糖尿病的周围神经病变:研究与治疗

背景:糖尿病周围神经病变致残率高,是最常见的糖尿病慢性并发症之一,其发病机制复杂多样,目前尚无公认的治疗方式。临床上治疗和管理这种慢性疾病仍是一种挑战,但该方面的综述较少。目的:探讨糖尿病周围神经病变的相关发病机制,并就不同治疗方式对糖尿病周围神经病变的应用效果展开综述。方法:由第一作者检索中国知网、万方数据库及PubMed数据库中收录的相关文献,中文检索词为“糖尿病周围神经病变,糖尿病并发症,发病机制,诊断,治疗,中医,外科治疗,手术,电刺激,神经松解术,神经减压术”,英文检索词为“DPN,diabetic peripheral neuropathy,pathogenesis,diagnosis,therapy,treatment,drug,surgery,nervedecompression,nerveelectricalstimulation,gene,exosome”。文献检索时间限定在2000年1月至2022年1月,通过阅读文章摘要对文献进行初步筛选,排除与文章主题不相关的文献,纳入的文献数为88篇。结果与结论:①高血糖是糖尿病周围神经病变的根本病因,加强控制血糖是治疗糖尿病周围神经病变的最基础也是最重要的一步;②镇痛药物可显著减轻糖尿病周围神经病变患者的疼痛症状,α-硫辛酸、依帕司他通过抗氧化应激发挥作用,甲钴胺、神经生长因子可促进神经功能恢复;③根据糖尿病周围神经病变的“双重挤压”的致病机制,神经松解术和神经转移术可改善糖尿病周围神经病变患者神经病变程度、减轻疼痛、提高神经传导速度;④基因及干细胞等疗法是具有前景的新疗法,它们具有靶向性,但目前缺乏临床研究,且存在伦理及安全性问题。

空气波压力结合中药封包治疗糖尿病周围神经病的疗效观察

目的观察空气波压力结合中药封包治疗糖尿病周围神经病的临床疗效。方法将60例糖尿病周围神经病下肢型患者分随机分为治疗组30例和对照组30例,两组均接受相同的糖尿病专科药物治疗,治疗组在此基础上增加空气波压力结合中药封包治疗,比较两组治疗的有效率及治疗前后腓神经传导速度。结果治疗组采用空气波压力结合中药封包治疗糖尿病周围神病变的有效率93.3%,显著优于对照组的53.3%(P<0.01);治疗组经治疗后腓神经传导速度(45.6±1.8)m/s,显著优于对照组的(39.6±1.6)m/s(P<0.01)。结论空气波压力结合中药封包治疗在改善糖尿病周围神经病变、神经传导速度及相关症状等方面的临床效果显著。

血塞通与甲钴胺联合治疗糖尿病周围神经病变

目的:观察血塞通与甲钴胺联用和单用甲钴胺治疗糖尿病周围神经病变(DPN)的疗效。方法:对90例DPN患者进行随机阳性对照,观察临床疗效和神经传导速度(NCV)。治疗组48例联合应用血塞通与甲钴胺,血塞通注射液300 mg静脉滴注,1次/d,同时甲钴胺500μg肌内注射,3次/周,4周后改口服血塞通片100 mg,3次/d,同时口服甲钴胺片500μg,服用8周。对照组42例单用甲钴胺,500μg肌内注射,3次/周,4周后改口服,500μg,3次/d,服用8周。结果:治疗组的疗效明显优于对照组,两组比较,差异有统计学意义(P<0.01);治疗组NCV的改变较对照组有明显的增加,两组间差异有统计学意义(P<0.01)。结论:甲钴胺与血塞通联合应用是治疗DPN的安全有效的临床治疗措施之一。

自拟愈消痹方治疗糖尿病周围神经病变

目的观察自拟愈消痹方联合西药治疗糖尿病周围神经病变的疗效。方法将98例糖尿病周围神经病变患者按1:1随机分为治疗组和对照组,2组患者均给予西药常规治疗,治疗组49例在对照组治疗基础上加用自拟愈消痹加减治疗。2组疗程疗均为10d,连续治疗3个疗程后,观察2组患者治疗前后临床症状及Toronto临床评分和神经传导速度的改善情况。结果治疗组临床症状改善优于对照组(P<0.05);治疗组和对照组治疗前临床症状积分与Toronto临床评分分别和本组治疗后比较,差异有显著性意义(P<0.05);治疗组疗效优于对照组,差异有显著性意义(P<0.05)。结论自拟愈消痹汤联合西药治疗糖尿病周围神经病变疗效确定。

从脏腑相关理论论治糖尿病周围神经病变

糖尿病周围神经病变（络病），乃糖尿病常见的并发症之一。中医认为“脾主肌肉”、“肾主骨”,故糖尿病周围神经病变的发病主要与脾肾功能失调有关。现从脏腑相关理论探讨，本病痛机与治则。治疗糖尿病周围神经病变在应用西医西药有效控制血糖的基础上，明辨五脏腑相关理论，采取、辨病、辨脏腑，辨证论治的治疗法则。

CLINICAL AND ELECTROPHYSIOLOGICAL OBSERVATIONS ON DIABETIC PERIPHERAL NEUROPATHYTREATED BY WARM NEEDLING AND MOXIBUSTION

Objective To observe clinical therapeutic effects of warm needling and moxibustion on diabetic peripheral neuropathy （DPN） and their influence on nerve conduction velocity. Methods Fifty two cases were randomly divided into a treatment group （n =26） and a control group （n =26）. In addition to basic treatment for lowering blood sugar in both groups, Pǐshū （BL 20）, Shènshū （BL 23）, Huántiào （GB 30）, Zùsānlǐ （ST 36）, Yánglíngquán （GB 34）, Sānyīnjiāo （SP 6）, Tàixī （KI 3）, Qǔchí （LI 11）, Wàiguān （TE 5） and Hégǔ （LI 4） were selected for warm needling and moxibustion in the treatment group. Methycobal was intramuscularly injected in the control group. Clinical symptoms and conduction velocities of the tibial nerve and common peroneal nerve were compared before and after treatment. Results Warm needling and moxibustion could alleviate such clinical symptoms as numbness of limbs, pain and hypoesthesia, and obviously improve the conduction velocities of both tibial and common peroneal nerves. Conclusion Warm needling and moxibustion exhibit good therapeutic effects on diabetic peripheral neuropathy.

THERAPEUTIC EFFECTS OF ACUPUNCTURE COMBINED WITH MEDICINE ON DIABETIC NEUROPATHY

Objective To search for a good therapeutic method for treating diabetic neuropathy. Methods Patients were randomly divided into an acupuncture group （n =30） and a control group （n =26）. In the control group, gliclazide, at the dose of 80 mg/d, for lowering blood sugar, and adenosine coenzyme B12, at the dose of 0.75 mg, for improving nutrition of nerves were orally administered. In the acupuncture group, acupuncture at bilateral Yishu point was added. Three weeks of treatments were given for both groups. Therapeutic effects and changes in fasting blood sugar, fasting glucose in urine and blood fat were observed. Results The total effective rate was 93.3% and 67.3% in the acupuncture and control group, respectively. Fasting blood sugar, fasting glucose in urine, total cholesterol and triglyceride were obviously lowered, and high density lipoprotein markedly elevated in the acupuncture group with significant differences, compared with those in the control group （P〈0.05）. Conclusion Acupuncture combined with medicine can improve disorder of fat metabolism in diabetic patients at the early and intermediate stages and depress and stabilize blood glucose to improve neural functions.

Identification of differentially expressed genes in dorsal root ganglion in early diabetic rats

Objective To screen and identify differentially expressed genes in the dorsal root ganglion （DRG） in early experimental diabetic rats. Methods Diabetic model rats were induced by single intraperitoneal injection of streptozotocin （STZ）. At the second week after STZ injection, the sensory nerve conduction velocities （SNCV） of sciatic nerve were measured as an indicator of neuropathy. The technique of silver-staining mRNA differential display polymerase chain reaction （DD-PCR） was used to detect the levels of differentially expressed genes in rat DRG. The cDNA fragments that displayed differentially were identified by reverse-hybridization, cloned and sequenced subsequently, and then confirmed by Northern blot. Results The SNCV in the diabetic model group [n = 9, （45.25±10.38） m/s] reduced obviously compared with the control group [n = 8, （60.10± 11.92） m/s] （P 〈 0.05）. Seven distinct cDNA clones, one was up-regulated gene and the others were downregulated ones, were isolated by silver-staining mRNA differential display method and confirmed by Northern blot. According to the results of sequence alignment with GenBank data, majority of the clones had no significant sequence similarity to previously reported genes except only one that showed high homology to 6-pyruvoyl-tetrahydropterin synthase mRNA （accession No., BC059140）, which had not been reported to relate to diabetic neuropathy. Conclusion These differentially expressed genes in the diabetic DRG may contribute to the pathogenesis of diabetic peripheral neuropathy.

Impaired contractility and remodeling of the upper gastrointestinal tract in diabetes mellitus type-1

AIM: To investigate that both the neuronal function of the contractile system and structural apparatus of the gastrointestinal tract are affected in patients with longstanding diabetes and auto mic neuropathy. METHODS: The evoked esophageal and duodenal contractile activity to standardized bag distension was assessed using a specialized ultrasound-based probe. Twelve type-1 diabetic patients with autonomic neuropathy and severe gastrointestinal symptoms and 12 healthy controls were studied. The geometry and biomechanical parameters (strain, tension/stress, and stiffness) were assessed. RESULTS: The diabetic patients had increased frequency of distension-induced contractions (6.0 ± 0.6 vs 3.3 ± 0.5, P < 0.001). This increased reactivity was correlated with the duration of the disease (P = 0.009). Impaired coordination of the contractile activity in diabetic patients was demonstrated as imbalance between the time required to evoke the first contraction at the distension site and proximal to it (1.5 ± 0.6 vs 0.5 ± 0.1, P = 0.03). The esophageal wall and especially the mucosa-submucosa layer had increased thickness in the patients (P < 0.001), and the longitudinal and radial compressive stretch was less in diabetics (P <0.001). The esophageal and duodenal wall stiffness and circumferential deformation induced by the distensions were not affected in the patients (all P > 0.14). CONCLUSION: The impaired contractile activity with an imbalance in the distension-induced contractions likely reflects neuronal abnormalities due to autonomic neuropathy. However, structural changes and remodeling of the gastrointestinal tract are also evident and may add to the neuronal changes. This may contribute to the pathophysiology of diabetic gut dysfunction and impact on future management of diabetic patients with gastrointestinal symptoms.

Early diabetic neuropathy:Triggers and mechanisms

Pedpheral neuropathy, and specifically distal peripheral neuropathy （DPN）, is one of the most frequent and troublesome complications of diabetes mellitus. It is the major mason for morbidity and mortality among diabetic patients. It is also frequently associated with debilitating pain. Unfortunately, our knowledge of the natural history and pathogenesis of this disease remains limited. For a long time hyperglycemia was viewed as a major, if not the sole factor, responsible for all symptomatic presentations of DPN. Multiple clinical observations and animal studies supported this view. The control of blood glucose as an obligatory step of therapy to delay or reverse DPN is no longer an arguable issue. However, while supporting evidence for the glycemic hypothesis has accumulated, multiple controversies accumulated as well. It is obvious now that DPN cannot be fully understood without considering factors besides hyperglycemia. Some symptoms of DPN may develop with little, if any, correlation with the glycemic status of a patient. It is also dear that identification of these putative non-glycemic mechanisms of DPN is of utmost importance for our understanding of failures with existing treatments and for the development of new approaches for diagnosis and therapy of DPN. In this work we will review the strengths and weaknesses of the glycemic hypothesis, focusing on dinical and animal data and on the pathogenesis of early stages and triggers of DPN other than hyperglycemia.

Increased prevalence of symptoms of gastroesophageal reflux diseases in type 2 diabetics with neuropathy

AIM： To analyze the prevalence of gastroesophageal reflux disease （GERD） related symptoms in patients with diabetes mellitus （DM） and to find out the relationship between diabetic neuropathy and the prevalence of GERD symptoms. METHODS： In this prospective questionnaire study, 150 consecutive type 2 diabetic patients attending the endocrine clinic were enrolled. A junior physician helped the patients to understand the questions. Patients were asked about the presence of five most frequent symptoms of GERD that included heartburn （at least 1/wk）, regurgitation, chest pain, hoarseness of voice and chronic cough. Patients with past medical history of angina, COPD, asthma, cough due to ACEI or preexisting GERD prior to onset of diabetes and apparent psychiatric disorders were excluded from the survey. We further divided the patients into two groups based on presence or absence of peripheral neuropathy. Out of 150 patients, 46 had neuropathy, whereas 104 patients did not have neuropathy. Data are expressed as mean ± SD, and number of patients in each category and percentage of total patients in that group. Normal distributions between groups were compared with Student t test and the prevalence rates between groups were compared with Chi-square tests for significance. RESULTS： The average duration of diabetes were 12 ± 9.2 years and the average HbAlc level of this group was 7.7% ± 2.0%. The mean weight and BMI were 198 ± 54 Ibs. and 32 ± 7.2 kg/m^2. Forty percent （61/150） patients reported having at least one of the symptoms of GERD and thirty percent （45/150） reported having heartburn at least once a week. The prevalence of GERD symptoms is higher in patients with neuropathy than patients without neuropathy （58.7% vs 32.7%, P 〈 0.01）. The prevalence of heartburn, chest pain and chronic cough are also higher in patients with neuropathy than in patients without neuropathy （43.5% vs 24%; 10.9% vs 4.8% and 17.8% vs 6.7% respectively, P 〈 0.05）. CONCLUSION： The prevalence of GERD symptoms in type 2 DM is higher than in the general population. Our data suggest that DM neuropathy may be an important associated factor for developing GERD symptoms.

Neuroprotective action of Ginkgo biloba on the enteric nervous system of diabetic rats

AIM: To investigate the effect of Ginkgo biloba extract on the enteric neurons in the small intestine of diabetic rats. METHODS: Fifteen Wistar rats were divided into three groups: control group (C), diabetic group (D) and diabetic-treated (DT) daily with EGb 761 extract (50 mg/kg body weight) for 120 d. The enteric neurons were identified by the myosin-V immunohistochemical technique. The neuronal density and the cell body area were also analyzed. RESULTS: There was a significant decrease in the neuronal population (myenteric plexus P = 0.0351; submucous plexus P = 0.0217) in both plexuses of the jejunum in group D when compared to group C. With regard to the ileum, there was a significant decrease (P = 0.0117) only in the myenteric plexus. The DT group showed preservation of the neuronal population in the jejunum submucous plexus and in the myenteric plexus in the ileum. The cell body area in group D increased significantly (P = 0.0001) in the myenteric plexus of both segments studied as well as in the ileum submucosal plexus, when compared to C. The treatment reduced (P = 0.0001) the cell body area of the submucosal neurons of both segments and the jejunum myenteric neurons. CONCLUSION: The purified Ginkgo biloba extract has a neuroprotective effect on the jejunum submucous plexus and the myenteric plexus of the ileum of diabetic rats.

Myenteric neurons and intestinal mucosa of diabetic rats after ascorbic acid supplementation

AIM: To investigate the effect of ascorbic acid (AA) dietary supplementation on myenteric neurons and epithelial cell proliferation of the jejunum of adult rats with chronic diabetes mellitus. METHODS: Thirty rats at 90 d of age were divided into three groups: Non-diabetic, diabetic and diabetic treated with AA (DA) (1 g/L). After 120 d of treatment with AA the animals were killed. The myenteric neurons were stained for myosin-V and analyzed quantitatively in an area of 11.2 mm2/animal. We further measured the cellular area of 500 neurons per group. We also determined the metaphasic index (MI) of the jejunum mucosa layer of about 2500 cells in the intestinal crypts, as well as the dimensions of 30 villi and 30 crypts/animal. The data area was analyzed using the Olympus BX40 microscope. RESULTS: There was an increase of 14% in the neuronal density (792.6 ± 46.52 vs 680.6 ± 30.27) and 4.4% in the cellular area (303.4 ± 5.19 vs 291.1 ± 6.0) respectively of the diabetic group treated with AA when compared to control diabetic animals. There were no signifi cant differences in MI parameters, villi height or crypt depths among the groups.CONCLUSION: Supplementation with AA in the diabetic animal promoted moderate neuroprotection. There was no observation of alteration of the cellular proliferation of the jejunum mucosa layer of rats with chronic diabetes mellitus with or without supplementation with AA.

THE ROLE OF IGF-1 GENE EXPRESSION ABNORMALITY IN PATHOGENESIS OF DIABETIC PERIPHERAL NEUROPATHY

Objective. To explore the role of insulin-like growth factor 1 (IGF-1)gene expression abnormality in neurotrophic causes of diabetic peripheral neurophathy.Methods. Diabetes was induced in Sprague Dawley rats by alloxan. The parameters were measured as follows: IGF-1 mRNA by reverse transcriptase-polymerase chain reaction (RT-PCR); IGF-1 peptide by enzyme-linked immunosorbent assay (ELISA); electrophysiological parameters of nerves by evoked electromyogram; morphometric evaluation of sciatic nerves under light microscope and transmission electron microscope.Results. During early diabetic stage, IGF-1 mRNA [(0.430±0.031)vs. (0.370±0.016), P ＜0.01,(0.430 ± 0.031 ) vs. (0.280 ± 0.010) , P ＜0.001, respectively], IGF - 1 peptide contents [ (38.44 ± 3.60)ng/mgvs. (30.06±2.41) ng/mg, P ＜0.01, (38.44±3.6) ng/mgvs. (3.71 +2.70) ng/mg, P ＜0.001,respectively] in sciatic nerve tissue reduced in diabetic rats with hyperglycemia and varied with severity of diabetic state when compared with non-diabetic control rats, and further gradually down-regulated in the diabetic rats with duration of diabetes [IGF-1 mRNA (0. 320 ± 0. 021) ～ (0. 230 + 0. 060); IGF-1 peptide (28.80 ± 3.30) ～(19. 51 + 1.80)ng/mg]. Furthermore, they correlated with nerve functional (sensory nerve conduction velocity:r = 0. 741, P ＜0. 001; amplitude ofevokedpotential: r = 0. 716, P ＜0. 001, respectively)andstructuralabnormality (axonal areas r = 0. 81, P ＜ 0. 001 ) of sciatic nerve. No difference was found in the above parameters between diabetic rats with euglycemia and non-diabetic control group.Conclusion. IGF-1 gene expression in tissues was down-regulated from early diabetic stage, and varied with the severity and duration of diabetic state. The decrement in IGF-1 level might contribute to the initiation and development of diabetic neuropathy via autocrine or paracrine pathway.

Prevalence and determinants of delayed gastric emptying in hospitalised Type 2 diabetic patients

AIM: To determine the prevalence of delayed gastric emptying (GE) in older patients with Type 2 diabetes mellitus. METHODS: One hundred and forty seven patients with Type 2 diabetes, of whom 140 had been hospitalised, mean age 62.3 ± 8.0 years, HbA1c 9.1% ± 1.9%, treated with either oral hypoglycemic drugs or insulin were studied. GE of a solid meal (scintigraphy), autonomic nerve function, upper gastrointestinal symptoms, acute and chronic glycemic control were evaluated. Gastric emptying results were compared to a control range of hospitalised patients who did not have diabetes. RESULTS: Gastric emptying was delayed (T50 > 85 min) in 17.7% patients. Mean gastric emptying was slower in females (T50 72.1 ± 72.1 min vs 56.9 ± 68.1 min, P = 0.02) and in those reporting nausea (112.3 ± 67.3 vs 62.7 ± 70.0 min, P < 0.01) and early satiety (114.0 ± 135.2 vs 61.1 ± 62.6 min, P = 0.02). There was no correlation between GE with age, body weight, duration of diabetes, neuropathy, current glycemia or the total score for upper gastrointestinal symptoms. CONCLUSION: Prolonged GE occurs in about 20% of hospitalised elderly patients with Type 2 diabetes when compared to hospitalised patients who do not have diabetes. Female gender, nausea and early satiety areassociated with higher probability of delayed GE.

meta-analysis of randomized controlled trials of combined treatment with DGSN and western medicine on diabetic peripheral neuropathy

Objective:To systematically study the clinical effects of combined treatment with Dang gui si ni tang(DGSN)and western medicine(WM)on diabetic peripheral neuropathy.Methods:Seven databases,including Chinese National Knowledge Infrastructure(CNKI),Chinese Biomedical Database(CBM),Wanfang full-text database,VIP Database for Chinese Technical Periodicals,MEDLINE,PubMed,Embase,were retrieved.Related references about randomized controlled trials on the combination of DGSN and WM on diabetic peripheral neuropathy published during January 2012 up to now(recent 5 years)were reviewed.Related grey literatures were also reviewed according to the selected articles.RevMan5.3 software was used to analyze the publish bias,and to compare the total clinical effects of the combination of DGSN and WM with WM alone.Results:Ultimately,19 randomized controlled trials with 1690 patients were incorporated.The results of meta-analysis showed that combined treatment of diabetic peripheral neuropathy with DGSN and WM showed better general efficacy compared with control group,with a statistically significant difference(P<0.05).The results of study showed homogeneity(P=0.94>0.05).The general efficacy of combined treatment with DGSN and WM was significantly higher than that of control group(P<0.00001,OR=3.98,95%CI:3.01~5.27).Conclusion:Compared with treatment with WM alone,combined treatment of diabetic peripheral neuropathy with DGSN and WM is more effective.Meanwhile,due to the limited literature samples and low quality of literatures,large samples and high quality of multi-center randomized controlled double-blind trials are needed to verify these results.

Nursing students’knowledge and attitude toward diabetic ulcer care and their contributing factors in Indonesia

Objective:The prevalence of diabetic foot ulcer in Indonesia is far greater than the global prevalence.Nursing students are expected to have good knowledge and positive attitudes regarding diabetic ulcer care in order to deliver high-quality wound care during clinical practice.This study aimed to assess nursing students’knowledge and attitudes toward diabetic ulcer care and to investigate the factors related to them.Methods:A cross-sectional study was conducted on 396 academic and clinical phases in three nursing schools in Indonesia from September 2021 to February 2022.Participants completed a survey including a questionnaire about knowledge and attitudes regarding diabetic ulcer care.The data were analyzed using a Chi-square test and multivariate logistic regression analysis.Results:The results show that 43.2%(171/396)of nursing students had inadequate knowledge of diabetic ulcer care.However,88.9%(352/396)had a favorable attitude toward the topic.Nursing students lacked knowledge about the characteristics of diabetic ulcers,diabetic neuropathy,wound infection,and adjunctive therapy for diabetic ulcers,and many of them believe that diabetic ulcer care is too timeconsuming to carry out.Students in the clinical phase of their studies had significantly better knowledge than those in the academic phase(aOR=9.99,95%CI 4.96e20.08,P<0.001).Male nursing students were significantly less likely to have positive attitude toward the topic than female students(aOR=0.42,95%CI 0.19e0.96,P=0.048),and students accustomed to sharing with peers as a source of knowledge had better attitudes than those who were not(aOR=2.76,95%CI 1.40e5.41,P=0.003).Conclusion:Findings show that almost half of the nursing students have insufficient knowledge of diabetic ulcer care.Curriculum developers and educators need to improve the curriculum regarding diabetic wound care and provide strategic programs to improve students’knowledge and attitudes based on the factors discovered in this study.

Treatment of Diabetic Neuropathy——Principles and Methods

Diabetic neuropathy (DN) is one of the common complications of diabetes mellitus (DM), its incidence can be as high as over 90%. The lesion can involve the sensory, motor and vegetative nerves. As a whole, the lesion can be divided into symmetric multiple neuropathy and asymmetric single neuropathy. Because the pathogenesis of the disease is not clear, no specific therapy is available so far. Besides control of blood sugar level, vitamin B, vasodilators and analgesics are often used in Western medicine for expectant treatment. Basic studies on chronic complications of DM show that aldose reductase and non-enzymatic glycosylation of protein are factors initiating the pathological changes, inhibitors against them have been tested in experimental studies and proved effective. Unfortunately, they are not used clinically due to severe side effects. Screening for herbal drugs to treat DN is still a popular trend in the TCM circle.