C-peptide: protection aganist disbetic complications

说明（申请人提供）：虽然一般认为C肽（一种与胰岛素共同分泌的胰腺激素）本身不具有生物活性，但我们研究小组和其他人最近的工作对这一观点提出了质疑。虽然累积的临床和实验证据表明，C肽替代可能对I型糖尿病的肾功能不全有影响，其生物活性，膜相互作用和对肾微循环的生理作用的确切性质需要进一步澄清。我们计划研究这些方面，使用多方面的方法，在离体肾内皮细胞和创新的肾皮质微循环，其中原生环境的影响持续在体内生物成像的体外生物化学。糖尿病患者在慢性微血管功能障碍的发展之前具有氧化还原调节的异常。这种失调的一个可能的解释在于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）活性受损导致血管保护作用降低可能是导致此类事件的原因。这种氧化还原敏感系统的最终功能取决于充足的NADPH库。哺乳动物NADPH的主要来源是葡萄糖-6-磷酸脱氢酶（G6 PD），它是戊糖磷酸途径的限速酶。在糖尿病期间，G6 PD活性降低，降低了内皮NADPH的合成和生物利用度。我们相信，阐明C肽增强NADPH合成和增强HO介导的血管保护作用的机制将导致对I型糖尿病肾微血管发病机制的基本见解。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作用，并且这种C肽介导的肾血管保护作用的一个组分与重建内皮抗氧化潜力有关。为解决这一问题，我们将：i）确定C-肽是否通过恢复内源性肾血管保护使基础肾皮质微血管功能正常化，ii）评估C-肽是否通过重建NADPH合成改善基础肾皮质内皮NADPH水平，和iii）确定C-肽是否减少肾皮质微循环中的氧化剂产生。总结：除了胰岛素，其他胰腺激素在I型糖尿病患者中缺乏，可能有助于调解糖尿病并发症的恢复。我们认为，这些产品之一，C-肽，参与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相互作用，并在I型糖尿病患者中重建适当的微血管功能。

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.