C-peptide: protection aganist disbetic complications

描述(申请人提供)：虽然人们普遍认为C-肽，一种与胰岛素共同分泌的胰腺激素，本身并不具有生物活性，但我们的研究团队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肽替代疗法可能对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影响的确切性质尚需进一步阐明。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。糖尿病患者氧化还原调节异常，这是慢性微血管功能障碍发生的先兆。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。由于血红素加氧酶(HO)活性受损而导致的血管保护作用减弱，可能是导致这种情况的原因。这个氧化还原敏感系统的最终功能依赖于充足的NADPH池。哺乳动物NADPH的主要来源是葡萄糖-6-磷酸脱氢酶(G6PD)，它是磷酸戊糖途径的限速酶。在糖尿病期间，G6PD活性降低，降低了内皮细胞NADPH的合成和生物利用度。我们相信，解开C-肽促进NADPH合成和增强HO介导的血管保护的机制(S)将有助于从根本上深入了解I型糖尿病肾脏微血管的发病机制。我们假设C-肽可改善肾内皮细胞NADPH，从而恢复I型糖尿病患者的血管保护作用，并且这种C-肽介导的肾血管保护作用的一部分与重建内皮细胞的抗氧化潜能有关。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而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合成来改善基础肾皮质内皮细胞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。总结：除胰岛素外，I型糖尿病患者缺乏其他胰腺激素，可能有助于糖尿病并发症的恢复。我们认为这些产物之一，C-肽，参与了重要的微血管功能过程。我们已经证明，C肽可以恢复肾脏的微血管功能。我们希望确定C-肽如何与其他细胞因子(S)相互作用，以及重建I型糖尿病患者适当的微血管功能的过程。

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.