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C-peptide: protection aganist disbetic complications

C肽：预防糖尿病并发症的保护作用

基本信息

批准号：
7341081
负责人：
ROBERT W BROCK
金额：
$ 25.12万
依托单位：
WEST VIRGINIA UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2007
资助国家：
美国
起止时间：
2007-02-01 至 2012-01-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7341081
关键词：
Accounting Address Adenylate Cyclase Affect Anti-Inflammatory Agents Anti-inflammatory Antiatherogenic Antioxidants Biochemical Biochemistry Biological Biological Availability Blood capillaries C-Peptide Cells Chronic Clinical Clinical Research Complex Complications of Diabetes Mellitus Data Defect Development Diabetes Mellitus Diabetic Angiopathies Diabetic mouse End stage renal failure Endothelial Cells Environment Enzyme Inhibition Enzymes Event Exhibits Functional disorder Generations Glucosephosphate Dehydrogenase Heme Impairment In Vitro Individual Insulin Insulin-Dependent Diabetes Mellitus Kidney Lead Link Maintenance Mediating Mediator of activation protein Membrane Microcirculation Microscopy Modeling Molecular Morbidity - disease rate Mus NADP NADPH Oxidase Nature Nitric Oxide Synthase Oxidants Oxidation-Reduction Oxygenases Pancreatic Hormones Pathogenesis Pathway interactions Pentosephosphate Pathway Peptide Synthesis Peroxidase Physiological Plasma Process Production Rate Recovery Regulation Renal function Research Research Personnel Rest Role Source System Techniques Therapeutic Intervention Uncertainty Vasomotor Work base bioimaging capillary diabetic functional restoration glycemic control improved in vivo innovation insight mortality mouse model non-diabetic novel novel therapeutics programs response type I diabetic

项目摘要

DESCRIPTION (provided by applicant): Although it is generally held that C-peptide, a pancreatic hormone that is co-secreted with insulin, does not possess biological activity of its own, recent work by our research team and others has raised doubts concerning this view. Although cumulative clinical and experimental evidence indicate that C-peptide replacement may have an impact on renal dysfunction in type I diabetes, the exact nature of its bioactivity, membrane interactions, and physiological effect on the renal microcirculation require further clarity. We plan to examine these aspects using a multi-faceted approach of in vitro biochemistry in isolated renal endothelial cells and innovative in vivo bioimaging of the renal cortical microcirculation, in which the influences of the native environment persist. Diabetics have an anomaly in redox regulation that precedes the development of chronic microvascular dysfunction. A potential explanation for this dysregulation rests with the interaction between defective vasoprotective systems and cellular redox status. Reduced vasoprotection as a consequence of compromised heme oxygenase (HO) activity could account for such an event. The ultimate function of this redox-sensitive system depends upon an adequate pool of NADPH. The major source of mammalian NADPH is glucose-6-phosphate dehydrogenase (G6PD), the rate-limiting enzyme of the pentose phosphate pathway. During diabetes, G6PD activity is diminished, reducing the synthesis and bioavailability of endothelial NADPH. We believe that unraveling the mechanism(s) by which C-peptide augments NADPH synthesis and enhances HO-mediated vasoprotection will lead to fundamental insights into the renal microvascular pathogenesis of type I diabetes. We hypothesize that C-peptide improves renal endothelial NADPH thereby restoring vasoprotection in type I diabetes, and that a component of this C- peptide-mediated renal vasoprotection is related to re-establishing endothelial antioxidant potential. To address this we will: i) determine if C-peptide normalizes basal renal cortical microvascular function by restoring endogenous renal vasoprotection, ii) evaluate whether C-peptide improves basal renal cortical endothelial NADPH levels by re-establishing NADPH synthesis, and iii) determine if C-peptide reduces oxidant production in the renal cortical microcirculation. LAY SUMMARY: In addition to insulin, other pancreatic hormones are absent in type I diabetics and may help to mediate recovery from diabetic complications. We believe that one of these products, C-peptide, participates in important microvascular functional processes. We have already shown that C-peptide restores kidney microvascular function. We hope to determine how C-peptide interacts with other cellular factor(s) and processes to re-establish proper microvascular function in type I diabetics.

描述（由申请人提供）：虽然一般认为c肽是一种与胰岛素共同分泌的胰腺激素，其本身不具有生物活性，但我们课题组和其他人最近的工作对这一观点提出了质疑。尽管累积的临床和实验证据表明c肽替代可能对I型糖尿病患者的肾功能障碍有影响，但其生物活性、膜相互作用和对肾脏微循环的生理作用的确切性质需要进一步明确。我们计划在分离的肾内皮细胞中使用多方面的体外生物化学方法和创新的肾皮质微循环体内生物成像来检查这些方面，其中自然环境的影响持续存在。糖尿病患者在发生慢性微血管功能障碍之前存在氧化还原调节异常。对这种失调的一种可能的解释是有缺陷的血管保护系统和细胞氧化还原状态之间的相互作用。血红素加氧酶（HO）活性受损导致的血管保护功能降低可以解释这一事件。这个氧化还原敏感系统的最终功能取决于足够的NADPH池。哺乳动物NADPH的主要来源是葡萄糖-6-磷酸脱氢酶（G6PD），它是戊糖磷酸途径的限速酶。糖尿病期间，G6PD活性降低，降低内皮细胞NADPH的合成和生物利用度。我们相信，揭示c肽增强NADPH合成和增强ho介导的血管保护的机制将有助于从根本上了解I型糖尿病的肾微血管发病机制。我们假设C肽改善肾内皮NADPH从而恢复I型糖尿病的血管保护，并且这种C肽介导的肾血管保护的一个组成部分与重建内皮抗氧化潜能有关。为了解决这个问题，我们将：i)确定c肽是否通过恢复内源性肾血管保护来正常化基底肾皮质微血管功能，ii)评估c肽是否通过重建NADPH合成来改善基底肾皮质内皮NADPH水平，以及iii)确定c肽是否减少肾皮质微循环中氧化剂的产生。摘要：除胰岛素外，I型糖尿病患者缺乏其他胰腺激素，这些激素可能有助于调节糖尿病并发症的恢复。我们认为其中一种产物c肽参与了重要的微血管功能过程。我们已经证明c肽可以恢复肾脏微血管功能。我们希望确定c肽如何与其他细胞因子和过程相互作用，以重建I型糖尿病患者适当的微血管功能。