Omega-3 Polyunsaturated Fatty Acids in the Treatment of Diabetic Peripheral Neuropathy: Is the source important?
Omega-3 多不饱和脂肪酸治疗糖尿病周围神经病变:来源重要吗?
基本信息
- 批准号:10447652
- 负责人:
- 金额:--
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:2021
- 资助国家:美国
- 起止时间:2021-07-01 至 2025-06-30
- 项目状态:未结题
- 来源:
- 关键词:AddressAdverse effectsAffectAfferent NeuronsAlgaeAmputationAnti-Inflammatory AgentsBehavioralBlindnessBlood CirculationBlood VesselsBrainCardiovascular DiseasesCardiovascular systemCaringCholesterolChronicChronic DiseaseClinical TrialsComplexComplications of Diabetes MellitusConsumptionCorneaDiabetes MellitusDietary intakeDiseaseDocosahexaenoic AcidsDoseEicosapentaenoic AcidEnd stage renal failureEquilibriumErythrocytesEstersEtiologyEventFatty AcidsFish OilsFishesFunctional disorderGoalsGreenlandHealth Care CostsHealthcareHeartHeavy MetalsHigh Density LipoproteinsHypertriglyceridemiaIndustrializationInflammatoryInsulin-Dependent Diabetes MellitusInuitsLimb structureMeasuresModelingMolecular TargetMotorNerveNerve RegenerationNon-Insulin-Dependent Diabetes MellitusNumbnessObesityOilsOmega-3 Fatty AcidsOutcomeOverweightPainParesthesiaPathologicPathway interactionsPatientsPeripheral Nervous System DiseasesPharmacologic SubstancePhysiciansPopulationPrediabetes syndromeProductionPropertyQuality of lifeRattusResearchRiskRisk FactorsRodentSeriesSerumSkinSourceStressSumSymptomsTherapeuticType 2 diabeticUlcerUnited StatesVeteransblood glucose regulationcardioprotectiondensitydesigndiabeticdiabetic rateffective therapyefficacious treatmentfallsglycemic controlhuman subjectimprovedin vivoindexingmenhadenmilitary veteranmortality risknerve damagenerve repairpatient populationpreclinical studyrelating to nervous systemrepaired
项目摘要
In 2015, 9.4% of the United States population had diabetes and statistically about 50% of these patients will or
already have developed diabetic peripheral neuropathy (DPN). This problem is even more critical in the
veteran health care population with nearly 25% of veterans having diabetes, primarily type 2. In veterans
diabetes is the leading cause of blindness, end-stage renal disease and non-trauma related amputations. The
only treatment for DPN is glycemic control, which is ineffective in subjects with type 2 diabetes. Thus, there is a
critical need of a treatment for DPN. Our studies have demonstrated that treating diabetic rodents with DPN
with omega-3 polyunsaturated fatty acids (PUFA) derived from menhaden (fish) oil initiates nerve damage
repair and reverses DPN. Eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA) are the predominate
omega-3 PUFA found in fish oil and are the precursors of E and D series resolvins, respectively, which have
anti-inflammatory and neuroprotective properties. We have shown that these metabolites alone elicit repair of
nerve damage caused by diabetes when administered endogenously in vivo. As we initiate plans to advance
omega-3 PUFA to a clinical trial for DPN there remains several questions to be addressed. One common
problem with the design of many of the previous clinical trials of omega-3 PUFA primarily for treatment of
cardiovascular disease were that they failed to determine the circulating levels of omega-3 PUFA or their
metabolites over the course of the study. For most of these studies it was unknown whether dosing was
sufficient to make a therapeutic change in the omega-3 index, defined as the sum of EPA and DHA as a
percentage of total fatty acids in red blood cells. Another poorly explored question has been what is the best
source or composition of omega-3 PUFAs that will provide the most favorable and safe outcome? This is
highlighted by the recent REDUCE-IT study that found that a 4 g daily dose of icosapent ethyl (ethyl ester of
EPA) to have a statistical benefit on reducing ischemic events in subjects with hypertriglyceridemia. Was the
significant outcome achieved in this study due to icosapent ethyl being a more effective source of omega-3
PUFA or use of a higher dose than many previous studies? We have shown that treating type 2 diabetic rats
with fish oil that achieved an omega-3 PUFA concentration in serum that was obtained in human subjects
treated with 4 g of fish oil per day is an efficacious treatment for DPN. However, is fish oil the best source of
omega-3 PUFA for the treatment of DPN or are the ethyl ester derivatives of EPA and/or DHA more
efficacious? Ethyl esters of EPA (Vascepa®) or the combination of EPA and DHA (Lovaza®) are
pharmaceutical compounds and represent a highly purified and concentrated source of EPA and DHA and void
of the less favorable compounds found in fish oil. Studies have shown that EPA and DHA and their metabolites
have different molecular targets. Since the etiology of DPN is complex having both vascular and neural
pathological pathways it is likely that a combination of EPA and DHA as found in Lovaza® will be needed for
an effective treatment of DPN. Besides these pharmaceutical compounds are there other “healthy” alternatives
to fish oil for the treatment of DPN? Commercially available algae's that primarily produce EPA or DHA may be
another environmental friendly and safe source of omega-3 PUFA. The studies presented in this application
will rigorously address the use of these alternative sources of omega-3 PUFA as a treatment for DPN and
determine if omega-3 PUFA derived from pharmaceutical compounds i.e. ethyl ester derivatives of EPA or
EPA/DHA or from industrial sources such as algae's that solely produce EPA or DHA free of cholesterol may
be a better choice than fish oil. The proposed studies will be conducted in rat models of pre-diabetes and type
2 diabetes and will investigate translational endpoints including assessment of motor coordination and balance
and function and density of sensory neurons to track the efficacy of omega-3 PUFA on peripheral neuropathy
and the results correlated with the omega-3 index and circulating levels of omega-3 PUFA metabolites.
2015 年,9.4% 的美国人口患有糖尿病,据统计,其中约 50% 的患者将或
已经患有糖尿病周围神经病变(DPN)。这个问题在
退伍军人医疗保健人群中近 25% 的退伍军人患有糖尿病,主要是 2 型糖尿病。
糖尿病是失明、终末期肾病和非创伤相关截肢的主要原因。这
DPN 的唯一治疗方法是控制血糖,这对 2 型糖尿病患者无效。因此,有一个
DPN 迫切需要治疗。我们的研究表明,用 DPN 治疗糖尿病啮齿动物
源自鲱鱼油的 omega-3 多不饱和脂肪酸 (PUFA) 会引发神经损伤
修复并逆转 DPN。二十碳五烯酸(EPA)和二十二碳六烯酸(DHA)是主要成分
鱼油中发现的 omega-3 PUFA 分别是 E 和 D 系列分解素的前体,它们具有
抗炎和神经保护特性。我们已经证明,这些代谢物本身就能引起修复
体内内源性给药时由糖尿病引起的神经损伤。当我们启动推进计划时
omega-3 PUFA 到 DPN 的临床试验仍有几个问题需要解决。一种常见的
之前许多 omega-3 PUFA 主要用于治疗以下疾病的临床试验的设计存在问题
心血管疾病的一个原因是他们未能确定 omega-3 PUFA 的循环水平或其
研究过程中的代谢。对于大多数这些研究,尚不清楚剂量是否是
足以对 omega-3 指数进行治疗性改变,该指数定义为 EPA 和 DHA 的总和
红细胞中总脂肪酸的百分比。另一个尚未探讨的问题是什么是最好的
omega-3 PUFA 的来源或成分将提供最有利和最安全的结果?这是
最近的 REDUCE-IT 研究强调了这一点,该研究发现每日 4 克剂量的二十碳五烯乙酯(二十碳五烯乙酯)
EPA)对减少高甘油三酯血症受试者的缺血事件具有统计益处。是
由于二十碳五烯乙酯是 omega-3 的更有效来源,因此本研究取得了重大成果
PUFA 或使用比许多先前研究更高的剂量?我们已经证明治疗 2 型糖尿病大鼠
使用鱼油,在人类受试者的血清中达到 omega-3 PUFA 浓度
每天服用 4 克鱼油可有效治疗 DPN。然而,鱼油是最好的来源吗?
用于治疗 DPN 的 omega-3 PUFA 或 EPA 和/或 DHA 的乙酯衍生物 更多
有效果吗? EPA 乙酯 (Vascepa®) 或 EPA 和 DHA 的组合 (Lovaza®)
药物化合物,代表高度纯化和浓缩的 EPA 和 DHA 来源,并且无效
鱼油中发现的不太有利的化合物。研究表明EPA和DHA及其代谢物
有不同的分子靶点。由于 DPN 的病因复杂,既有血管性的,也有神经性的。
病理途径很可能需要 Lovaza® 中发现的 EPA 和 DHA 组合
DPN 的有效治疗方法。除了这些药物化合物之外,还有其他“健康”的替代品
鱼油可以治疗 DPN?主要产生 EPA 或 DHA 的市售藻类可能是
另一种环保且安全的 omega-3 PUFA 来源。本申请中提出的研究
将严格解决使用这些 omega-3 PUFA 替代来源治疗 DPN 的问题
确定 omega-3 PUFA 是否源自药物化合物,即 EPA 的乙酯衍生物或
EPA/DHA 或来自工业来源(例如仅生产不含胆固醇的 EPA 或 DHA 的藻类)可能
是比鱼油更好的选择。拟议的研究将在糖尿病前期和糖尿病类型的大鼠模型中进行
2 型糖尿病,并将研究转化终点,包括评估运动协调和平衡
以及感觉神经元的功能和密度,以追踪 omega-3 PUFA 对周围神经病变的疗效
结果与 omega-3 指数和 omega-3 PUFA 代谢物的循环水平相关。
项目成果
期刊论文数量(0)
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Mark A. Yorek其他文献
Mark A. Yorek的其他文献
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{{ truncateString('Mark A. Yorek', 18)}}的其他基金
Omega-3 Polyunsaturated Fatty Acids in the Treatment of Diabetic Peripheral Neuropathy: Is the source important?
Omega-3 多不饱和脂肪酸治疗糖尿病周围神经病变:来源重要吗?
- 批准号:
10313537 - 财政年份:2021
- 资助金额:
-- - 项目类别:
Omega-3 Polyunsaturated Fatty Acids in the Treatment of Diabetic Peripheral Neuropathy:Is the source important?
Omega-3 多不饱和脂肪酸治疗糖尿病周围神经病变:来源重要吗?
- 批准号:
10610377 - 财政年份:2021
- 资助金额:
-- - 项目类别:
Effect of exogenous fatty acids on diabetes neural/neurovascular complications
外源性脂肪酸对糖尿病神经/神经血管并发症的影响
- 批准号:
9391186 - 财政年份:2015
- 资助金额:
-- - 项目类别:
Insulin Resistance and Vascular Complications in Obesity and Type 2 Diabetes
肥胖和 2 型糖尿病中的胰岛素抵抗和血管并发症
- 批准号:
8327947 - 财政年份:2012
- 资助金额:
-- - 项目类别:
Insulin Resistance and Vascular Complications in Obesity and Type 2 Diabetes
肥胖和 2 型糖尿病中的胰岛素抵抗和血管并发症
- 批准号:
8457977 - 财政年份:2012
- 资助金额:
-- - 项目类别:
Insulin Resistance and Vascular Complications in Obesity and Type 2 Diabetes
肥胖和 2 型糖尿病中的胰岛素抵抗和血管并发症
- 批准号:
8698322 - 财政年份:2012
- 资助金额:
-- - 项目类别:
Peroxynitrite, protein nitration and advanced diabetic neuropathy
过氧亚硝酸盐、蛋白质硝化和晚期糖尿病神经病变
- 批准号:
8625363 - 财政年份:2010
- 资助金额:
-- - 项目类别:
Peroxynitrite, protein nitration and advanced diabetic neuropathy
过氧亚硝酸盐、蛋白质硝化和晚期糖尿病神经病变
- 批准号:
8664835 - 财政年份:2010
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-- - 项目类别:
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