Risks for sensorimotor peripheral neuropathy and autonomic neuropathy in non-insulin-dependent diabetes mellitus (NIDDM)

Identification of risk factors for development of diabetic sensorimotor peripheral neuropathy (DSPN) and diabetic autonomic neuropathy (DNA) may help to prevent or modify these complications. The ABCD Trial, a prospective study of diabetic complications, has identified risk factors of the presence and staging of peripheral neuropathy based on neurological symptom scores, neurological disability scores, autonomic function testing and quantitative sensory examination. DSPN is independently associated with diabetes duration [odds ratio (OR) = 1.5 per 10 years], body weight (OR = 1.1 per 5 kg), age (OR = 1.8 per 10 years), retinopathy (OR = 2.3), overt albuminuria (OR = 2.5), height (OR = 1.2 per 10 cm), duration of hypertension (OR = 1.1 per 10 years), insulin use (OR = 1.4), and race/ethnicity [African American vs. non-Hispanic white (OR = 0.4) and Hispanic vs. non-Hispanic white (OR = 0.8)]. DAN is independently associated with diabetes duration (OR = 1.2 per 10 years), body weight (OR = 1.1 per 5 kg), glycosylated hemoglobin (OR = 1.1 per 2.5%), overt albuminuria (OR = 1.6), and retinopathy (OR = 1.8). © 1998 John Wiley & Sons, Inc. Muscle Nerve, 21: 72–80, 1998.     

Bimoclomol (BRLP-42) Ameliorates Peripheral Neuropathy in Streptozotocin-Induced Diabetic Rats

A reduction in nerve conduction velocity and an increase in resistance to ischemic conduction failure are early signs of neural dysfunction in both diabetic patients and animal models of diabetes. The effect of Bimoclomol (BRLP-42), a drug under clinical development for the treatment of diabetic complications, on experimental peripheral neuropathy was examined in rats made diabetic by injection of streptozotocin. Daily oral doses of Bimoclomol (10 or 20 mg/kg) or control dose of γ-linolenic acid (260 mg/kg), an agent with known neuropathy-improving effects, were administered for 3 months. Treatments began 1 day after diabetes induction to assess the prophylactic efficacy of Bimoclomol. Neuropathy was evaluated electrophysiologically by measuring motor and sensory nerve conduction velocities and resistance to ischemic conduction failure of sciatic nerve in vivo. Bimoclomol significantly reduced nerve conduction slowing and retarded the typical elevated ischaemic resistance due to streptozotocin-induced neuropathy, suggesting that the drug might be a useful treatment for diabetic peripheral neuropathies.     

Diabetes mellitus and the peripheral nervous system: manifestations and mechanisms

Diabetes targets the peripheral nervous system with several different patterns of damage and several mechanisms of disease. Diabetic polyneuropathy (DPN) is a common disorder involving a large proportion of diabetic patients, yet its pathophysiology is controversial. Mechanisms considered have included polyol flux, microangiopathy, oxidative stress, abnormal signaling from advanced glycation endproducts and growth factor deficiency. Although some clinical trials have demonstrated modest benefits in disease stabilization or pain therapy in DPN, robust therapy capable of reversing the disease is unavailable. In this review, general aspects of DPN and other diabetic neuropathies are examined, including a summary of recent therapeutic trials. A particular emphasis is placed on the evidence that the neurobiology of DPN reflects a unique yet common and disabling neurodegenerative disorder.     

Visual evoked potentials in diabetes mellitus

25 diabetic patients have been studied in order to investigate the possible effects of the disease on the central nervous system by means of pattern shift visual evoked potentials. Patients with diabetic retinopathy, glaucoma and cataract were excluded from the study. Results obtained from a control group of 30 normal subjects were compared to those of the patient group in which sural nerve conduction velocities have also been determined to see whether there is a correlation between peripheral and central involvement of the nervous system. In diabetic patients latency prolongation in the P100 and N140 components were observed. The N90-N140 interpeak latency was also prolonged. In addition, in patients with longstanding diabetes mellitus the incidence of VEP abnormalities was found to be high. Pathologic changes in VEP latencies did not show any correlation with sural nerve conduction abnormalities.     

Peripheral neuropathy in type 2 diabetes mellitus in Isfahan, Iran: prevalence and risk factors

BACKGROUND: To estimate the prevalence and risk factors of peripheral neuropathy (PN) in people with type 2 diabetes mellitus. METHODS: A total of 810 patients with type 2 diabetes (289 men and 521 women) from Isfahan Endocrinology and Metabolism Research Centre outpatient clinics, Iran, were examined. Part of examination included an assessment of neurological function including neuropathic symptoms and physical signs and nerve conduction velocity. RESULTS: The prevalence of PN was 75.1% (95% confidence interval 72.1, 78.0). PN was associated with age, proteinuria, and duration of diabetes, insulin-treatment, and presence of any retinopathy and ischaemic heart disease (IHD). The age-adjusted prevalence rate of PN was 78% higher among patients with IHD, 64% higher among patients with any retinopathy, 66% higher among insulin-treated type 2 diabetes, and it was greater with duration of diabetes. Using a stepwise binary logistic regression model, age, duration of diabetes and proteinuria were significant independent predictors of PN. CONCLUSION: Peripheral neuropathy is a common complication in this population of Iranian type 2 diabetic patients. It increases with age, duration of diabetes and proteinuria.     

不同病程糖尿病周围神经病患者的临床及肌电图特点分析

目的:探讨不同病程糖尿病周围神经病(DPN)患者的临床及肌电图特点.方法:对2015年3月～2016年3月在北京市隆福医院肌电图室检查的164例不同病程2型糖尿病合并周围神经病症状患者的临床及肌电图特点进行回顾性分析.结果:164例DPN患者中男性78例,女性86例,年龄50～87岁.病程5年以下患者以正常肌电图为最常见,肌电图异常者以交感神经皮肤反射(SSR)异常最为多见;病程10年以上以远端对称性多发性周围神经病、自主神经病、嵌压性周围神经病为最常见3种类型.不同年龄组患者上述3种类型分布无明显差异.结论:糖尿病病程是影响DPN进展的重要因素,年龄与疾病进展无明显相关性.肌电图检查对于早期评价DPN具有重要价值.     

Cardiovascular autonomic neuropathy in patients with type 2 diabetes with and without sensorimotor polyneuropathy

Background and Aims

Cardiovascular autonomic neuropathy (CAN) in patients with diabetes is associated with poor prognosis. We aimed to assess signs of CAN and autonomic symptoms and to investigate the impact of sensorimotor neuropathy on CAN by examining type 2 diabetes patients with (DPN [distal sensorimotor polyneuropathy]) and without distal sensorimotor polyneuropathy (noDPN) and healthy controls (HC). Secondarily, we aimed to describe the characteristics of patients with CAN.

Methods

A population of 374 subjects from a previously described cohort of the Danish Centre for Strategic Research in Type 2 Diabetes (DD2) were included. Subjects were examined with the Vagus™ device for the diagnosis of CAN, where two or more abnormal cardiovascular autonomic reflex tests indicate definite CAN. Autonomic symptoms were assessed with Composite Autonomic Symptom Score 31 (COMPASS 31) questionnaire. DPN was defined according to the Toronto consensus panel definition.

Results

Definite CAN was present in 22% with DPN, 7% without DPN and 3% of HC, and 91% of patients with definite CAN had DPN. Patients with DPN and definite CAN reported higher COMPASS 31 scores compared to patients with noDPN (20.0 vs. 8.3, p < 0.001) and no CAN (22.1 vs. 12.3, p = 0.01). CAN was associated with HbA1c and age in a multivariate logistic regression analysis but was not associated with IEFND or triglycerides.

Interpretation

One in five patients with DPN have CAN and specific CAN characteristics may help identify patients at risk for developing this severe diabetic complication. Autonomic symptoms were strongly associated with having both DPN and CAN, but too unspecific for diagnosing CAN.     

Distal neuropathy in spontaneous diabetes mellitus in the dog

Summary Peripheral nerves of three mature dogs with chronic spontaneous diabetes mellitus were examined using qualitative and quantitative techniques. The principal pathologic findings in single-teased fibers were remyelination and axonal regeneration. It is suggested that these changes which occurred in distal plantar nerves but not in more proximal tibial nerves result from a distal axonopathy. The dog may prove to be another useful spontaneous model of diabetic neuropathy.Supported by funds from Scott-Ritchey Research Program, School of Veterinary Medicine, Auburn University     

同型半胱氨酸与糖尿病周围神经病变的关系

目的：了解血浆同型半胱氨酸(Hcy)与2型糖尿病周围神经病变间的关系及叶酸对Hcy水平的影响和对糖尿病周围神经病变的防治作用。方法：24只糖尿病KKAy小鼠分为3组：糖尿病诱发饮食组(KA组)；高蛋氨酸饮食组(KB组)；喂养高蛋氨酸饮食的基础上加用叶酸组(Kc组)。16只C57小鼠为正常对照组，分为2组：糖尿病诱发饮食组(CA组)；高蛋氨酸饮食组(CB组)。测定血糖、体重、血浆HCY、叶酸浓度，并观察光镜下及电镜下坐骨神经结构变化。结果：糖尿病小鼠喂饲蛋氨酸后出现高Hcy血症，对照组无此改变。糖尿病小鼠的坐骨神经出现不同程度的缺血性改变，且与Hcy水平相关。叶酸可减轻坐骨神经损害的程度。结论：高同型半胱氨酸为糖尿病微血管病变的危险因素，叶酸可起到干预作用。     

糖尿病周围神经病的发病机制及治疗展望

糖尿病周围神经病（DPN）是常见的糖尿病并发症。发病机制主要有多元醇途径的激活、糖基化终末产物的形成、蛋白激酶C途径的激活、氨基己糖途径的激活、线粒体内氧自由基过量生成的共同病理生理学机制以及氧自由基直接损伤机制等6个方面。抗氧化治疗是目前临床主要的治疗手段。以阻断共病机制为靶点的药物是今后的研究方向。本文主要针对DPN的发病机制及治疗等研究进展作介绍。     

Postprandial hypotension treated with acarbose in a patient with type 1 diabetes mellitus

Abstract Treatment of postprandial hypotension (PPH) is often unsuccessful. We report a case of a type 1 diabetic patient suffering from severely symptomatic PPH. The patient was treated with acarbose and showed definite improvement of both glycemic control and PPH.     

Nodes of Ranvier in skin biopsies of patients with diabetes mellitus

Paranodal demyelination has been discussed as a potential mechanism of nerve fiber damage in diabetic neuropathy (DNP). Studies on human tissue are limited, as nerve biopsies are invasive and only rarely performed in patients with confirmed DNP. Skin biopsy has recently been suggested as a tool to analyze paranodal and nodal changes of myelinated fibers. We analyzed the myelinated fibers of skin biopsies of 35 patients with DNP, 17 patients with diabetes mellitus (DM) without neuropathy, and 30 normal controls. Immunofluorescence of skin sections with antibodies against Caspr, neurofascin, sodium channels, and myelin basic protein was performed to assess paranodal/nodal architecture, segmental demyelination, and myelinated nerve fibers. Staining with antibodies against protein gene product 9.5 was used to quantify unmyelinated nerve fibers. There was an increase of elongated Ranvier nodes and a dispersion of neurofascin at the distal leg in patients with DM with and without neuropathy and at the finger in patients with DNP. An increased dispersion of Caspr was only found in biopsies of the finger in patients with DNP. Skin biopsy may be an appropriate tool to analyze nodes of Ranvier in patients with DM. Structural nodal changes are detectable in DNP and even in diabetic patients without neuropathy.     

糖尿病患者周围神经传导速度的研究

目的:通过周围神经传导速度(NCV)的研究,早期诊断糖尿病(DM)患者的糖尿病性周围神经病变。方法:应用上海海军医学研究所NDI-200F神经电检诊仪,对DM组95例患者行尺神经、正中神经、胫神经和腓神经运动传导速度(MCV)及尺神经、正中神经、腓肠神经感觉传导速度(SCV)检测与30例健康人组对照。结果:DM组95例, NCV异常率为77.89%(74/95)。共检测665条神经,MCV380条,异常率55.26%,SCV285条,异常率50.88%,差异无显著性意义(P>0.05)。上肢检测380条神经,异常率45.53%,下肢检测285条神经,异常率63.86%,差异有显著性意义(P<0.05)。DM组SCV波幅减低率为53.66%。DM组按病程分为三组,<5年,30例,异常率28.10%;≥5年,31 例,异常率为54.84%;≥10年,34例,异常率74.37%,组间差异均有非常显著性意义(P<0.01)。DM组中29例无周围神经病变症状与体征,NCV异常11例(37.93%)。结论:周围神经传导速度检测不但可以早期诊断糖尿病患者的糖尿病性周围神经病变,而且此方法可靠、简便、无创。     

Phenotyping animal models of diabetic neuropathy: a consensus statement of the diabetic neuropathy study group of the EASD (Neurodiab)

NIDDK, JDRF, and the Diabetic Neuropathy Study Group of EASD sponsored a meeting to explore the current status of animal models of diabetic peripheral neuropathy. The goal of the workshop was to develop a set of consensus criteria for the phenotyping of rodent models of diabetic neuropathy. The discussion was divided into five areas: (1) status of commonly used rodent models of diabetes, (2) nerve structure, (3) electrophysiological assessments of nerve function, (4) behavioral assessments of nerve function, and (5) the role of biomarkers in disease phenotyping. Participants discussed the current understanding of each area, gold standards (if applicable) for assessments of function, improvements of existing techniques, and utility of known and exploratory biomarkers. The research opportunities in each area were outlined, providing a possible roadmap for future studies. The meeting concluded with a discussion on the merits and limitations of a unified approach to phenotyping rodent models of diabetic neuropathy and a consensus formed on the definition of the minimum criteria required for establishing the presence of the disease. A neuropathy phenotype in rodents was defined as the presence of statistically different values between diabetic and control animals in 2 of 3 assessments (nocifensive behavior, nerve conduction velocities, or nerve structure). The participants propose that this framework would allow different research groups to compare and share data, with an emphasis on data targeted toward the therapeutic efficacy of drug interventions.     

晚期糖基化终产物对糖尿病周围神经病变的作用

目前的研究表明,晚期糖基化终产物(AGEs)通过多种途径引起神经组织结构、代谢和功能的改变,在糖尿病周围神经病的发病中具有重要作用。本文就AGEs的产生、结构以及造成糖尿病周围神经病的可能机制作一综述。     

糖尿病周围神经病97例临床特征与神经电生理分析

目的:探讨糖尿病周围神经病(DPN)患者的临床特征与神经电生理变化。方法:分析97例DPN患者的临床特征,比较DPN组和对照组的神经传导速度(NCV)、远端潜伏期、远端波幅3个参数。结果:①临床特征以肢体麻木(59%)最多见、其次为疼痛(42%)。②患者组NCV、远端波幅值低于对照组,远端潜伏期比对照组延长;两组3个参数比较,除腓总神经远端波幅、尺神经感觉传导速度和正中、尺、腓肠神经远端潜伏期外,差异均有统计学意义(P<0.05)。结论:①DPN患者临床特征以肢体麻木和疼痛最多见;②检测NCV、远端潜伏期、远端波幅,能较早发现临床患者。     

Electrophysiological findings of peripheral neuropathy in newly diagnosed type II diabetes mellitus

This study was aimed at assessing the electrophysiological signs of peripheral neuropathy in diabetes mellitus (DM) type II patients at diagnosis. Nerve conduction studies (NCS) of median, ulnar, peroneal, tibial and sural nerves were performed in 39 newly diagnosed DM subjects and compared to those of 40 healthy controls. Metabolic indices were also investigated. Electrophysiological alterations were found in 32 (82%) of the DM patients, and more than half of them (62.2%) showed multiple (two to five) abnormal parameters. Because most of the subjects (84.4%) had from two to five nerves involved, these alterations were widespread in the seven nerves evaluated. Forty-two percent of the patients had NCS alterations suggestive of distal median mononeuropathy, implying that metabolic factors in DM make the median nerve more susceptible to focal entrapment. A reduced sensory nerve action potential (SNAP) amplitude was observed in the median nerve in 70% of the patients, in the ulnar in 69% and in the sural nerve only in 22%. In the presence of a decrease in the SNAP amplitude of the ulnar or median nerve, the SNAP amplitude of the sural nerve was normal in 82 or 80% of the subjects, respectively. This finding may be in keeping with a distal involvement of the sensory fibres, as explored by routine median or ulnar NCS. No correlation was found between metabolic indices and NCS parameters. In conclusion, a high percentage of newly diagnosed DM patients show signs of neuropathy, and upper limb nerve sensory NCS seem to be more sensitive in detecting it than lower limb NCS.     

Impaired peripheral nerve regeneration in diabetes mellitus

Diabetes mellitus impairs peripheral nerve regeneration. Regenerative failure likely exacerbates deficits from polyneuropathy or focal neuropathies in patients who might otherwise exhibit spontaneous improvement. Some focal neuropathies, like carpal tunnel syndrome, are common, yet render ongoing disability because of their delayed recovery. Why diabetic nerves fail to regenerate is an interesting question to consider because several mechanisms likely contribute. In this review, we examine a number of these causes. These causes include microangiopathy or disease of small blood vessels, failure to provide proper metabolic support for repair, defects in the entry and actions of inflammatory cells within the injury milieu, less robust support of axons by their Schwann cells, and lack of a full repertoire of trophic factors. A number of the mechanisms that generate neuropathy in the first place also likely contribute to failed regenerative programs, but how they do so is not clear.     

Nonenzymatic glycation of peripheral and central nervous system proteins in experimental diabetes mellitus

Nonenzymatic glycation of neural proteins could underlie diabetic peripheral neuropathy. Cytoskeletal and myelin protein fractions of central nervous system and peripheral nervous system (PNS) tissue from rats with streptozotocin-induced diabetes of 1.5 and 8 months duration were analyzed for glycation products. In sciatic nerve cytoskeletal preparations from both diabetic and control animals we found high levels of the early glycation product (measured as furosine) after 6 weeks, which had fallen markedly by 8 months. Conversely the advanced glycation end product (AGE), pentosidine, was low at 6 weeks and high by 8 months in diabetic animals. The levels of glycation products were much lower in spinal cord and spinal nerve from diabetic animals. There was increased borotritride labeling of neurofilament subunits, and of cross-linked material, in cytoskeletal fractions of diabetic sciatic nerves. These results show that the PNS cytoskeleton is vulnerable to nonenzymatic glycation, resulting in AGE formation, in diabetic rats and to a lesser extent in normals. © 1997 John Wiley & Sons, Inc. Muscle Nerve, 20, 577–584, 1997.