Preventative Biomarkers and Potential Pharmacotherapies for Nicotine Use and Diabetes

摘要 糖尿病和尼古丁的使用是产生复合健康的重大公共卫生问题 后果，特别是在女性身上。被提议的神经科学家团队利用啮齿动物模型来提供 更好地了解促进代谢紊乱患者使用尼古丁的潜在因素， 比如糖尿病。我们之前的临床前工作已经证实，尼古丁的回报效应在 表现出胰岛素信号中断的啮齿动物，胰岛素信号是糖尿病的主要媒介。这项工作已经提高了 关于胰岛素抵抗(IR)的发展或其他指标的重要补充问题 代谢综合征与女性比男性对尼古丁的依赖程度更高是一致的或预示着这一点。另外， 尼古丁暴露对代谢综合征的各种生物标志物的出现的影响尚不清楚。 重要的是，关于降低IR或用作尼古丁的药物的疗效的信息也很缺乏 戒毒剂对1型或2型糖尿病啮齿动物模型尼古丁依赖形成的影响。至 为了解决这些问题，目标1将评估与性别和时间相关的IR变化，IR是代谢的血浆生物标记物 症状和尼古丁依赖的行为指标，包括尼古丁自我给药的升级 和戒断严重程度。目标1将使用一个程序来检查以下IR的自然出现 长期获得高脂肪饮食(HFD)。我们还将包括喂食HFD的大鼠，这些大鼠接受药物治疗 加速IR诱导的干预措施。AIM 2将评估各种药物疗法的疗效 糖尿病(胰岛素、埃塞那肽、葡聚糖和溴隐亭)或戒烟(安非他酮和伐伦克林) 在目标1中使用1型和2型糖尿病啮齿动物模型收集的相同措施。科学的 前提是IR的发展将与尼古丁摄入量的升级和更多的戒断相一致 两种类型的糖尿病大鼠的严重程度。我们预计糖尿病女性将表现出最大的 尼古丁摄入量和比男性更强烈的戒断症状。此外，药物干预措施 治疗IR可抑制糖尿病大鼠尼古丁依赖的形成。这些研究是严谨的。 因为它们包含了1型和2型糖尿病的啮齿动物模型，并将评估与时间相关的变化 尼古丁依赖和代谢综合征的各种生物标记物。拟议的工作意义重大 因为这些结果将促进我们对代谢的各种生物标志物之间的关系的理解 综合征与尼古丁依赖的发展。我们的工作还将揭示尼古丁暴露如何改变 导致糖尿病的代谢综合征的各种生物标志物。最后，我们的结果将为有效性提供信息 临床批准的药物疗法在降低糖尿病患者使用尼古丁风险方面的作用。这是在 符合美国国立卫生研究院改善患有衰弱疾病的人的生活的使命，特别是在 因糖尿病和尼古丁的使用而产生的复合健康后果的患者。

ABSTRACT Diabetes and nicotine use are significant public health problems that produce compounded health consequences, particularly in women. The proposed team of neuroscientists employ rodent models to provide a better understanding of the underlying factors that promote nicotine use in persons with metabolic disorders, such as diabetes. Our prior pre-clinical work has established that the rewarding effects of nicotine are greater in rodents that display a disruption in insulin signaling, the primary mediator of diabetes. This work has raised important additional questions regarding whether the development of insulin resistance (IR) or other indices of metabolic syndrome coincide with or predict greater nicotine dependence in females versus males. Also, the effects of nicotine exposure on the emergence of various biomarkers of metabolic syndrome are unclear. Importantly, there is also a lack of information on the efficacy of medications that reduce IR or serve as nicotine cessation agents on the development of nicotine dependence in rodent models of Type 1 or Type 2 diabetes. To address these issues, Aim 1 will assess sex- and time-dependent changes in IR, plasma biomarkers of metabolic syndrome, and behavioral indices of nicotine dependence that include escalation of nicotine self-administration and withdrawal severity. Aim 1 will use a procedure that will examine the natural emergence of IR following chronic access to a high fat diet (HFD). We will also include HFD-fed rats that receive a pharmacological intervention that accelerates the induction of IR. Aim 2 will assess the efficacy of various pharmacotherapies for diabetes (insulin, exenatide, glucophage, and bromocriptine) or smoking cessation (bupropion and varenicline) on the same measures collected in Aim 1 using rodent models of Type 1 and Type 2 diabetes. The scientific premise is that the development of IR will coincide with the escalation of nicotine intake and greater withdrawal severity in both types of diabetic rats. We anticipate that diabetic females will display the greatest escalation of nicotine intake and more intense withdrawal symptoms than males. Also, pharmacological interventions that treat IR will suppress the development of nicotine dependence in diabetic rats. These studies are rigorous because they incorporate rodent models of Type 1 and Type 2 diabetes and will assess time-dependent changes in nicotine dependence and various biomarkers of metabolic syndrome. The proposed work is significant because the results will advance our understanding of the relationship between various biomarkers of metabolic syndrome and the development of nicotine dependence. Our work will also inform how nicotine exposure alters various biomarkers of metabolic syndrome that lead to diabetes. Lastly, our results will inform the effectiveness of clinically approved pharmacotherapies in reducing the risk of nicotine use in persons with diabetes. This is in line with the mission of NIH to improve the lives of persons suffering from debilitating diseases, particularly in patients inflicted by compounded health consequences produced by diabetes and nicotine use.