Preventative Biomarkers and Potential Pharmacotherapies for Nicotine Use and Diabetes

尼古丁使用和糖尿病的预防性生物标志物和潜在药物疗法

• 批准号: 10659126
• 负责人: LAURA ELENA ODELL
• 金额: $ 15.35万
• 依托单位: UNIVERSITY OF TEXAS EL PASO
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-07-05 至 2026-06-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10659126
• 关键词: Acceleration; Address; Behavioral; Biological Factors; Biological Markers; Bromocriptine; Bupropion; Chronic; Clinical; Clinical effectiveness; Dependence; Development; Diabetes Mellitus; Disease; Dopamine Agonists; Drug usage; Female; Goals; Health; High Fat Diet; Inflammation; Insulin; Insulin Resistance; Insulin-Dependent Diabetes Mellitus; Intake; Intervention; Knowledge; Measures; Mediator; Metabolic; Metabolic Diseases; Metabolic Marker; Metabolic syndrome; Mission; Modeling; Nicotine; Nicotine Dependence; Non-Insulin-Dependent Diabetes Mellitus; Pathology; Patients; Peptides; Persons; Pharmaceutical Preparations; Pharmacotherapy; Physiology; Plasma; Positioning Attribute; Predisposition; Prevalence; Procedures; Public Health; Rattus; Reduce health disparities; Regimen; Reporting; Research; Research Support; Rewards; Risk Reduction; Rodent; Rodent Model; Severities; Smoking; Smoking Cessation Intervention; Streptozocin; Supplementation; Testing; Time; Tobacco use; United States National Institutes of Health; Vulnerable Populations; Withdrawal; Withdrawal Symptom; Woman; Work; addiction; anxiety-like behavior; behavior measurement; clinical effect; clinical efficacy; cohort; diabetic; diabetic rat; efficacy evaluation; exenatide; experience; feeding; glucagon-like peptide 1; glucophage; improved; indexing; insulin signaling; male; men; negative affect; nicotine cessation; nicotine exposure; nicotine self-administration; nicotine use; pharmacologic; pre-clinical; preference; programs; sex; smoking cessation; type I and type II diabetes; varenicline

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.

摘要 糖尿病和尼古丁使用是产生复合健康的重大公共卫生问题 后果，尤其是对女性。拟议中的神经科学家团队采用啮齿动物模型来提供一个 更好地了解促进代谢障碍患者使用尼古丁的潜在因素， 例如糖尿病。我们先前的临床前工作已经确定，尼古丁的奖励作用在以下情况下更大： 这种啮齿类动物显示出胰岛素信号的中断，而胰岛素信号是糖尿病的主要介质。这项工作提高了 关于胰岛素抵抗（IR）或其他指标的发展是否存在重要的额外问题， 与男性相比，代谢综合征与女性更大的尼古丁依赖性一致或预测。还 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，也缺乏关于减少IR或充当尼古丁的药物的功效的信息 戒烟剂对1型或2型糖尿病啮齿动物模型中尼古丁依赖性发展的影响。到 为了解决这些问题，目标1将评估IR的性别和时间依赖性变化，代谢产物的血浆生物标志物 综合征和尼古丁依赖的行为指标，包括尼古丁自我给药的升级 和戒断严重性。目标1将使用一个程序，将检查IR的自然出现， 长期摄入高脂肪饮食（HFD）。我们还将包括HFD喂养的大鼠，其接受药理学治疗。 目的2将评估各种药物治疗对IR的疗效， 糖尿病（胰岛素、依塞那肽、格华止和溴隐亭）或戒烟（安非他酮和伐尼克兰） 使用1型和2型糖尿病的啮齿动物模型，对目标1中收集的相同测量进行了研究。科学 前提是IR的发展将与尼古丁摄入量的增加和更大的戒断相一致 两种类型糖尿病大鼠的严重程度。我们预计，女性糖尿病患者将表现出最大的升级， 尼古丁摄入量和更强烈的戒断症状比男性。此外，药物干预， 治疗IR将抑制糖尿病大鼠尼古丁依赖的发展。这些研究是严谨的 因为它们结合了1型和2型糖尿病的啮齿动物模型， 尼古丁依赖和代谢综合征的各种生物标志物。拟议的工作意义重大 因为这些结果将促进我们对各种代谢生物标志物之间关系的理解， 综合征和尼古丁依赖的发展。我们的工作还将告知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，我们的结果将告知有效性 临床批准的药物疗法在降低糖尿病患者使用尼古丁的风险。这是 符合美国国立卫生研究院的使命，以改善患有衰弱性疾病的人的生活，特别是在 糖尿病和尼古丁使用对健康造成的复合影响。