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
• 负责人: Mark A. Yorek
• 金额: $ 28.35万
• 依托单位: UNIVERSITY OF IOWA
• 依托单位国家: 美国
• 财政年份: 2015
• 资助国家: 美国
• 起止时间: 2015-12-01 至 2019-11-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9391186
• 关键词: Acids; Adverse effects; Anti-Inflammatory Agents; Anti-inflammatory; Arachidonate 15-Lipoxygenase; Aspirin; Biopsy; Blood Circulation; Blood Vessels; Blood flow; Chronic; Clinic; Clinical; Clinical Treatment; Clinical Trials; Complications of Diabetes Mellitus; Confocal Microscopy; Cornea; Diabetes Mellitus; Diabetic Diet; Diabetic mouse; Diet; Dietary Fatty Acid; Disease; Docosahexaenoic Acids; Eicosapentaenoic Acid; Etiology; Family; Fatty Acids; Fish Oils; Functional disorder; Health Care Costs; Hemorrhage; Hyperglycemia; Immunohistochemistry; In Vitro; Inflammation; Inflammatory; Intervention; Linoleic Acids; Linseed Oil; Lipids; Lipoxygenase 1; Mediating; Menhaden oil; Modeling; Motor; N-3 polyunsaturated fatty acid; Nerve; Nerve Fibers; Nerve Regeneration; Neural Conduction; Neurites; Non-Insulin-Dependent Diabetes Mellitus; Oils; Oleic Acids; Olive oil preparation; Omega-3 Fatty Acids; Operative Surgical Procedures; Oxidative Stress; Patients; Peripheral Nerves; Peripheral Nervous System Diseases; Principal Investigator; Prodrugs; Production; Property; Protocols documentation; Quality of life; Rattus; Risk; Risk Factors; Rodent; Rodent Model; Safety; Safflower Oil; Salicylic Acids; Series; Serum; Severities; Skin; Stomach; Stress; Testing; Tissues; afferent nerve; alpha-Linolenic Acid; arteriole; density; diabetes management; diabetic; diabetic rat; effective therapy; evening primrose oil; gamma-Linolenic Acid; glycemic control; improved; insulin sensitivity; irritation; lipid mediator; menhaden; neurovascular; novel; overtreatment; preclinical study; programs; public health relevance; relating to nervous system; repaired; salicylsalicylic acid; sciatic nerve

 DESCRIPTION (provided by applicant): Good glycemic control is the only recognized treatment for diabetic peripheral neuropathy (DPN) but studies have shown that it only slows progression. Therefore, other factors besides hyperglycemia must contribute to DPN, and there is a need for a better understanding of what these factors are in order to discover effective treatments. In the proposed studies we will test the hypothesis that different fatty acid classes have either a negative, neutral or positive effect on DPN. Lipids have been shown to be a major risk factor for diseases but there has been no comprehensive analysis of the effect of different classes of fatty acids on DPN. We will use novel rodent models of type 2 diabetes and manipulate diets so as to increase circulating and tissue levels of monounsaturated (MUFA) and polyunsaturated (PUFA) fatty acids. Specifically we will examine the potential negative, neutral or positive benefits of dietary enrichment with oleic acid (18:1, MUFA), linoleic acid (18:2, n-6 PUFA), γ-linolenic acid (18:3, n-6 PUFA), α-linolenic acid (18:3, n-3 PUFA) or eicosapentaenoic acid (20:5, EPA, n-3 PUFA) and docosahexaenoic acid (22:6, DHA, n-3 PUFA) on DPN and neurovascular function. The DPN endpoints will include determination of motor and sensory nerve conduction velocity and changes in the density and function of small sensory nerves in the skin and cornea. The latter endpoints will allow us to examine the effect of fatty acid dietary changes on nerve damage or repair. It is expected that supplementing diets of diabetic rodents with oils enriched in oleic acid (olive oil) or linoleic acid (safflower oil) will have little beneicial effect or may even exacerbate DPN and neurovascular dysfunction. Diets supplemented with γ- linolenic acid (evening primrose oil) or α-linolenic acid (flaxseed oil) are expected to be beneficial but to a lesser extent than diets supplemented with EPA and DHA, to be derived from menhaden (fish) oil. We propose that increasing dietary levels of n-3 PUFA (derived from flaxseed oil or menhaden oil) but not γ- linolenic acid (n-6 PUFA derived from evening primrose oil) will lower the n-6 to n-3 fatty acid ratio, a marker for reduced inflammation. Due to reduced ability in diabetes of conversion of α-linolenic acid to EPA we predict that increasing dietary levels of EPA and DHA but not α-linolenic acid will lead to an increased production of resolvins. Resolvins are produced from EPA and DHA by 15-lipoxygenase-1 (15-LOX-1) and have anti-inflammatory and neuroprotective properties. We propose that EPA and DHA treatment of rodents with type 2 diabetes will have the greatest impact on DPN through reducing inflammatory stress, improving neurovascular function and mediating nerve repair. We also propose that treating rodents with salicylsalicylic acid (salsalate) will increase tissue expressio of 15-LOX-1 leading to increased production of resolvins and even greater efficacy toward DPN and neurovascular complications when rodents with type 2 diabetes are treated with the combination of salsalate and menhaden oil. These preclinical studies will provide needed information to justify clinical trials for the treatment of DPN with fish oils and salsalate.