes "tailoring to the individual," selecting the most appropriate combination of multidisciplinary interventions based on the scope and severity of the patient's autonomic damage to achieve maximum symptom improvement and complication prevention.

Existing treatment strategies indicate that for complex diseases like DAN, it is difficult for a single intervention to achieve significant results. The primary foundation of treatment is strict and stable glycemic control. Secondly, targeted medications and symptom management tools should be used in combination based on the primary target organs involved. For refractory cases, neuromodulation techniques can be considered as a supplementary treatment. Furthermore, continuous patient education, lifestyle interventions, and dynamic functional assessments are also crucial. Through such multifaceted comprehensive management, it is possible to improve the long-term prognosis and quality of life for patients.

5 结论与展望

Diabetic Autonomic Neuropathy (DAN) represents one of the most complex phenotypes of diabetic nerve damage. It frequently leads to multi-system functional impairments involving the cardiovascular, digestive, urinary, reproductive, and integumentary systems, significantly impacting patient prognosis. Although current intervention strategies can achieve certain clinical outcomes through rigorous glycemic control and symptomatic management, the overall therapeutic efficacy remains limited. Consequently, there is an urgent need to explore more effective diagnostic and therapeutic approaches to improve the quality of life and long-term outcomes for patients suffering from this multifaceted condition.

Controlling blood glucose and other metabolic risk factors can, to a certain extent, prevent or delay the onset and progression of autonomic neuropathy. However, effective means to reverse established structural nerve damage are still lacking. This reflects a significant clinical bottleneck in the field, indicating that many fundamental questions remain to be answered.

Although existing research has made significant progress in elucidating various metabolic pathways, oxidative stress, and inflammatory responses, the systemic biological mechanisms underlying Diabetic Autonomic Neuropathy (DAN) have not yet been fully clarified. The limitations of current research are primarily reflected in several key areas. First, most mechanistic studies remain fragmented, lacking an integrated understanding of the cascade of pathological damage triggered by hyperglycemia. Second, there are notable differences in susceptibility to injury among different autonomic nerve subpopulations, and the intrinsic molecular mechanisms governing these differences remain unclear. Furthermore, there is a scarcity of biomarkers available for early diagnosis and therapeutic evaluation. Current clinical diagnosis relies heavily on functional examinations, which typically identify lesions only after significant functional abnormalities have manifested, thereby hindering early intervention.

These limitations collectively constrain the development of targeted therapeutic strategies. Consequently, clinical practice must place greater emphasis on autonomic neuropathy, recognizing it as a critical component of diabetes management that requires proactive prevention and treatment.

Looking ahead, both scientific research and clinical practice are advancing in several key directions. To progress, this field must address the following critical issues: first, determining how hyperglycemia triggers damage to specific autonomic nerve subpopulations through complex metabolic and immunological pathways; and second, elucidating the specific mechanistic roles of mitochondrial dysfunction and genetic susceptibility in the onset and progression of autonomic neuropathy. A deeper understanding of these underlying mechanisms will be instrumental in the discovery of novel therapeutic targets.

At the same time, it is essential to actively explore novel neuromodulation strategies in hopes of improving autonomic nervous system dysfunction. In clinical practice, emphasis should be placed on individualized and precision medicine. Prevention and treatment plans should be tailored based on the results of each patient's autonomic function assessment. By leveraging emerging diagnostic technologies, early signs of autonomic damage can be identified, allowing for timely interventions that contain the injury while it is still in a reversible stage.

In summary, as research into the role of the autonomic nervous system (ANS) in diabetic complications deepens, we are poised to enter an era of more comprehensive and effective interventions. By fostering a close integration of basic research and clinical practice, it will be possible to develop innovative therapies based on autonomic regulation. Integrating these novel approaches with traditional metabolic control measures will allow for the formulation of optimized, individualized treatment plans tailored to different patients. Ultimately, these advancements will significantly improve the prognosis and quality of life for patients with diabetic nephropathy (DN).

Author Contributions: Ziyun Pan and Hao Yin were responsible for the conception and design of the study, as well as the drafting of the manuscript. Zhirou Lin, Jingyi Mao, Yan Huang, Yanhua Luo, and Jiafu Xiao were responsible for the revision of the manuscript, quality control, and proofreading. Yin Hu provided supervision, critical revision and review of the manuscript, and financial support.

The authors declare no conflicts of interest.

参考文献

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Diabetic Neuropathy Diagnosis and Treatment Expert Consensus (2021 Edition)

Neuropathy Research Group of the Diabetes Society of the Chinese Medical Association. Chinese Journal of Diabetes, 2021, 13(6): 540-557. DOI: 10.3760/cma.j.cn115791-20210310-00143.

Introduction

Diabetic neuropathy (DN) is one of the most common chronic complications of diabetes, characterized by high prevalence, complex clinical manifestations, and significant morbidity. It can affect various parts of the nervous system, including the peripheral, autonomic, and central nervous systems. Among these, diabetic peripheral neuropathy (DPN) is the most frequent clinical presentation. If left untreated, DN can lead to severe consequences such as foot ulcers, amputations, and cardiovascular events, placing a heavy burden on patients and the healthcare system.

To standardize the clinical diagnosis and treatment of diabetic neuropathy in China, the Neuropathy Research Group of the Diabetes Society of the Chinese Medical Association has updated the previous guidelines based on the latest international and domestic evidence-based medical research. This 2021 edition of the consensus aims to provide clinicians with updated strategies for screening, diagnosis, and comprehensive management.

Classification and Definition

Diabetic neuropathy is a heterogeneous group of disorders. According to the anatomical site and clinical characteristics, it is primarily classified into the following categories:

1. Diabetic Peripheral Neuropathy (DPN)

DPN refers to the presence of symptoms and/or signs of peripheral nerve dysfunction in patients with diabetes after excluding other causes. The most common form is Distal Symmetric Polyneuropathy (DSPN).

2. Diabetic Autonomic Neuropathy (DAN)

DAN involves the autonomic nerves controlling internal organs. Clinical manifestations include cardiovascular autonomic neuropathy (CAN), gastrointestinal neuropathy, urogenital neuropathy, and sudomotor dysfunction.

3. Atypical Neuropathies

These include mononeuropathies (e.g., cranial nerve palsies), radiculoplexus neuropathy (e.g., diabetic amyotrophy), and treatment-induced neuropathy of diabetes (TIND).

Screening and Diagnosis

1. Screening Recommendations

• Type 2 Diabetes: Screening for DPN should be performed at the time of diagnosis and at least annually thereafter.
• **Type

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Therapeutic Efficacy of Epalrestat Combined with Intravenous Alpha-Lipoic Acid in the Treatment of Diabetic Peripheral Neuropathy

Author: Zhang Bin
Source: China Practical Medicine, 2025, 20(3): 30-33.
DOI: 11-5547/r.2025.03.007

Abstract

Objective: To investigate the clinical efficacy of combining Epalrestat with intravenous alpha-lipoic acid ($\alpha$-LA) for the treatment of diabetic peripheral neuropathy (DPN).

Methods: A total of 84 patients with DPN treated at our hospital between January 2022 and December 2023 were selected as research subjects. The patients were randomly divided into a control group and an experimental group, with 42 cases in each group. Both groups received conventional treatments, including blood glucose control. The control group was treated with intravenous $\alpha$-LA, while the experimental group received a combination of Epalrestat and intravenous $\alpha$-LA. Clinical efficacy, nerve conduction velocities, oxidative stress markers, and the incidence of adverse reactions were compared between the two groups.

Results: The total effective rate in the experimental group was significantly higher than that in the control group ($P < 0.05$). Following treatment, both the motor nerve conduction velocity (MNCV) and sensory nerve conduction velocity (SNCV) of the median and common peroneal nerves improved in both groups, with the experimental group showing significantly greater improvements than the control group ($P < 0.05$). Furthermore, the experimental group demonstrated superior improvements in oxidative stress markers compared to the control group ($P < 0.05$). There was no statistically significant difference in the incidence of adverse reactions between the two groups ($P > 0.05$).

Conclusion: The combination of Epalrestat and intravenous $\alpha$-LA is effective in treating DPN. It significantly improves nerve conduction velocity, reduces oxidative stress, and maintains a high safety profile, making it worthy of clinical application.

1. Introduction

Diabetic peripheral neuropathy (DPN) is one of the most common chronic complications of diabetes mellitus, characterized by sensory, motor, and autonomic nerve dysfunction. The pathogenesis of DPN is complex, involving polyol pathway activation, oxidative stress, and microvascular disturbances.

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