Diabetic peripheral neuropathy(DPN) is a chronic complication resulted from peripheral nerve injury in the late stage of diabetes. It involves a variety of pathological changes such as oxidative stress, endoplasmic reticulum stress, neuroinflammation, and apoptosis of Schwann cells(SCs). DPN is the main factor leading to lower limb disability or amputation in diabetic patients, with high incidence, long disease course, and poor prognosis. The modern medicine treatment of DPN mainly focuses on controlling blood glucose and improving microcirculation and nerve nutrition, which can only mitigate the clinical symptoms and not fundamentally reverse the pathological changes of peripheral nerves. Autophagy is a self-clearing mechanism that maintains cellular homeostasis by removing excess metabolites. Traditional Chinese medicine(TCM), featuring the holistic concept and syndrome differentiation, can treat chronic diseases in a multi-target, multi-pathway, and wide-range manner. Modern studies have shown that the occurrence and development of DPN are related to a variety of pathological changes, and autophagy is a key mechanism associated with DPN. The environment with persistent high glucose can lead to the inhibition or over-activation of peripheral nerve cells, which causes irreversible damage of nerve cells and the occurrence and development of DPN. Therefore, restoring autophagy balance and reducing nerve damage is one of the key ways to treat DPN. The recent studies have confirmed that some active ingredients in traditional Chinese medicines and TCM compound prescriptions can inhibit the oxidative stress, endoplasmic reticulum stress, mitochondrial damage, inflammation, and apoptosis of SCs in DPN by regulating the autophagy pathway, thus playing a role in the prevention and treatment of DPN. However, the systematic induction in this field remains to be carried out. This paper reviewed the relevant literature, explained the mechanism of TCM in the prevention and treatment of DPN by regulating autophagy, and summarized the potential targets of TCM in the treatment of DPN, with a view to providing new ideas for clinical research and drug development.
Humans ; Autophagy ; Diabetes Mellitus ; Diabetic Neuropathies/complications* ; Medicine, Chinese Traditional ; Oxidative Stress ; Schwann Cells/pathology*

Diabetic neuropathy is a common diabetic complication.The application of metabolomics in the research on diabetic neuropathy is beneficial for us to understand the pathophysiological processes and overall metabolic disturbance of the nervous system under the condition of hyperglycemia,decipher the pathogenesis of diabetic neuropathy,and mine the potential biomarkers for clinical diagnosis and treatment.Long-term hyperglycemia may lead to disorders in multiple pathways,such as tricarboxylic acid circle,amino acid metabolism,and lipid metabolism.These metabolic changes are closely associated with the injuries of the peripheral and central nervous system.In the paper,we reviewed the metabolomics-based studies about diabetic neuropathy in the last five years.
Biomarkers ; Diabetes Mellitus ; Diabetic Neuropathies ; Humans ; Hyperglycemia/complications* ; Metabolomics

BACKGROUND: Corneal confocal microscopy (CCM) is a noninvasive technique to detect early nerve damage of diabetic sensorimotor polyneuropathy (DSPN). Time in range (TIR) is an emerging metric of glycemic control which was reported to be associated with diabetic complications. We sought to explore the relationship between TIR and corneal nerve parameters in asymptomatic patients with type 2 diabetes (T2DM). METHODS: In this cross-sectional study, 206 asymptomatic inpatients with T2DM were recruited. After 7 days of continuous glucose monitoring, the TIR was calculated as the percentage of time in the glucose range of 3.9 to 10.0 mmol/L. CCM was performed to determine corneal nerve fiber density, corneal nerve branch density, and corneal nerve fiber length (CNFL). Abnormal CNFL was defined as ≤15.30 mm/mm 2 . RESULTS: Abnormal CNFL was found in 30.6% (63/206) of asymptomatic subjects. Linear regression analyses revealed that TIR was positively correlated with CCM parameters both in the crude and adjusted models (all P   <  0.05). Each 10% increase in TIR was associated with a 28.2% (95% CI: 0.595-0.866, P  = 0.001) decreased risk of abnormal CNFL after adjusting for covariates. With the increase of TIR quartiles, corneal nerve fiber parameters increased significantly (all P for trend <0.01). The receiver operating characteristic curve indicated that the optimal cutoff point of TIR was 77.5% for predicting abnormal CNFL in asymptomatic patients. CONCLUSIONS There is a significant independent correlation between TIR and corneal nerve fiber loss in asymptomatic T2DM patients. TIR may be a useful surrogate marker for early diagnosis of DSPN.
Humans ; Diabetes Mellitus, Type 2/complications* ; Cross-Sectional Studies ; Blood Glucose Self-Monitoring ; Blood Glucose ; Nerve Fibers ; Diabetic Neuropathies ; Cornea ; Microscopy, Confocal/methods*

BACKGROUND: Vitamin D deficiency has been reported to be associated with diabetic microvascular complications, but previous studies have only focused on the relationship between vitamin D and specific complications. Therefore, we aimed to explore the relationship between vitamin D level and diabetic microvascular complications in general, including diabetic retinopathy (DR), diabetic nephropathy (DN), and diabetic peripheral neuropathy (DPN). METHODS: This was a cross-sectional study of 815 patients with type 2 diabetes mellitus (T2DM). Clinical information and laboratory results were collected from the medical records. The relationship between vitamin D and the three diabetic microvascular complications was investigated. RESULTS: The serum 25-hydroxyvitamin D (25 [OH] D) level of patients with DPN and/or DN was significantly lower than that of T2DM patients without any microvascular complications (P < 0.01). Univariate analysis showed that the 25 (OH) D level was related to DPN and DN, but not DR. After adjustment, the 25 (OH) D level was confirmed to be an independent protective factor for DPN (odds ratio [OR]: 0.968, P = 0.004]) and DN (OR: 0.962, P = 0.006). The prevalence of DPN and DN increased significantly as the serum 25 (OH) D levels decreased. Furthermore, patients with both DPN and DN had the lowest concentration of serum 25 (OH) D (P < 0.001), and the prevalence of macroalbuminuria increased more abruptly than that of microalbuminuria across the 25 (OH) D tertiles. Among the patients with vitamin D insufficiency, those with DPN presented more comorbid macroalbuminuria than those without DPN (15.32% vs. 4.91%; P = 0.001). CONCLUSIONS Vitamin D deficiency is independently associated with higher risk of DPN and DN, but not DR, in T2DM patients. Further, it may be a potential predictor for both the occurrence and severity of DPN and DN.
Cross-Sectional Studies ; Diabetes Mellitus, Type 2/complications* ; Diabetic Nephropathies ; Diabetic Neuropathies ; Humans ; Risk Factors ; Vitamin D

OBJECTIVES: To explore the improvement of neurological symptoms in patients with Type 2 diabetic peripheral neuropathy via resistance exercise. METHODS: A total of 100 patients with Type 2 diabetic peripheral neuropathy were selected as the research objects, and they were randomly divided into an observation group who performed resistance exercise ( RESULTS: Compared with the control group, there was statistically difference in the TCSS scores in the observation group at 3 months ( CONCLUSIONS After the intervention of resistance exercise, the blood glucose and DPN can be improved in a certain extent, and which can be popularized in Type 2 diabetes patients.
Blood Glucose ; Body Mass Index ; Diabetes Mellitus, Type 2/complications* ; Diabetic Neuropathies ; Humans ; Resistance Training

Painful diabetic neuropathy (PDN) is a diabetes mellitus complication. Unfortunately, the mechanisms underlying PDN are still poorly understood. Adenosine triphosphate (ATP)-gated P2X7 receptor (P2X7R) plays a pivotal role in non-diabetic neuropathic pain, but little is known about its effects on streptozotocin (STZ)-induced peripheral neuropathy. Here, we explored whether spinal cord P2X7R was correlated with the generation of mechanical allodynia (MA) in STZ-induced type 1 diabetic neuropathy in mice. MA was assessed by measuring paw withdrawal thresholds and western blotting. Immunohistochemistry was applied to analyze the protein expression levels and localization of P2X7R. STZ-induced mice expressed increased P2X7R in the dorsal horn of the lumbar spinal cord during MA. Mice injected intrathecally with a selective antagonist of P2X7R and P2X7R knockout (KO) mice both presented attenuated progression of MA. Double-immunofluorescent labeling demonstrated that P2X7R-positive cells were mostly co-expressed with Iba1 (a microglia marker). Our results suggest that P2X7R plays an important role in the development of MA and could be used as a cellular target for treating PDN.
Acetamides/pharmacology* ; Animals ; Diabetes Mellitus, Experimental/complications* ; Diabetes Mellitus, Type 1/complications* ; Diabetic Neuropathies/etiology* ; Hyperalgesia/etiology* ; Male ; Mice ; Mice, Inbred C57BL ; Quinolines/pharmacology* ; Receptors, Purinergic P2X7/physiology* ; Spinal Cord/physiology* ; Streptozocin/pharmacology*

Patients with diabetic peripheral neuropathy experience debilitating pain that significantly affects their quality of life (Abbott et al., 2011), by causing sleeping disorders, anxiety, and depression (Dermanovic Dobrota et al., 2014). The primary clinical manifestation of painful diabetic neuropathy (PDN) is mechanical hypersensitivity, also known as mechanical allodynia (MA) (Callaghan et al., 2012). MA's underlying mechanism remains poorly understood, and so far, based on symptomatic treatment, it has no effective therapy (Moore et al., 2014).
Animals ; CX3C Chemokine Receptor 1/physiology* ; Chemokine CX3CL1/physiology* ; Diabetes Mellitus, Experimental/complications* ; Diabetes Mellitus, Type 1/complications* ; Diabetic Neuropathies/etiology* ; Hyperalgesia/etiology* ; Mice ; Mice, Inbred C57BL ; Spinal Cord/physiology* ; Streptozocin/pharmacology*

Oxidative stress is considered a major contributor in the pathogenesis of diabetic neuropathy and in diabetes complications, such as nephropathy and cardiovascular diseases. Diabetic neuropathy, which is the most frequent complications of diabetes, affect sensory, motor, and autonomic nerves. This study aimed to investigate whether 7,8-dihydroxyflavone (7,8-DHF) protects SH-SY5Y neuronal cells against high glucose-induced toxicity. In the current study, we found that diabetic patients exhibited higher lipid peroxidation caused by oxidative stress than healthy subjects. 7,8-DHF exhibits superoxide anion and hydroxyl radical scavenging activities. High glucose-induced toxicity severely damaged SH-SY5Y neuronal cells, causing mitochondrial depolarization; however, 7,8-DHF recovered mitochondrial polarization. Furthermore, 7,8-DHF effectively modulated the expression of pro-apoptotic protein (Bax) and anti-apoptotic protein (Bcl-2) under high glucose, thus inhibiting the activation of caspase signaling pathways. These results indicate that 7,8-DHF has antioxidant effects and protects cells from apoptotic cell death induced by high glucose. Thus, 7,8-DHF may be developed into a promising candidate for the treatment of diabetic neuropathy.
Antioxidants ; Autonomic Pathways ; Cardiovascular Diseases ; Cell Death ; Diabetes Complications ; Diabetic Neuropathies ; Glucose ; Healthy Volunteers ; Humans ; Hydroxyl Radical ; Lipid Peroxidation ; Neurons* ; Oxidative Stress* ; Superoxides

The influence of β-cell function on cardiovascular autonomic neuropathy (CAN), an important diabetes-related complication, is still unclear. In this study, we aimed to investigate the association between residual β-cell function and CAN in patients newly diagnosed with type 2 diabetes. We enrolled 90 newly-diagnosed type 2 diabetic patients and 37 participants with normal glucose tolerance as controls. The patients were divided into a CAN+ group (diabetic patients with CAN, n = 20) and a CAN- group (diabetic patients without CAN, n = 70) according to the standard Ewing battery of tests. Fasting and postprandial plasma glucose, insulin, and C-peptide were measured. Homeostasis model assessment-beta cells (HOMA-B) and HOMA-insulin resistance (IR) were calculated. The prevalence of CAN in this population was 22.2%. Compared with the CAN- group, the CAN+ group had significantly lower fasting plasma insulin (6.60 ± 4.39 vs 10.45 ± 7.82 μ/L, P = 0.029), fasting C-peptide (0.51 ± 0.20 vs 0.82 ± 0.51 nmol/L, P = 0.004), and HOMA-B (21.44 ± 17.06 vs 44.17 ± 38.49, P = 0.002). Fasting C-peptide was correlated with the Valsalva ratio (r = 0.24, P = 0.043) and the 30:15 test (r = 0.26, P = 0.023). Further analysis showed that fasting C-peptide (OR: 0.041, 95% CI 0.003-0.501, P = 0.012) and HOMA-B (OR: 0.965, 95% CI 0.934-0.996, P = 0.028) were independently associated with cardiovascular autonomic nerve function in this population. The patients with fasting C-peptide values < 0.67 nmol/L were more likely to have CAN than those with C-peptide levels ≥0.67 nmol/L (OR: 6.00, 95% CI 1.815-19.830, P = 0.003). A high prevalence of CAN was found in patients with newly-diagnosed type 2 diabetes. Decreased β-cell function was closely associated with CAN in this population.
Adult ; Asian Continental Ancestry Group ; Blood Glucose ; analysis ; Diabetes Mellitus, Type 2 ; complications ; metabolism ; Diabetic Neuropathies ; etiology ; Fasting ; physiology ; Female ; Glucose ; metabolism ; Humans ; Insulin ; metabolism ; Insulin Resistance ; physiology ; Insulin-Secreting Cells ; metabolism ; Male ; Middle Aged

Mahuang Fuzi Xixin Decoction recorded in Treatise on Febrile Diseases by Zhang Zhongjing in the Han Dynasty have been widely used in treating Yang deficiency and exogenous wind-cold syndrome by traditional Chinese medicine physicians for thousands of years. The indications of Mahuang Fuzi Xixin Decoction include bradyarrhythmia,sinus bradycardia,sick sinus node syndrome,senile exogenous,asthmatic cold,rhinitis,bronchial asthma,optic neuritis,optic atrophy,sudden blindness,sudden onset of cough,laryngeal obstruction,migraine,joint pain,low back pain,insomnia,shock,heart failure,renal failure,accompanied by fever or nosocomial infection,and hyperpyrexia after tracheotomy; dark complexion,chills,cold limbs,listlessness,fatigue,insomnia,lack of thirst,liking hot drinks,slightly swollen limbs or whole body,pale fat tongue,greasy fur,and deep pulse. Mahuang Fuzi Xixin Decoction is a potential drug for Shaoyin disease complicated with fever and pain. Tracheal intubation is an artificial ephedrine syndrome. It is necessary to distinguish Yin and Yang syndrome in treating hyperpyrexia after tracheotomy. However,it belongs to Yin syndrome,which could be treated by Mahuang Fuzi Xixin Decoction. Mahuang Fuzi Xixin Decoction is effective in the treatment of sick sinus syndrome,second degree atrioventricular block and third degree atrioventricular block. It can significantly alleviate symptoms,improve heart rate,and heart rhythm in a short period of time. However,after one year of drug withdrawal,the diseases may recur,indicating that Mahuang Fuzi Xixin Decoction may not improve the long-term prognosis of slow arrhythmia. Mahuang Fuzi Xixin Decoction is often used for fever or nosocomial infection in critical care medicine. In the treatment of critical care medicine complicated with high fever,Mahuang Fuzi Xixin Decoction is often taken continuously by stomach tube.
Critical Care ; Cross Infection/drug therapy* ; Diabetes Mellitus ; Diabetic Neuropathies/complications* ; Drugs, Chinese Herbal/pharmacology* ; Fever/drug therapy* ; Humans ; Medicine, Chinese Traditional ; Myocardial Infarction/complications* ; Pain, Postoperative/drug therapy* ; Phytotherapy ; Syndrome ; Tracheotomy/adverse effects*