糖尿病脑病研究进展

目的糖尿病脑病是糖尿病并发症之一，以认知功能障碍为主要表现。此病的发病机制复杂，其诊断标准不明确。本文从糖尿病脑病的发病机制、病理形态改变、临床表现及与Alzheimer病、神经营养因子之间的关系等方面阐述糖尿病脑病的研究现状和进展。     

糖尿病周围神经病变发病机制及治疗研究进展

近来发现神经营养因子及其相关神经肽、受体等的缺乏在糖尿病周围神经病变的发病机制中起作用 ,而外源性补充神经营养因子可通过神经营养支持作用减轻神经损害。针对不同病因机制的治疗对糖尿病周围神经病变均有部分改善作用 ,如应用醛糖还原酶抑制剂、改善神经血流、清除氧自由基、降低氧化压力、应用血管紧张素转换酶抑制剂、高肌醇饮食、抗糖基化等     

糖尿病周围神经病变发病机制及治疗研究进展

近来发现神经营养因子及其相关神经肽、受体等的缺乏在糖尿病周围神经病变的发病机制中起作用，而外源性补充神经营养因子可通过神经营养支持作用减轻神经损害。针对不同病因机制的治疗对糖尿病周围神经病变均有部分改善作用，如应用醛糖还原配抑制剂、改善神经血流、清除氧自由基、降低氧化压力、应用血管紧张素转换酶抑制剂、高肌醇饮食、抗糖基化等。     

胰岛素样生长因子与糖尿病脑病

胰岛素样生长因子是一类结构上与胰岛素部分同源并具有胰岛素样活性的多肽,广泛分布于中枢和外周神经系统,具有神经营养作用。近年来研究发现,胰岛素样生长因子与糖尿病脑病密切相关,胰岛素样生因子水平下降可引起糖尿病脑病患者认知功能受损,补充胰岛素样生长因子可能对糖尿病脑病认知功能的改善有治疗作用。     

AGE-RAGE系统与糖尿病周围神经病变

糖尿病神经病变是糖尿病常见并发症之一,但其发病机制尚不完全清楚,当前提出的机制有氧化应激学说、蛋白激酶C激活、神经胶质细胞和轴突联系异常、神经元代谢异常、神经营养因子缺乏、非酶糖基化产物等。其中晚期糖基化终产物及其受体系统在周围神经病变中起重要的作用。今就目前国内外研究进展综述如下。     

糖尿病认知功能障碍及其发病机制

近年来的研究发现,糖尿病并发认知功能障碍的发生率显著增高.本文综述了糖尿病认知功能障碍的临床表现,并从高血糖的毒性作用、脑血管病理学改变.神经营养因子和神经调节改变等4个方面阐述了其可能的发病机制.     

神经营养因子受体的研究进展

神经营养因子家族在神经细胞的生长发育、保护修复过程中起着极其重要的作用.而神经营养因子受体是启动信号转导,产生生物学效应的重要物质.根据同源性大小、基因表达部位和蛋白作用的专一性以及信号传递机制的不同,可将神经营养因子分为三个家族:神经生长因子家族、睫状神经营养因子家族和胶质细胞源性神经营养因子.本文从结构、功能、信号传递机制等方面,对其相应受体的最新研究进展作一综述.     

神经节苷脂GM1与神经系统疾病

神经节苷脂是一类含唾液酸的鞘糖脂,在脑内的含量非常丰富.它不但能够促进神经细胞分化、神经突生长以及突触形成,而且参与了神经可塑性的凋节和脑损伤后的功能恢复.GM1是迄今研究最为深入的神经节苷脂,对细胞内C4~(2+)稳态的调节被认为是GM1神经营养/神经保护作用的基础,而它与神经营养因子的相互作用则是其神经保护作用的关键.此外,它还具有抗兴奋性毒性、抗氧化、扩血管等作用.各种神经变性疾病以及缺血缺氧性脑病均与神经元脱失和凋亡有关,而GM1的神经营养/神经保护作用能在这些疾病的治疗中发挥重要作用.目前,GM1已被广泛用于帕金森病、卒中、新生儿缺血缺氧性脑病、脑外伤、脊髓损伤以及周围神经病的治疗,对其作用机制的进一步研究有望为上述疾病的治疗提供新的思路.     

β-淀粉样蛋白与糖尿病脑病

脑内β-淀粉样蛋白的增多通过神经毒性作用及诱导神经细胞凋亡等机制损伤认知功能,在糖尿病脑病的发生发展中发挥重要作用,但其代谢过程尚不十分清楚。因此,阐明糖尿病时β-淀粉样蛋白生成,聚集及清除的分子途径是研究糖尿病脑病病因,寻求合理治疗方法的关键。本文仅就目前β-淀粉样蛋白参与糖尿病脑病发病机制的研究进展作一综述。     

雌激素与糖尿病脑病

雌激素与糖尿病脑病密切相关.雌激素可增加脑血流量及大脑对葡萄糖的摄取和利用;减少β淀粉样蛋白(Aβ)的生成;改善突触可塑性;提高海马神经元的兴奋性;增加脑源性神经营养因子(BDNF)在海马的表达水平,对认知功能产生有利影响.雌激素通过多种途径影响糖尿病脑病的发生,发展过程,为糖尿病脑病的研究和治疗提供了新的思路.     

Nerve growth factor and diabetic neuropathy

Neuropathy is one of the most debilitating complications of both type 1 and type 2 diabetes, with estimates of prevalence between 50-90% depending on the means of detection. Diabetic neuropathies are heterogeneous and there is variable involvement of large myelinated fibers and small, thinly myelinated fibers. Many of the neuronal abnormalities in diabetes can be duplicated by experimental depletion of specific neurotrophic factors, their receptors or their binding proteins. In experimental models of diabetes there is a reduction in the availability of these growth factors, which may be a consequence of metabolic abnormalities, or may be independent of glycemic control. These neurotrophic factors are required for the maintenance of the neurons, the ability to resist apoptosis and regenerative capacity. The best studied of the neurotrophic factors is nerve growth factor (NGF) and the related members of the neurotrophin family of peptides. There is increasing evidence that there is a deficiency of NGF in diabetes, as well as the dependent neuropeptides substance P (SP) and calcitonin gene-related peptide (CGRP) that may also contribute to the clinical symptoms resulting from small fiber dysfunction. Similarly, NT3 appears to be important for large fiber and IGFs for autonomic neuropathy. Whether the observed growth factor deficiencies are due to decreased synthesis, or functional, e.g. an inability to bind to their receptor, and/or abnormalities in nerve transport and processing, remains to be established. Although early studies in humans on the role of neurotrophic factors as a therapy for diabetic neuropathy have been unsuccessful, newer agents and the possibilities uncovered by further studies should fuel clinical trials for several generations. It seems reasonable to anticipate that neurotrophic factor therapy, specifically targeted at different nerve fiber populations, might enter the therapeutic armamentarium.     

Clinical observations and experiments in diabetic neuropathy

Summary Diabetic neuropathies form a group of diverse conditions, which can be distinguished between those which recover (acute painful neuropathies, radiculopathies, mononeuropathies) and those which progress (sensory and autonomic neuropathies). These two main groups can be distinguished in several ways: sensory and autonomic neuropathies are classic diabetic complications progressing gradually in patients with long-standing diabetes who often have other specific complications, while the reversible neuropathies do not have these features. The latter are characterised by their occurrence at any stage of diabetes, often at diagnosis, they may be precipitated on starting insulin treatment, and they are more common in men; they can occur at any age, though more often in older patients, and are unrelated to other diabetic complications. The two groups of neuropathies also show differences in nerve structural abnormalities and with regard to distinctive blood flow responses. The underlying mechanisms responsible for these very different forms of neuropathy remain speculative, but evidence for an immunological basis for the development of severe symptomatic autonomic neuropathy is presented.This review was presented as the Camillo Golgi lecture at the EASD meeting in Copenhagen, September 1990     

Diabetic peripheral neuropathies

Diabetic peripheral neuropathies are a group of heterogeneous syndromes with considerable morbidity. At least 50% of diabetic patients develop one or several of these neuropathies within 25 years after the diagnosis. In recent years several pathogenetic mechanisms have been proposed, with the newest findings suggesting a link between several of these hypotheses. The hypoxic hypothesis has revived the role of vascular factors in the pathogenesis of diabetic peripheral neuropathies. Although the exact role of hyperglycemia in the development of peripheral neuropathy is not known, the balance of evidence indicates that attainment and maintenance of normal blood glucose remains the cornerstone of treatment of diabetes and diabetic neuropathies. There is no convincing evidence that any of the treatments devised to correct the metabolic derangements in nerve are of sufficient value or safety to be recommended for routine use.     

Regulation of gonadotropin-releasing hormone neurons by basic fibroblast growth factor.

The development of a functional network of gonadotropin-releasing hormone (GnRH) neurons in the central nervous system requires a series of complex regulatory mechanisms, presumably mediated in part by neurotrophic factors. The difficulty in studying factors regulating the development of GnRH neurons stems from their paucity and scattered distribution in the brain; as a result, little was known about the role of neurotrophic factors in the development of the mature GnRH neuronal network. Recent utilization of immortalized GnRH neuronal cell lines (GT1) has enabled us to identify and study specific neurotrophic factors and their functions in vitro. The potent neurotrophic effect of basic fibroblast growth factor (bFGF) and the presence of a high abundance of receptors for bFGF in GT1 cells have led to the hypothesis that bFGF may be an important regulator of GnRH neuron expansion, survival, migration, and connectivity.     

Insulin receptors and insulin actions in the nervous system

Insulin receptors are widely distributed in the brain. They are also present in peripheral nerve. Insulin signaling through its receptors in the brain is responsible for the hormone's effects on the regulation of food intake, body weight, and reproduction. Signaling through the insulin receptor also appears to influence higher cognitive functions. In peripheral nerve, insulin signaling may play a role in the maintenance and repair of myelinated fibers. Future studies should determine the extent to which a defective insulin signal may be linked to the pathogenesis of diabetic neuropathies and neurodegenerative disorders such as Alzheimer's disease.     

Pain-related differential expression of NGF, GDNF, IL-6, and their receptors in human vasculitic neuropathies

OBJECTIVE: Pain-related differential expressions of nerve growth factor (NGF), glial cell line-derived neurotrophic factor (GDNF) and interleukin-6 (IL-6), and their receptors were investigated in human vasculitic neuropathies. MATERIALS AND METHODS: The mRNA levels of pain-related neurotrophic factors, NGF, GDNF and IL-6, were examined in the sural nerves of 22 painful and non-painful patients with acute necrotizing vasculitic neuropathies, together with their concomitant soluble receptors (p75, GFR(alpha)-1 and IL-6R(alpha)). RESULTS: The mRNAs for these factors and receptors in the lesioned nerves were up-regulated to a variable extent in both groups. NGF mRNA expression was more closely correlated with that of p75 in painful neuropathy with relatively preserved large fiber density, compared with non-painful neuropathy, though the NGF mRNA level in painful neuropathy was lower than that in non-painful neuropathy. GDNF was closely associated with GFR(alpha)-1 in mRNA levels regardless of the pain state, but IL-6 was not associated with IL-6R(alpha). CONCLUSION: The differential expression of neurotrophic factors and their cognate soluble receptors in human vasculitic neuropathy suggests that NGF, which was effectively transferred to sensory axons with p75, may induce pain.     

Prevention of sensory disorders in diabetic Sprague-Dawley rats by aldose reductase inhibition or treatment with ciliary neurotrophic factor

Aims/hypothesis Sensory neuropathy in diabetic patients frequently presents itself as progressive loss of thermal perception, while some patients describe concurrent spontaneous pain, allodynia or hyperalgesia. Diabetic rats develop thermal hypoalgesia and tactile allodynia by unknown mechanisms. We investigated whether sensory disorders in rats were related to glucose metabolism by aldose reductase. We also explored the therapeutic potential of exogenous neurotrophic factors.Methods Behavioural assessments of thermal and tactile sensitivity were performed in normal rats and in rats with streptozotocin-induced diabetes. Some of the rats were treated with insulin, aldose reductase inhibitors, ciliary neurotrophic factor or brain-derived neurotrophic factor.Results Thermal hypoalgesia was present after 8 weeks of diabetes and was prevented by insulin treatment, which maintained normoglycaemia, by the aldose reductase inhibitor Statil or by ciliary neurotrophic factor. Brain-derived neurotrophic factor did not have an effect. When diabetic rats were tested after shorter durations of diabetes, they showed transient thermal hyperalgesia after 4 weeks which progressed to thermal hypoalgesia after 8 weeks. The aldose reductase inhibitor IDD 676 (Lidorestat), given from the onset of diabetes, prevented the development of thermal hyperalgesia and also stopped progression to thermal hypoalgesia when delivered in the last 4 weeks of an 8-week period of diabetes. Tactile allodynia was not prevented by neurotrophic factor or aldose reductase inhibitor treatment.Conclusions/interpretation Transient thermal hyperalgesia and subsequent progressive thermal hypoalgesia occur in diabetic rats secondary to exaggerated flux through the polyol pathway. A depletion of ciliary neurotrophic factor mediated by the polyol pathway may be involved in the aetiology of thermal hypoalgesia.Abbreviations CNTF ciliary neurotrophic factor - BDNF brain-derived neurotrophic factor     

International Neuropathy Workshop of 2009: Introduction to the final reports

Neuropathies are amongst the most common of the long‐term complications of diabetes, affecting up to 50% of patients. Their clinical features vary immensely and patients may present with a wide spectrum of specialties, from neurology to urology, for example, or from cardiology to podiatry. Neuropathies are typically characterized by a progressive loss of nerve fibres which may affect both of the principal divisions of the peripheral nervous system. The epidemiology and natural history of the diabetic neuropathies remain poorly defined. The International Consensus Workshop in Toronto in 2009 arose from the fact that at the moment there are no clear, universally accepted guidelines regarding the definition of diabetic neuropathies. This has resulted in a massive variation in how neuropathy is diagnosed in different centres and countries. A preliminary summary report of the Toronto meeting was published in 2010. The series of papers published in this issue of Diabetes/Metabolism Research and Reviews are the detailed reports that came from each sub‐group of this Consensus panel. These reviews cover the problems with definitions and classification of neuropathy, the management of painful neuropathy and then the sub‐group of small fibre neuropathies. There are also 3 papers on the autonomic neuropathies, covering cardiovascular autonomic neuropathies, as well as other areas of the autonomic neuropathies including gastrointestinal, urogenital and pseudomotor neuropathies. This series of papers will give the reader detailed information on the diverse aspects of diabetic neuropathies, their measurement and management, and will also assist in the selection of appropriate measures of both autonomic and somatic nerve function in clinical trials. This is clearly work in progress as diagnostic criteria for diabetic neuropathies are likely to evolve with developments in the field. Copyright © 2011 John Wiley & Sons, Ltd.     

油酰乙醇胺对糖尿病大鼠脑内炎性因子及神经相关因子表达的影响

目的探讨油酰乙醇胺(OEA)对糖尿病小鼠脑内炎性和神经营养因子的影响。方法采用高脂高糖加STZ链脲佐菌素(STZ)诱导T2DM小鼠模型,OEA[15、30、60 mg/(kg·d)]连续腹腔注射给药6周,通过Real time-PCR及Western blot检测海马内白介素-6(IL-6)、白介素-1β(IL-1β)、肿瘤坏死因子-α(TNF-α)、突触成长相关蛋白-43(GAP-43)、突触素(SYN)、BDNF和NT-3的mRNA和蛋白表达水平。结果糖尿病模型小鼠海马内炎症因子IL-6、IL-1β和TNFα的表达水平下降,并显著上调海马内GAP-43、SYN、BDNF和NT3 mRNA表达水平。结论OEA具有降低糖尿病后海马内炎症,增加海马内突触相关因子和神经营养因子的作用,从而发挥神经保护作用。     

Gene therapy for the treatment of diabetic neuropathy

Neuropathy is a common, untreatable complication of type 1 and type 2 diabetes. In animal models peptide neurotrophic factors can be used to protect against the development of neuropathy, but the combination of short half-life and off-target effects of these potent pleiotropic peptides has limited translation to human therapy. Gene transfer is a promising strategy that may circumvent these limitations. In this article, we review the basic methods of gene transfer and the preclinical data in rodent models that support the use of this approach in the treatment of diabetic neuropathy. The path to clinical applications and potential pitfalls in developing gene therapy for the treatment of diabetic neuropathy are considered.