粘附分子与糖尿病

粘附分子是一类分布于细胞表面或细胞外基质中的糖蛋白,它参与了机体炎症、免疫等多种生理、病理过程。近年研究发现,粘附分子参与了1型糖尿病的发生、发展,其与糖尿病大血管病变、糖尿病微血管病变的关系也十分密切。循环粘附分子的测定可能有助于糖尿病及其并发症的早期诊断,而拮抗粘附分子作用有望为糖尿病治疗提供新的途径。     

粘附分子与糖尿病

粘附分子是一类分布于细胞表面或细胞外基质中的糖蛋白 ,它参与了机体炎症、免疫等多种生理、病理过程。近年研究发现 ,粘附分子参与了 1型糖尿病的发生、发展 ,其与糖尿病大血管病变、糖尿病微血管病变的关系也十分密切。循环粘附分子的测定可能有助于糖尿病及其并发症的早期诊断 ,而拮抗粘附分子作用有望为糖尿病治疗提供新的途径。     

糖尿病乳腺病的最新进展

糖尿病乳腺病（Diabetesmastopathy，DMP）是一种良性瘤样增生性乳腺病，1984年由Soler和Khardori对内分泌门诊的88例，年龄在20-40岁之间的1型糖尿病（T1DM）妇女进行了乳腺检查，发现其中12例（13％）有无痛性乳腺肿块，经病理检查确定为纤维性乳腺瘤（Fibrous breastlumps）。这12位患者多合并微血管并发症，11例有视网膜病变，7例有手关节病，5例有周围神经病变，     

基质金属蛋白酶与糖尿病血管病变

糖尿病血管病变的发生发展涉及多个环节。基质金属蛋白酶 (MMPs)在细胞外基质 (ECM)动态平衡、组织重塑、修复等病理生理过程中起重要作用。糖尿病合并血管病变患者循环MMPs水平升高 ,且先于血管病变。在病变血管部位MMPs表达增加 ,提示MMPs在糖尿病血管病变的发生、发展中起重要作用。糖尿病时MMPs的改变与高血糖及胰岛素缺乏有关。应用干预措施降低MMPs产物活性有助于阻抑糖尿病血管病变的发生发展     

基质金属蛋白酶与糖尿病血管病变

糖尿病血管病变的发生发展涉及多个环节。基质金属蛋白酶（ＭＭＰｓ）在细胞外基质（ＥＣＭ）动态平衡、组织重塑、修复等病理生理过程中起重要作用。糖尿病合并血管病变患者循环ＭＭＰｓ水平升高,且先于血管病变。在病变血管部位ＭＭＰｓ表达增加,提示ＭＭＰｓ在糖尿病血管病变的发生、发展中起重要作用。糠尿病时ＭＭＰｓ的改变与高血糖及胰岛素缺乏有关。应用干预措施降低ＭＭＰｓ产物活性有助于阻抑糖尿病血管病变的发生发展。     

糖尿病微血管病变发生机制研究现状

糖尿病微血管病变是糖尿病慢性并发症的病理基础,病理机制涉及内皮受损及一氧化氮合成减少、多元醇代谢异常、糖化反应的亢进、氧化应激、蛋白激酶C激活等多个方面,现对糖尿病微血管病变的研究现状进行探讨,以提高对糖尿病微血管病变的认识水平。     

糖尿病周围神经病变的病理生理机制研究进展

糖尿病周围神经病变是糖尿病最常见的并发症之一,其发病机制较为复杂,现多数研究集中于糖脂代谢紊乱、氧化—抗氧化系统失衡、细胞凋亡及自身免疫等。本文对这些病理生理机制予以阐述。     

微血管内皮细胞功能改变与糖尿病微血管病变研究热点

糖尿病微血管病变是糖尿病多种并发症的病理基础,也是糖尿病预后的决定性因素,主要包括糖尿病视网膜病、糖尿病肾病、糖尿病神经病变及糖尿病心肌病变等。目前研究的热点主要涉及两方面,即糖基化终产物及其信号通路在糖尿病病变发生中的作用、微血管内皮细胞的功能改变与糖尿病血管病变的发生。本文就上述两方面的研究进展作一综述,并介绍本研究室的相关研究结果。     

阿托伐他汀在糖尿病大血管病变中的防治作用

糖尿病大血管病变是糖尿病患者主要的致残、致死原因,是危害最大的糖尿病慢性并发症。糖尿病大血管病变的病理基础为动脉粥样硬化,它与单纯的动脉粥样硬化相比病变范围大、程度重、发生早。他汀类药物除降脂作用外还具有改善血管内皮功能、抗炎、稳定斑块等作用,其代表药物阿托伐他汀能明显降低糖尿病患者心血管事件,在糖尿病大血管病变的预防和治疗中起重要作用。     

线粒体氧化应激在糖尿病微血管并发症发病机制中的研究进展

糖尿病并发症是糖尿病患者致残致死的首要原因, 而线粒体作为细胞能量代谢的中心, 其功能障碍与多种并发症的发生发展密切相关。本文针对常见的糖尿病微血管并发症, 包括糖尿病溃疡、糖尿病肾病及糖尿病视网膜病变等, 阐述其病理机制涉及线粒体功能与氧化应激的研究进展, 为靶向线粒体氧化应激治疗上述疾病提供更多的理论依据。     

Zukünftige Ausgestaltung der Diabetesversorgung

Background

Due to the epidemiological significance of diabetes as a widespread disease, it is essential to deal with future fields of action in diabetes care. This article aims to emphasize future fields of action and derive measures for diabetes care and prevention from the perspective of health insurance funds.

Results

The delivery of novel, evidence-based and patient-centered diabetes care as well as the improvement of population-based prevention and health promotion measures are seen as main aspects of future diabetes care. Particular attention needs to be paid to the needs-driven improvement of disease management programs (DMP) to pursue their positive impetus for diabetes care. In this regard the future aim should be to transform DMP to a more flexible as well as prevention and target-group oriented program. Thus, the timely integration of innovative health care elements and the idea of prevention as an integral part of DMP could be further improvements. In addition, greater consideration should be given to the numerous potentials of digitization for future diabetes care, including the utilization of e?health services to make healthcare processes more patient-centered. Furthermore, a significant reduction of the diabetes incidence is only achievable by collective efforts from society as a whole by creating living conditions that promote health and reducing the socioeconomic impact on the risk to develop diabetes.

Conclusion

Improvements in diabetes care can be achieved by further tailoring successful programs such as DMP to diabetes patients needs and smartly integrating innovative e?health services into health care. The national diabetes strategy is a starting point toward a definite shift in society as a whole regarding the expansion of prevention and health promotion measures.

     

Short-term memory impairment and reduced hippocampal c-Fos expression in an animal model of fetal alcohol syndrome

BACKGROUND: Previous work in our laboratory has shown that exposure to ethanol during the brain growth spurt impairs spatial short-term memory in rats on the delayed matching-to-place (DMP) version of the Morris water maze. The objectives of this study were to ascertain whether this impairment could: 1) be prevented by increasing the length of encoding time and 2) be related to hippocampal c-Fos expression. METHODS: Using an artificial rearing model, male Long-Evans rats were fed 6.5 g/Kg/day of ethanol from postnatal days 6-9, with controls fed an isocaloric amount of maltose dextrin. As adults, rats in each treatment condition were trained and subsequently tested on either the DMP version of the Morris water maze, or on a random platform version (RAN) that incorporated the same performance requirements, but disallowed spatial learning. Brains were processed for c-Fos expression. RESULTS: Ethanol-exposed rats showed longer search trials during training and took longer to learn the DMP task. When the delay between search and recall trials was increased from 60 sec to 120 min, the performance of ethanol-exposed rats was impaired compared with that of controls after a 10 sec, but not after a 45 sec, encoding time. Brain c-Fos expression was increased in hippocampus, prefrontal cortex and visual cortex in rats trained on the DMP compared to the RAN task. Furthermore, in the DMP-trained rats, hippocampal c-Fos expression was lower in ethanol-exposed rats. CONCLUSIONS: These results suggest that the short-term memory impairment of ethanol-exposed rats 1) can be improved slightly by an increase in encoding time and 2) is related to a decrease in c-Fos expression in the hippocampus.     

Abrechnungsmodalitäten von zertifizierten Schulungs- und Behandlungsprogrammen

Background

Diabetes education is an integral and effective part of diabetes care. In Germany the disease management programs (DMP) for type 1 and type 2 diabetes entitle registered patients to participate in an evaluated structured diabetes education program.

Aim

The article gives a comparative overview of contractually defined conditions of diabetes education and its reimbursement modalities within the DMPs in the different regions in Germany.

Material and methods

Diabetes education programs certified by the German Federal Insurance Office (Bundesversicherungsamt, BVA) were compared concerning implementation and reimbursement modalities based on available DMPs. In this way the differences concerning the implementation and reimbursement of education programs within the DMPs of the 17 regional Associations of Statutory Health Insurance Physicians (KVen) are also illustrated.

Results

The DMPs are very different in relation to the number of authorized education programs, the required qualification of diabetes educators as well as duration and reimbursement of training courses and patient materials.

Conclusion

The efforts to ensure the quality of established education programs should be intensified against the background of a large number of qualified diabetes educators as well as authorized education programs.     

Dentin matrix protein 1 induces membrane expression of VE-cadherin on endothelial cells and inhibits VEGF-induced angiogenesis by blocking VEGFR-2 phosphorylation

Dentin matrix protein 1 (DMP1) is a member of the small integrin-binding ligand N-linked glycoprotein (SIBLING) family, a group of proteins initially described as mineralized extracellular matrices components. More recently, SIBLINGs have been implicated in several key steps of cancer progression, including angiogenesis. Although proangiogenic activities have been demonstrated for 2 SIBLINGs, the role of DMP1 in angiogenesis has not yet been addressed. We demonstrate that this extracellular matrix protein induced the expression of vascular endothelial cadherin (VE-cadherin), a key regulator of intercellular junctions and contact inhibition of growth of endothelial cells that is also known to modulate vascular endothelial growth factor receptor 2 (VEGFR-2) activity, the major high-affinity receptor for VEGF. DMP1 induced VE-cadherin and p27(Kip1) expression followed by cell-cycle arrest in human umbilical vein endothelial cells (HUVECs) in a CD44-dependent manner. VEGF-induced proliferation, migration, and tubulogenesis responses were specifically blocked on DMP1 pretreatment of HUVECs. Indeed, after VE-cadherin induction, DMP1 inhibited VEGFR-2 phosphorylation and Src-mediated signaling. However, DMP1 did not interfere with basic fibroblast growth factor-induced angiogenesis. In vivo, DMP1 significantly reduced laser-induced choroidal neovascularization lesions and tumor-associated angiogenesis. These data enable us to put DMP1 on the angiogenic chessboard for the first time and to identify this protein as a new specific inhibitor of VEGF-induced angiogenesis.     

Reversible drug-induced oxyntic atrophy in rats

BACKGROUND & AIMS: Oxyntic atrophy is the hallmark of chronic gastritis. Many studies have sought to develop animal models for oxyntic atrophy, but none of them are reversible. We now report that rats administered high doses of DMP 777 demonstrate reversible oxyntic atrophy. METHODS: DMP 777 was administered to CD-1 rats by oral gavage (200 mg. kg(-1). day(-1)). Serum gastrin level, in vivo acid secretion, and gastric histological changes were evaluated in DMP 777-dosed animals. Direct effects of DMP 777 on parietal cells were evaluated by assessment of aminopyrine accumulation into isolated rabbit parietal cells, as well as by assessment of DMP 777 effects on acridine orange fluorescence and H(+),K(+)-adenosine triphosphatase (ATPase) activity in isolated tubulovesicles. RESULTS: Oral dosing with DMP 777 caused a rapid increase in serum gastrin levels and severe hypochlorhydria. DMP 777 inhibited aminopyrine accumulation into rabbit parietal cells stimulated with either histamine or forskolin. DMP 777 reversed a stimulated proton gradient in isolated parietal cell tubulovesicles. Oral dosing with DMP 777 led to rapid loss of parietal cells from the gastric mucosa. In response to the acute loss of parietal cells, there was an increase in the activity of the progenitor zone along with rapid expansion of the foveolar cell compartment. DMP 777 treatment also led to the emergence of bromodeoxyuridine-labeled cells and cells positive for periodic acid-Schiff in the basal region of fundic glands. With extended dosing over 3-6 months, foveolar hyperplasia and oxyntic atrophy were sustained while chief cell, enterochromaffin-like cell, and somatostatin cell populations were decreased. No histological evidence of neoplastic transformation was observed with dosing up to 6 months. Withdrawal of the drug after 3 or 6 months of dosing led to complete restitution of the normal mucosal lineages within 3 months. CONCLUSIONS: DMP 777 acts as a protonophore with specificity for parietal cell acid-secretory membranes. DMP 777 in high doses leads to the specific loss of parietal cells. Foveolar hyperplasia, loss of normal gland lineages, and the emergence of basal mucous cells appear as sequelae of the absence of parietal cells. The results suggest that parietal cells are critical for the maintenance of the normal mucosal lineage repertoire.     

Household decision-making power and the mental health and well-being of women initiating antiretroviral treatment in Oromia,Ethiopia

Low decision-making power (DMP) has been associated with HIV seropositivity among women in sub-Saharan Africa. As treatment accessibility and life expectancy for HIV-positive individuals increase, greater attention to the mental health and well-being of HIV-positive women is needed. This study examined whether low DMP was associated with psychological distress, social support or health-related quality of life (HRQoL) among women initiating ART. The sample included 722 women aged 18 or older initiating ART during 2012–2013 at six HIV clinics in Oromia, Ethiopia. DMP was assessed with five questions about household resource control and decision-making. Psychological distress was assessed with the Kessler Psychological Distress Scale (K10). HRQoL was assessed with the overall subscale of the HIV/AIDS-Targeted Quality of Life instrument. Multivariable logistic regression analyses controlled for age, education, and location (urban/rural). Most respondents (63%) reported high DMP, followed by medium (27%) and low (10%) DMP. More than half (57%) reported psychological distress. Compared to medium DMP, low DMP among married or cohabitating women was associated with greater odds of low social support (aOR: 1.9 [1.3, 2.9]; high DMP among women not in a relationship was associated with greater odds of low social support (aOR: 4.4 [2.4, 8.1]) and psychological distress (aOR: 1.7 [1.1, 2.6]). Interventions to reduce psychological distress among women initiating ART should consider the familial context, as high DMP among women not in a relationship was associated with psychological distress. High DMP may indicate weak social ties and fewer material resources, particularly among women not in a relationship.     

Pharmacology and Pharmacokinetics of A Novel Nonpeptide Angiotensin II Receptor Antagonist–DMP 811

DMP 811 exhibited high binding affinity for the angiotensin II subtype receptor AT₁ in rat adrenal tissues with an IC₅₀ of 6 nM, but not for the subtype receptor AT₂. In the isolated rabbit aorta, DMP 811 inhibited the contractile response to angiotensin II selectively and noncompetitively with a K_B value of 0.1 nM. In conscious renal hypertensive rats, DMP 811 decreased blood pressure with i.v. and p.o. ED3_30s of 0.005 and 0.03 mg/kg, respectively (p.o. ED₃₀ for losartan=0.59 mg/kg). In conscious furosemide-treated dogs, DMP 811 given either at 0.3 or 1 mg/kg p.o. decreased blood pressure. DMP 811 has oral bioavailabilities of 7 and 29% in rats and dogs, respectively, after a solution dose and 8 and 13%, respectively, after a suspension or capsule dosing. Our study indicates that DMP 811 is a selective and insurmountable AT₁ receptor antagonist and is a 20-fold more potent orally-active antihypertensive agent than losartan.     

Studies of pharmacokinetics and therapeutic effects of glucocorticoids entrapped in liposomes after intraarticular application in healthy rabbits and in rabbits with antigen-induced arthritis

Summary Dexamethasone palmitate (DMP) entrapped in liposomes of defined sizes was administered intraarticularly in healthy rabbits and in rabbits with antigen-induced arthritis. The pharmacokinetics and therapeutic effect of liposomal DMP were measured and compared with corresponding experiments using microcrystalline triamcinolone acetonide (TAC). The small DMP liposomes (diameter 160 nm) showed a greater decrease in joint circumference than the 3-times-higher dose of microcrystalline TAC. Moreover, about 98% of administered TAC had already disappeared from the joint 6 h after injection, whereas about 36% of liposomal DMP was still measured in synovial fluid and synovium at the same time. Increasing the vesicle diameter from 160 to 750 nm (large liposomes) improved the retention of DMP by a factor of 2.6 within 48 h after injection in healthy rabbits. In addition, none of the liposomal glucocorticoid preparations ever suppressed the endogenous plasma cortisol level, which is in contrast to the suppression measured after administration of the microcrystalline preparation.     

Mineral Trioxide Aggregate (MTA) Upregulates the Expression of DMP1 in Direct Pulp Capping in the Rat Molar

Mineral trioxide aggregate (MTA) is an alternative endodontic material that predicts conductive or inductive calcified tissue formation from immature pulp mesenchymal stem cells (IPMSCs). The purpose of this study was to investigate whether MTA could promote reparative odontoblast differentiation via IPMSCs in the early phase of regeneration and compare with calcium hydroxide (CH). Direct pulp capping using calcium hydroxide (CH), MTA, and MTA with platelet-rich plasma (MTA + PRP) was performed on maxillary first molars of 8-week-old male Wistar rats (n = 36). After 3, 7, or 14 days, the teeth were analyzed for mineral density (MD) and volume of MD (VMD) via micro-focusing computed tomography (µCT), nestin, dentin matrix acidic phosphoprotein 1 (DMP1) immunohistochemistry, and real-time PCR for DMP1 mRNA expression. MTA stimulated the early phase differentiation of the IPMSCs into odontoblasts, with positive results for nestin and DMP1 compared with CH. Moreover, MTA + PRP stimulated calcified granule and dentin bridge formation through calcium mineral deposition, following the induction of DMP1 mRNA expression in IPMSCs. Our results suggested that the combination of MTA and PRP is an effective and clinically applicable method for activating endogenous dental pulp stem cells into odontoblasts in the early stages of pulp regeneration.